Guidelines for the Diagnosis and Management of Food Allergy in the PDF
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Guidelines for the Diagnosis and Management of Food Allergy in the United States: Report of the NIAID-Sponsored Expert Panel Acknowledgments PrimaryAuthors NIAID-SponsoredExpertPanelAuthors JoshuaA.Boyce,MD S.HasanArshad,MBBS,MRCP,DM,FRCP DivisionofRheumatology,ImmunologyandAllergy SchoolofMedicine BrighamandWomen’sHospital UniversityofSouthampton DepartmentofMedicineHarvardMedicalSchool Southampton,UK Boston,Mass TheDavidHideAsthmaandAllergyResearchCentre StMary’sHospital AmalAssa’ad,MD Newport,IsleofWight,UK DivisionofAllergyandImmunology SouthamptonUniversityHospitalNHSTrust CincinnatiChildren’sHospitalMedicalCenter Southampton,UK UniversityofCincinnati Cincinnati,Ohio SamiL.Bahna,MD,DrPH A.WesleyBurks,MD DepartmentofPediatrics DivisionofAllergyandImmunology SectionofAllergyandImmunology DepartmentofPediatrics LouisianaStateUniversityHealthSciencesCenter DukeUniversityMedicalCenter Shreveport,La Durham,NC LisaA.Beck,MD StacieM.Jones,MD DepartmentofDermatology DivisionofAllergyandImmunology UniversityofRochesterMedicalCenter DepartmentofPediatrics Rochester,NY UniversityofArkansasforMedicalSciences CarolByrd-Bredbenner,PhD,RD,FADA ArkansasChildren’sHospital DepartmentofNutritionalSciences LittleRock,Ark RutgersUniversity HughA.Sampson,MD NewBrunswick,NJ ElliotandRoslynJaffeFoodAllergyInstitute DivisionofAllergyandImmunology CarlosA.CamargoJr,MD,DrPH DepartmentofPediatrics DepartmentofEmergencyMedicine MountSinaiSchoolofMedicine DivisionofRheumatology,AllergyandImmunology NewYork,NY DepartmentofMedicine MassachusettsGeneralHospital RobertA.Wood,MD HarvardMedicalSchool DivisionofAllergyandImmunology Boston,Mass DepartmentofPediatrics TheJohnsHopkinsUniversitySchoolofMedicine LawrenceEichenfield,MD Baltimore,Md DivisionofPediatricandAdolescentDermatology RadyChildren’sHospital MarshallPlaut,MD SanDiego,Calif DivisionofAllergy,Immunology,andTransplantation DepartmentsofPediatricsandMedicine NationalInstituteofAllergyandInfectiousDiseases UniversityofCalifornia,SanDiego NationalInstitutesofHealth SanDiego,Calif Bethesda,Md GlennT.Furuta,MD SusanF.Cooper,MSc SectionofPediatricGastroenterology,Hepatology,andNutrition DivisionofAllergy,Immunology,andTransplantation DigestiveHealthInstitute NationalInstituteofAllergyandInfectiousDiseases Children’sHospitalDenver NationalInstitutesofHealth Aurora,Colo Bethesda,Md DepartmentofPediatrics MatthewJ.Fenton,PhD NationalJewishHealth DivisionofAllergy,Immunology,andTransplantation Denver,Colo NationalInstituteofAllergyandInfectiousDiseases DepartmentofPediatrics NationalInstitutesofHealth UniversityofColoradoDenverSchoolofMedicine Bethesda,Md Aurora,Colo S1 S2 BOYCEETAL JALLERGYCLINIMMUNOL DECEMBER2010 JonM.Hanifin,MD ScrippsClinic DepartmentofDermatology SanDiego,Calif OregonHealthandScienceUniversity F.EstelleR.Simons,MD Portland,Ore DepartmentsofPediatricsandChildHealthandImmunology CarolJones,RN,AE-C FacultyofMedicine AsthmaEducatorandConsultant UniversityofManitoba AllergyandAsthmaNetworkMother’sofAsthmatics Winnipeg,Manitoba,Canada McLean,Va StephenJ.Teach,MD,MPH MonicaKraft,MD DivisionofEmergencyMedicine DivisionofPulmonary,Allergy,andCriticalCareMedicine Children’sNationalMedicalCenter DepartmentofMedicine Washington,DC DukeUniversityMedicalCenter BarbaraP.Yawn,MD,MPH,MSc Durham,NC DepartmentofResearch BruceD.Levy,MD OlmstedMedicalCenter PartnersAsthmaCenter Rochester,Minn PulmonaryandCriticalMedicine DepartmentofFamilyandCommunityHealth BrighamandWomen’sHospitalandHarvardMedicalSchool UniversityofMinnesotaSchoolofMedicine Boston,Mass Minneapolis,Minn PhilLieberman,MD ContributingAuthor DivisionofAllergyandImmunology DepartmentofMedicine JulieM.Schwaninger,MSc UniversityofTennesseeCollegeofMedicine DivisionofAllergy,Immunology,andTransplantation Memphis,Tenn NationalInstituteofAllergyandInfectiousDiseases StefanoLuccioli,MD NationalInstitutesofHealth OfficeofFoodAdditiveSafety Bethesda,Md USFoodandDrugAdministration CollegePark,Md CorrespondingAuthor KathleenM.McCall,BSN,RN MatthewJ.Fenton,PhD Children’sHospitalofOrangeCounty DivisionofAllergy,Immunology,andTransplantation Orange,Calif NationalInstituteofAllergyandInfectiousDiseases NationalInstitutesofHealth LyndaC.Schneider,MD Bethesda,Md DivisionofImmunology 6610RockledgeDrive,Room3105 Children’sHospitalBoston Bethesda,Md20892 Boston,Mass Phone:301-496-8973 RonaldA.Simon,MD Fax:301-402-0175 DivisionofAllergy,AsthmaandImmunology E-mail:[email protected] Sourcesoffunding PublicationofthisarticlewassupportedbytheFoodAllergyInitiative. Disclosureofpotentialconflictofinterest: J.A.BoycehasservedontheAdvisoryBoardofGlaxoSmithKline.Hehasservedasaconsultantand/orspeakerforAltana,GlaxoSmithKline,andMerck.Hehasreceivedfunding/ grantsupportfromtheNationalInstitutesofHealth. A.Assa’adholds,orislistedasaninventoron,USpatentapplication#10/566903,entitled‘‘Geneticmarkersoffoodallergy.’’ShehasservedasaconsultantforGlaxoSmithKlineandas aspeakerfortheAmericanCollegeofAllergy,Asthma,andImmunology,theNorthEastAllergySociety,theVirginiaAllergySociety,theNewEnglandAllergySociety,andthe AmericanAcademyofPediatrics.DrAssa’adhasreceivedfunding/grantsupportfromGlaxoSmithKline. A.W.Burksholds,orislistedasaninventoron,multipleUSpatentsrelatedtofoodallergy.HeownsstockinAllerteinandMastCell,Inc,andisaminoritystockholderinDannonCo Probiotics.HehasservedasaconsultantforActoGeniXNV,McNeilNutritionals,MeadJohnson,andNovartis.Hehasservedonthespeaker’sbureauforEpiPen/Dey,LP,andhas servedonthedatamonitoringcommitteeforGenentech.HehasservedonanexpertpanelforNutricia.DrBurkshasreceivedfunding/grantsupportfromtheFoodAllergyand AnaphylaxisNetwork,Gerber,MeadJohnson,andtheNationalInstitutesofHealth. S.M.JoneshasservedasaspeakerandgrantreviewerandhasservedonthemedicaladvisorycommitteefortheFoodAllergyandAnaphylaxisNetwork.Shehasreceivedfunding/grant supportfromDyaxCorp,theFoodAllergyandAnaphylaxisNetwork,MeadJohnson,theNationalPeanutBoard,andtheNationalInstitutesofHealth. H.A.Sampsonholds,orislistedasaninventoron,multipleUSpatentsrelatedtofoodallergy.HeownsstockinAllerteinTherapeutics.Heistheimmediatepastpresidentofthe AmericanAcademyofAllergy,Asthma,andImmunology.HehasservedasaconsultantforAllerteinTherapeutics,theAmericanAcademyofAllergy,Asthma,andImmunology, theFoodAllergyInitiative,andScheringPlough.Hehasreceivedfunding/grantsupportforresearchprojectsfromtheFoodAllergyInitiative,theNationalInstitutesofHealth (DivisionofReceiptandReferral,NationalInstituteofAllergyandInfectiousDiseases,NationalCenterforComplementaryandAlternativeMedicine),andPhadiaAB.Heisaco- ownerofHerbalSpring,LLC. R.A.Woodhasservedasaspeaker/advisoryboardmemberforGlaxoSmithKline,Merck,andDey.Hehasreceivedfunding/grantsupportfromGenentechandtheNationalInstitutesof Health(NationalInstituteofAllergyandInfectiousDiseases). S.H.Arshadhasreceivedfunding/grantsupportfromtheNationalInstitutesofHealthandtheNationalInstituteofHealthResearch,UK. S.L.Bahnahasreceivedfunding/grantsupportfromGenentech. L.A.Beckhasreceivedfunding/grantsupportfromtheAmericanAcademyofAllergy,Asthma,andImmunology,theNationalEczemaAssociation,andtheNationalInstitutesof Health. JALLERGYCLINIMMUNOL BOYCEETAL S3 VOLUME126,NUMBER6 C.Byrd-BredbennerownsstockinJohnson&Johnson.Shehasreceivedfunding/grantsupportfromtheUSDepartmentofAgriculture,theCannedFoodAlliance,andtheNewJersey DepartmentofHealthandSeniorServices. C.A.CamargoJrhasconsultedforDeyandNovartis.Hehasreceivedfunding/grantsupportfromavarietyofgovernmentagenciesandnot-for-profitresearchfoundations,aswellas DeyandNovartis. L.Eichenfieldhasreceivedfunding/grantsupportfromavarietyofnot-for-profitfoundations,aswellasAstellas,Ferndale,Johnson&Johnson,Novartis,Sinclair,Stiefel,and TherapeuticsInc. G.T.Furutahasservedasaconsultantand/orspeakertoCeptionTherapeuticsandTAP.Hehasreceivedfunding/grantsupportfromtheAmericanGastrointestinalAssociationandthe NationalInstitutesofHealth. J.M.HanifinhasservedasservedasaconsultantforALZA,Anesiva,Inc,BarrierTherapeutics,Inc,Milliken&Company,NordicBiotech,NovartisPharmaceuticalsCorporation, ShionogiUSA,TaishoPharmaceuticalR&D,Inc,TeikokuPharmaUSA,Inc,UCB,YorkPharma,ZARS,Inc,andZymoGenetics.Hehasservedasaninvestigatororreceived researchfundingfromALZA,AstellasPharmaUS,Inc,AsubioPharmaceuticals,Inc,Centocor,Inc,Corgentech,Novartis,NucrystPharmaceuticals,SeattleGenetics,andShionogi USA. M.Krafthasservedasaconsultantand/orspeakerforAstra-Zeneca,Genentech,GlaxoSmithKline,Merck,Novartis,andSepracor.Shehasreceivedfunding/grantsupportfrom Genentech,GlaxoSmithKline,theNationalInstitutesofHealthandNovartis. B.D.Levyholds,orislistedasaninventoron,USpatentapplications#20080064746entitled‘‘Lipoxinsandaspirin-triggeredlipoxinsandtheirstableanalogsinthetreatmentof asthmaandinflammatoryairwaydiseases’’and#20080096961entitled‘‘Useofdocosatrienes,resolvinsandtheirstableanalogsinthetreatmentofairwaydiseasesandasthma.’’He ownsstockinResolvyxPharmaceuticals.HehasservedasaconsultantforBayerHealthcareandResolvyxPharmaceuticals.DrLevyhasreceivedfunding/grantsupportfromthe NationalInstitutesofHealth. P.Liebermanhasservedasaconsultantand/orspeakertoDeyLaboratories,Novartis,Schering-Plough,AstraZenica,Merck,TEVA,Pfizer,MEDA,Alcon,Genentech,Intelliject,and theFoodAllergyandAnaphylaxisNetwork.HeispastpresidentoftheAmericanAcademyofAllergy,Asthma,andImmunology. L.C.Schneiderhasservedasaconsultant/clinicaladvisorfortheFoodAllergyInitiative.Shehasreceivedfunding/grantsupportfromavarietyofnot-for-profitresearchfoundations,as wellasNovartisandtheNationalInstitutesofHealth. R.A.SimonhasservedasaspeakerforDeyLaboratories,Genentech,GlaxoSmithKline,Merck,Novartis,andtheUSFoodandDrugAdministration. F.E.R.Simonsholdsapatenton‘‘Fast-disintegratingepinephrinetabletsforsublingualadministration.’’Sheisapast-presidentoftheAmericanAcademyofAllergy,Asthma,and ImmunologyandoftheCanadianSocietyofAllergyandClinicalImmunology.SheisamemberoftheadvisoryboardsofDey,Intelliject,andALK-Abello.Shehasreceivedfunding/ grantsupportfromAllerGen,theCanadianAllergy,AsthmaandImmunologyFoundation/AnaphylaxisCanada,andtheCanadianInstitutesofHealthResearch. S.J.TeachhasservedasaspeakerforAstraZeneca.Hehasreceivedfunding/grantsupportfromtheAstraZenecaFoundation,Aventis,theChildHealthCenterBoard,theCNMC ResearchAdvisoryCouncil,theNationalAssociationofChainDrugStoresFoundation,theNationalInstitutesofHealth(NationalInstituteofAllergyandInfectiousDiseases; NationalHeart,Lung,andBloodInstitute),Novartis/Genentech,theRobertWoodsJohnsonFoundation,theUSCentersforDiseaseControlandPrevention,theUSPublicHealth Service,andtheWashington,DC,DepartmentofHealth. Theotherauthorshavedeclaredthattheyhavenoconflictofinterest. S4 BOYCEETAL JALLERGYCLINIMMUNOL DECEMBER2010 Preface Food allergy is an immune-based disease that has become a knowledge,whichwillhelpfocusthedirectionoffutureresearch serioushealthconcernintheUnitedStates.Arecentstudy1esti- inthisarea. matesthatfoodallergyaffects5%ofchildrenundertheageof5 TheGuidelineswere developed overa2-yearperiodthrough yearsand4%ofteensandadults,anditsprevalenceappearstobe the combined efforts of an Expert Panel and Coordinating on the increase. The symptoms of this disease can range from Committee representing 34 professional organizations, federal mildtosevereand,inrarecases,canleadtoanaphylaxis,asevere agencies,andpatientadvocacygroups.TheExpertPaneldrafted and potentially life-threatening allergic reaction. There are no theGuidelinesusinganindependent,systematicliteraturereview therapiesavailabletopreventortreatfoodallergy:theonlypre- andevidencereportonthestateofthescienceinfoodallergy,as ventionoption for the patient is to avoid the food allergen, and well as their expert clinical opinion. The National Institute of treatmentinvolvesthemanagementofsymptomsastheyappear. Allergy and Infectious Diseases (NIAID), a component of the Andbecausethemostcommonfoodallergens—eggs,milk,pea- National Institutes of Health (NIH), provided funding for this nuts, tree nuts, soy, wheat, crustacean shellfish, and fish—are projectandplayedapivotalroleasorganizerand‘‘honestbroker’’ highlyprevalentintheUSdiet,patientsandtheirfamiliesmust oftheGuidelinesproject. remainconstantlyvigilant. AstheleadNIHinstituteforresearchonfoodallergy,NIAIDis ThedevelopmentoftheGuidelinesfortheDiagnosisandMan- deeply committed to improving the lives of patients with food agement of Food Allergy in the United States began in 2008 to allergyandisproudtohavebeeninvolvedinthedevelopmentof meet a long-standing need for harmonization of best clinical these Guidelines. As our basic understanding of the human practices relatedtofoodallergyacrossmedical specialties.The immunesystemandfoodallergyinparticularincreases,wehope resulting Guidelines reflect considerable effort by a wide range totranslatethisinformationintoimprovedclinicalapplications. of participants toestablish consensus and consistencyin defini- Although there are many challenges, the potential benefit for tions, diagnostic criteria, and management practices. They humanhealthwillbeextraordinary. provideconciserecommendationsonhowtodiagnoseandman- age foodallergy andtreatacutefood allergyreactions.In addi- AnthonyS.Fauci,MD tion,theyprovideguidanceonaddressingpointsofcontroversy Director in patient management and also identify gaps in our current NationalInstituteofAllergyandInfectiousDiseases JALLERGYCLINIMMUNOL BOYCEETAL S5 VOLUME126,NUMBER6 Guidelines for the Diagnosis and Management of Food Allergy in the United States: Report of the NIAID-Sponsored Expert Panel Foodallergyisanimportantpublichealthproblemthataffects childrenandadultsandmaybeincreasing inprevalence. Abbreviationsused Despitetheriskofsevereallergicreactionsandevendeath, AAP: AmericanAcademyofPediatrics thereisnocurrenttreatmentforfoodallergy:thedisease can ACD: Allergiccontactdermatitis ACIP: AdvisoryCommitteeonImmunizationPractices onlybemanagedbyallergenavoidance ortreatmentof AD: Atopicdermatitis symptoms.Thediagnosisandmanagementoffoodallergyalso AP: Allergicproctocolitis mayvaryfromone clinicalpracticesettingtoanother.Finally, APT: Atopypatchtest becausepatients frequentlyconfusenonallergicfoodreactions, BP: Bloodpressure suchasfoodintolerance,with foodallergies,thereisan CC: CoordinatingCommittee unfoundedbeliefamongthepublicthatfoodallergyprevalence CDC: CentersforDiseaseControlandPrevention ishigherthanittrulyis.Inresponsetotheseconcerns,the CI: Confidenceinterval NationalInstituteofAllergy andInfectiousDiseases,working CMA: Cow’smilkallergy with34professionalorganizations,federalagencies,andpatient COI: Conflictofinterest advocacygroups,ledthedevelopment ofclinicalguidelinesfor DBPCFC: Double-blind,placebo-controlledfoodchallenge DRACMA: DiagnosisandRationaleforActionagainstCow’sMilk thediagnosisandmanagementoffoodallergy.TheseGuidelines Allergy areintended forusebyawidevarietyofhealthcare EAACI: EuropeanAcademyofAllergyandClinicalImmunology professionals,includingfamilypracticephysicians,clinical EG: Eosinophilicgastroenteritis specialists, andnursepractitioners.TheGuidelinesincludea EGID: Eosinophilicgastrointestinaldisorder consensus definitionforfoodallergy,discusscomorbid eHF: Extensivelyhydrolyzedinfantformula conditionsoftenassociatedwithfoodallergy,andfocusonboth eHF-C: Extensivelyhydrolyzedcaseinformula IgE-mediated andnon-IgE-mediatedreactionstofood. Topics eHF-W: Extensivelyhydrolyzedwheyinfantformula addressedincludetheepidemiology,naturalhistory,diagnosis, EoE: Eosinophilicesophagitis andmanagementoffoodallergy,aswellasthemanagementof EP: ExpertPanel severesymptomsandanaphylaxis.TheseGuidelinesprovide43 FA: Foodallergy FAAN: FoodAllergyandAnaphylaxisNetwork concise clinicalrecommendationsandadditionalguidanceon FALCPA: FoodAllergenLabelingandConsumerProtectionAct pointsofcurrentcontroversyinpatientmanagement.Theyalso FPIES: Foodprotein-inducedenterocolitissyndrome identifygapsinthecurrentscientificknowledgetobeaddressed GI: Gastrointestinal throughfutureresearch.(JAllergyClin Immunol GINI: GermanNutritionalInterventionStudy 2010;126:S1-S58.) GRADE: GradingofRecommendationsAssessment,Development andEvaluation Keywords: Food,allergy,anaphylaxis,diagnosis,diseasemanage- ICD-9-CM: InternationalClassificationofDiseases,NinthRevision, ment,guidelines ClinicalModification ICU: Intensive-careunit IM: Intramuscular SECTION 1. INTRODUCTION IV: Intravenous 1.1. Overview MDI: Metered-doseinhaler MMR: Measles,mumps,andrubella Food allergy (FA) isan important public health problem that MMRV: Measles,mumps,rubella,andvaricella affectsadultsandchildrenandmaybeincreasinginprevalence. NIAID: NationalInstituteofAllergyandInfectiousDiseases Despitetheriskofsevereallergicreactionsandevendeath,there NICE: NationalInstituteforHealthandClinicalExcellence isnocurrenttreatmentforFA:thediseasecanonlybemanagedby (England/Wales) allergen avoidance or treatment of symptoms. Moreover, the NSAID: Nonsteroidalanti-inflammatorydrug diagnosisofFAmaybeproblematic,giventhatnonallergicfood OAS: Oralallergysyndrome reactions,suchasfoodintolerance,arefrequentlyconfusedwith pHF: Partiallyhydrolyzedinfantformula FAs.Additionalconcernsrelatetothedifferencesinthediagnosis pHF-W: Partiallyhydrolyzedwheyformula andmanagementofFAindifferentclinicalpracticesettings. PI: Packageinsert Due to these concerns, the National Institute of Allergy and RCT: Randomizedcontrolledtrial RR: Relativerisk Infectious Diseases (NIAID), part of the National Institutes of SAFE: Seeksupport,Allergenidentificationandavoidance, Health, working with more than 30 professional organizations, Followupwithspecialtycare,Epinephrinefor emergencies sIgE: Allergen-specificIgE SPT: Skinpricktest ReceivedforpublicationOctober12,2010;acceptedforpublicationOctober13,2010. WAO: WorldAllergyOrganization 0091-6749 doi:10.1016/j.jaci.2010.10.007 S6 BOYCEETAL JALLERGYCLINIMMUNOL DECEMBER2010 federal agencies, and patient advocacygroups, led the develop- development of the NICE guidelines is also very similar mentof‘‘bestpractice’’clinicalguidelinesforthediagnosisand to that used to generate the EAACI and US Guidelines. It management of FA (henceforth referred to as the Guidelines). is expected that NICE will release the final guidelines in Basedonacomprehensivereviewandobjectiveevaluationofthe early 2011. recentscientificandclinicalliteratureonFA,theGuidelineswere d In 2008, the World Allergy Organization (WAO) Special developedbyanddesignedforallergists/immunologists,clinical Committee on Food Allergy identified cow’s milk allergy researchers, and practitioners in the areas of pediatrics, family (CMA) as a topic that would benefit from a reappraisal medicine, internal medicine, dermatology, gastroenterology, of the more recent literature and an updating of existing emergencymedicine,pulmonaryandcriticalcaremedicine,and guidelines,whichsummarizedtheachievementsofthepre- others. cedingdecadeanddealtmainlywithprevention.Itisinthis The Guidelines focus on diseases that are definedas FA (see context that the WAO Diagnosis and Rationale for Action section2.1)andincludebothIgE-mediatedreactionstofoodand against Cow’s Milk Allergy (DRACMA) was created.4 somenon-IgE-mediatedreactionstofood.TheGuidelinesdonot Theevidence-basedDRACMAguidelinescoverdiagnostic discuss celiac disease, which is an immunologic non-IgE- algorithms, challenge-testing methodology, consideration mediatedreactiontocertainfoods.Althoughthisisanimmune- of appropriate sensitization tests, and the limitations of based disease involving food, existing clinical guidelines for diagnostic procedures for CMA. In addition, there is dis- celiacdiseasewillnotberestatedhere.2,3 cussion of appropriate substitute feeding formulas that Insummary,theGuidelines: can be used in various clinical situations, with consider- ation, for example, of patient preferences, costs, and local d Provide concise recommendations (guidelines numbered availability. 1through43)toawidevarietyofhealthcareprofessionals d In2006,anFApracticeparameterwaspublishedbyatask on how to diagnose FA, manage ongoing FA, and treat force established by the American College of Allergy, acute FA reactions Asthma and Immunology, the American Academy of d Identify gaps in the current scientific knowledge to be ad- Allergy, Asthma, and Immunology, and the Joint Council dressed through future research of Allergy, Asthma and Immunology.5 The document, d Identify and provide guidance on points of current contro- FoodAllergy:APracticeParameter,hasbeenanoutstand- versy in patient management ingresourcefortheallergyandimmunologyclinicalcom- A companion Summary of the NIAID-Sponsored Expert munity,butmaynothavehadbroadimpactoutsideofthis Panel Report has been prepared from the Guidelines. This community. Summary contains all 43 recommendations, all ‘‘In summary’’ Notably, the new US Guidelines are specifically aimed at all statements,definitions,1diagnostictableforFA,and1summary healthcareprofessionalswhocareforadultandpediatricpatients tableforthepharmacologicmanagementofanaphylaxis.Itdoes with FA and related comorbidities. Thus, it is hoped that these not contain background information, supporting evidence for Guidelineswillhavebroadimpactandbenefitforallhealthcare the recommendations and ‘‘In summary’’statements, and other professionals. summarytablesofdata.TheSummaryisnotintendedtobethe sole source of guidance for the health care professional, who 1.3. How the Guidelines were developed should consult the Guidelines for complete information. 1.3.1. The Coordinating Committee. NIAIDestablisheda Finally, these Guidelines do not address the management of Coordinating Committee (CC), whose members are listed in patients with FA outside of clinical care settings (for example, Appendix A, to oversee the development of the Guidelines; re- schoolsandrestaurants)ortherelatedpublichealthpolicyissues. view drafts of the Guidelines for accuracy, practicality, clarity, Theseissuesarebeyondthescopeofthisdocument. andbroadutilityoftherecommendationsinclinicalpractice;re- view the final Guidelines; and disseminate the Guidelines. The 1.2. Relationship of the US Guidelines to other CCmemberswerefrom34professionalorganizations,advocacy guidelines groups,andfederalagencies,andeachmemberwasvettedforfi- Otherorganizationshaverecentlydeveloped,orarecurrently nancialconflictofinterest(COI)byNIAIDstaff.PotentialCOIs developing,guidelinesforFA. werepostedontheNIAIDWebsiteathttp://www.niaid.nih.gov/ d TheEuropeanAcademyofAllergyandClinicalImmunol- topics/foodAllergy/clinical/Pages/FinancialDisclosure.aspx. ogy (EAACI) has created a task force that is currently 1.3.2. The Expert Panel. The CC convened an Expert Panel developing guidelines for the diagnosis and management (EP) in March 2009 that was chaired by Joshua Boyce, MD of FA. The model for development of guidelines by this (BrighamandWomen’sHospital,Boston,Mass).Panelmembers task force is very similar to that used to generate these werespecialistsfromavarietyofrelevantclinical,scientific,and USGuidelines.FollowingcompletionoftheEAACIguide- publichealthareas(seeAppendixB).Eachmemberwasvettedfor lines, additional efforts will be made to harmonize the US financialCOIbyNIAIDstaffandapprovedbytheCC.Potential Guidelines with the EAACI guidelines. COIswerepostedontheNIAIDWebsiteprovidedinsection1.3.1. d Clinical practice guidelines on FA in children and young The charge to the EP was to use an independent, systematic people are being developed for use in the National Health literaturereview(seesection1.3.3),inconjunctionwithconsen- ServiceinEngland,Wales,andNorthernIrelandbytheNa- susexpertopinionandEP-identifiedsupplementarydocuments, tionalInstituteforHealthandClinicalExcellence(NICE). todevelopGuidelinesthatprovideacomprehensiveapproachfor Theseguidelinesareintendedforusepredominantlyinpri- diagnosing and managing FA based on the current state of the mary care and community settings. The model used for science. JALLERGYCLINIMMUNOL BOYCEETAL S7 VOLUME126,NUMBER6 TheEPorganizedtheGuidelinesinto5majortopicareas: acompletelistofreferencesisavailableathttp://www.rand.org/ pubs/working_papers/WR757-1/. d Definitions,prevalence,andepidemiologyofFA(section2) 1.3.4. Assessing the quality of the body of evidence. d Natural history of FA and associated disorders (section 3) Foreachkeyquestion,inadditiontoassessingthequalityofeach d Diagnosis of FA (section 4) oftheincludedstudies,RANDassessedthequalityofthebodyof d Management of nonacute food-induced allergic reactions evidence using the Grading of Recommendations Assessment, and prevention of FA (section 5) Development and Evaluation (GRADE) approach,8 which was d Diagnosis and management of food-induced anaphylaxis developedin2004.GRADEprovidesacomprehensiveandtrans- and other acute allergic reactions to foods (section 6) parentmethodologytodeveloprecommendationsforthediagno- Subtopicsweredevelopedforeachofthese5broadtopicareas. sis,treatment,andmanagementofpatients.Inassessingthebody 1.3.3. The independent, systematic literature review of evidence, GRADE considers study design and other factors, and report. RAND Corporation prepared an independent, suchastheprecision,consistency,anddirectnessofthedata.Us- systematic literature review and evidence report on the state of ingthisapproach,GRADEthenprovidesagradeforthequalityof thescienceinFA.RANDhadrespondedtotheNIAIDRequest thebodyofevidence. for Proposal AI2008035, Systematic Literature Review and Based on the available scientific literature on FA, which in EvidenceBasedReportonFoodAllergy,andwassubsequently someareaswasminimal,RANDusedtheGRADEapproachto awardedthecontractinSeptember2008.Thecontract’sprincipal assess the overall quality of evidence for each key question investigator wasPaulG.Shekelle, MD,PhD,aninternationally assigned by the EP and assigned a grade according to the recognized expert in the fields of practice guidelines and followingcriteria9,10: meta-analysis. NIAIDandtheEPdevelopedanextensivesetofkeyquestions,6 d High—Furtherresearchisveryunlikelytohaveanimpact on the quality of the body of evidence, and therefore the whichwerefurtherrefinedindiscussionswithRAND.Literature confidence in the recommendation is high and unlikely to searcheswereperformedonPubMed,CochraneDatabaseofSys- change. tematicReviews,CochraneDatabaseofAbstractsofReviewsof d Moderate—Furtherresearchislikelytohaveanimpacton Effects,CochraneCentralRegisterofControlledTrials,andthe the quality of the body of evidence and may change the World Allergy Organization Journal, a relevant journal that is recommendation. notincludedinPubMed.Inmostcases,searcheswerelimitedto d Low—Furtherresearchisverylikelytohavean important theyears1988(January)to2009(September),withnolanguage impactonthebodyofevidenceandislikelytochangethe restrictions. Additional publications identified by the EP and recommendation. others involved in the review process alsowere included in the RAND review if and only if they met the RAND criteria for AGRADE designationof ‘‘Low’’for the quality of evidence inclusion. does not imply that an article is not factually correct or lacks RANDresearchersscreenedalltitlesfoundthroughsearches, scientificmerit.Forexample,aperfectlydesignedandexecuted as well as those that were submitted by the EP or NIAID. studyofatreatmentinasmallsamplethatisfromasinglesiteof Screeningcriteriawereestablishedtofacilitatetheidentification highly selected patients might still yield an overall GRADE of of articles concerning definitions, diagnoses, prevention, treat- ‘‘Low.’’ This is because a single small study is characterized as ment, management, and other topics. Articles were included or ‘‘sparse’’data, and the patient population may not be represen- excludedbasedonarticletypeandstudypurposeasfollows: tativeofthelargerpopulationofpatientswithFA.Eachofthese factorsreducesthelevelofevidencefrom‘‘High,’’whichishow d Article type randomized controlled trial (RCT) evidence is designated ini- – Included: Original research or systematic reviews tially.Itisworthemphasizingthatthese2limitationsarenotof – Excluded: Background or contextual reviews; nonsys- thestudyperse,butofthebodyofevidence.Replicationofthe tematic reviews; commentary; other types of articles study’sresultonotherpopulationswouldresultinaGRADEof d Study purpose ‘‘High.’’ItshouldbenotedthattheEPrecommendationsmadein – Included: Incidence/prevalence/natural history; diagno- theseGuidelinesareoftenbasedonaGRADEclassificationofthe sis; treatment/management/prevention qualityofevidenceas‘‘Low,’’thusnecessitatingmorecontribu- – Excluded:NotaboutFA;aboutsomeaspectnotlistedin tiontotherecommendationfromexpertopinion. the ‘‘included’’ category For additional information to understand the concept of ‘‘qualityofthebodyofevidence,’’pleaseseeAppendixC. RANDscreenedmorethan12,300titles,reviewedmorethan 1.3.5.PreparationofdraftGuidelinesandExpertPanel 1,200 articles, abstracted nearly 900 articles, and included 348 deliberations. The EP prepared a draft version of the Guide- articles in the final RAND report. Two RAND investigators linesbasedontheRANDevidencereportandalsosupplementary independentlyreviewedalltitlesandabstractstoidentifypoten- documentsthatwereidentifiedbytheEPbutnotincludedinthe tiallyrelevantarticles.Articlesthatmettheinclusioncriteriawere independentlyabstractedbyasingleRANDinvestigator.Because RANDreport. The supplementary documents contained information of sig- ofthelargenumberofarticlesandtheshorttimeforthereview, nificant value that was not included in the systematic literature articles were not independently abstracted by 2 RAND investi- gators (dual-abstracted). However, team members worked to- review due to the objective criteria for inclusion or exclusion established by RAND, such as limits on demographics, study gether closely and data were double-checked. Selected population size, and study design. The EP used this additional conclusions from the report have been published in a peer- reviewed journal,7 and the full version of the report with information only to clarify and refine conclusions drawn from S8 BOYCEETAL JALLERGYCLINIMMUNOL DECEMBER2010 sourcesinthesystematicliteraturereview.Thesedocumentsare TheGuidelinesareintendedtoassisthealthcareprofessionalsin denotedwithanasterisk(*)inReferences. making appropriate decisions about patient care in the United Italsoshouldbenotedthatincludedreferencesareillustrative States.Therecommendationsarenotfixedprotocolsthatmustbe ofthedataandconclusionsdiscussedineachsection,anddonot followed.HealthcareprofessionalsshouldtaketheseGuidelines represent the totality of relevant references. For a full list of intoaccountwhenexercisingtheirclinicaljudgment.However,this relevantreferences,thereadershouldrefertothefullversionof guidancedoesnotoverridetheirresponsibilitytomakedecisions theRANDreport. appropriate to the circumstances of the individual patient, in InOctober2009,theEPdiscussedthefirstwrittendraftversion consultation with the patient, guardian, or caregiver. Clinical of the Guidelines and their recommendations. Following the judgment on the management of individual patients remains meeting, the EP incorporated any panel-wide changes to the paramount.Healthcareprofessionals,patients,andtheirfamilies recommendations within the draft Guidelines. These revised needtodevelopindividualtreatmentplansthataretailoredtothe recommendationswerethensubjecttoaninitialpanel-widevote specificneedsandcircumstancesofthepatient.Thisdocumentis to identify where panel agreement was less than 90%. Contro- intended as a resource to guide clinical practice and develop versialrecommendationswerediscussedviateleconferenceand educationalmaterialsforpatients,theirfamilies,andthepublic.Itis e-mail to achieve group consensus. Following discussion and notanofficialregulatorydocumentofanygovernmentagency. revisionasnecessary,asecondvotewasheld.Allrecommenda- tionsthatreceived90%orhigheragreementwereincludedinthe SECTION 2. DEFINITIONS, PREVALENCE, AND draftGuidelinesforpublicreviewandcomment. Inadditiontothe43recommendations,sections3,5,and6ofthe EPIDEMIOLOGY OF FOOD ALLERGY Guidelinescontain‘‘Insummary’’statements.Thesestatementsare 2.1. Definitions intendedtoprovidehealthcareprofessionalswithsignificantinfor- 2.1.1. Definitions of food allergy, food, and food aller- mationthatdidnotwarrantarecommendation,orareinplaceofa gens.TheEPcametoconsensusondefinitionsusedthroughout recommendationwhentheEPortheCCcouldnotreachconsensus. theGuidelines. All‘‘Insummary’’statementsreceived90%orhigheragreement. A food allergy is defined as an adverse health effect arising 1.3.6. Public comment period and draft Guidelines from a specific immune response that occurs reproducibly on revision. ThedraftGuidelineswerepostedtotheNIAIDWeb exposuretoagivenfood. site in March 2010 for a period of 60 days to allow for public Afoodisdefinedasanysubstance—whetherprocessed,semi- review and comment. More than 550 comments were collected processed,orraw—thatisintendedforhumanconsumption,and andreviewedbytheCC,theEP,andNIAID.TheEPrevisedthe includesdrinks,chewinggum,foodadditives,anddietarysupple- Guidelinesinresponsetosomeofthesecomments. ments.Substancesusedonlyasdrugs,tobaccoproducts,andcos- FurtherdeliberationbetweentheCCandtheEPresultedinthe metics (such as lip-care products) that may be ingested are not revisionof5recommendations.Inaddition,section5.1.11,which included. discussesvaccinationinpatientswithallergytohen’segg(hence- Food allergens are defined as those specific components of forth referred to as egg), also underwent substantial revision to foodoringredientswithinfood(typicallyproteins,butsometimes bring it into better alignment with national vaccine policies. also chemical haptens) that are recognized by allergen-specific Consequently, the EP developed 1 recommendation for vaccina- immunecellsandelicitspecificimmunologicreactions,resulting tionwithMMRandMMRV,and3‘‘Insummary’’statementsfor in characteristic symptoms. Some allergens (most often from influenza, yellow fever, and rabiesvaccinations. All new recom- fruitsandvegetables)causeallergicreactionsprimarilyifeaten mendations and ‘‘In summary’’ statements were subjected to a whenraw.However,mostfoodallergenscanstillcausereactions panel-widevoteandachieved90%consensusormore. evenaftertheyhavebeencookedorhaveundergonedigestionin ThefinalGuidelineswerereviewedbytheCC. thestomachandintestines.Aphenomenoncalledcross-reactiv- 1.3.7. Dissemination of the final Guidelines. The final itymayoccurwhenanantibodyreactsnotonlywiththeoriginal Guidelineswerepublishedandmadepublicallyavailableviathe allergen,butalsowithasimilarallergen.InFA,cross-reactivity Internet. occurswhenafoodallergensharesstructuralorsequencesimilar- itywithadifferentfoodallergenoraeroallergen,whichmaythen 1.4. Defining the strength of each clinical guideline triggeranadversereactionsimilartothattriggeredbytheoriginal TheEPhasusedtheverb‘‘recommends’’or‘‘suggests’’ineach food allergen. Cross-reactivity is common,for example, among clinical guideline. These words convey the strength of the different shellfish and different tree nuts. (See Appendix D, guideline,definedasfollows: TableS-I.) d Recommend is used when the EP strongly recommended Foodoils—suchassoy,corn,peanut,andsesame—rangefrom for or against a particular course of action. very low allergenicity (if virtually all of the food protein is d Suggest is used when the EP weakly recommended for or removedinprocessing)toveryhighallergenicity(iflittleofthe against a particular course of action. foodproteinisremovedinprocessing). 2.1.2.Definitionsofrelatedterms.Thetermsallergyandal- 1.5. Summary lergicdiseasearebroadlyencompassingandincludeclinicalcon- The Guidelines present 43 recommendations by an indepen- ditionsassociatedwithalteredimmunologicreactivitythatmaybe dent EP for the diagnosis and management of FA and food- eitherIgEmediatedornon-IgEmediated.IgEisauniqueclassof inducedanaphylaxis.Three‘‘Insummary’’statementsprovidea immunoglobulinthatmediatesanimmediateallergicreaction. briefreviewofUSnationalvaccinepolicyspecificallyrelatedto Thetermfoodhypersensitivityalsoisoftenusedtodescribe vaccinationofpatientswitheggallergy. FA, although other groups have used this term more broadly to JALLERGYCLINIMMUNOL BOYCEETAL S9 VOLUME126,NUMBER6 describeallotherfoodreactions,includingfoodintolerances.In Non-immunemediatedreactionsorfoodintolerancesinclude theseGuidelines,theEPhasrefrainedfromusingthetermfood metabolic,pharmacologic,toxic,andundefinedmechanisms.In hypersensitivity except for the term immediate gastrointestinal some cases, these reactions may mimic reactions typical of an (GI)hypersensitivity,whichisIgEmediated. immunologic response. It is therefore important to keep these Becauseindividualscandevelopallergicsensitization(asevi- food components or mechanisms in mind when evaluating dencedbythepresenceofallergen-specificIgE(sIgE))tofoodal- adversefoodreactions.Mostadversereactionstofoodadditives, lergens without having clinical symptoms on exposure to those suchasartificialcolors(forexample,FD&Cyellow5[tartrazine]) foods,ansIgE-mediatedFArequiresboththepresenceofsensiti- andvariouspreservatives(forexample,sulfites),havenodefined zation and the development of specific signs and symptoms on immunologic mechanisms. These food components, as well as exposuretothatfood.Sensitizationaloneisnotsufficienttode- otherfoodscontributingtofoodintolerances,arenotspecifically fineFA. discussedintheseGuidelines. AlthoughFAismostoftencausedbysIgE-mediatedreactions 2.1.3.Definitions of specificfood-induced allergiccon- to food, the EP also considered literature relevant to reactions ditions.Anumberofspecificclinicalsyndromesmayoccurasa likely mediated by immunologic but non-IgE-induced mecha- resultofFA,andtheirdefinitionsareasfollows: nisms,includingfoodprotein-inducedenteropathy,exacerbations Food-inducedanaphylaxisisaseriousallergicreactionthatis of eosinophilic GI disorders (EGIDs) (eosinophilic gastritis, rapidinonsetandmaycausedeath.12,13Typically,IgE-mediated eosinophilicenteritis,eosinophiliccolitis,andeosinophilicgas- food-inducedanaphylaxisisbelievedtoinvolvesystemicmedia- troenteritis), and food-induced allergic contact dermatitis. In tor release from sensitized mast cells and basophils. In some theseconditions,sensitizationtofoodproteincannotbedemon- cases, such as food-dependent, exercise-induced anaphylaxis, stratedbasedonsIgE.Thediagnosisofnon-IgE-mediatedFAis theabilitytoinducereactionsdependsonthetemporalassocia- basedonsignsandsymptomsoccurringreproduciblyonexposure tion between food consumption and exercise, usually within 2 tofood,resolutionofthosesignsandsymptomswithspecificfood hours. avoidance, and, most often, histologic evidence of an immuno- GI food allergies include a spectrum of disorders that result logicallymediatedprocess,suchaseosinophilicinflammationof from adverse immunologic responses to dietary antigens. Al- theGItract. though significant overlap may exist between these conditions, TheseGuidelinesgenerally usethe termtoleratetodenotea several specific syndromes have been described. These are de- condition where an individual has either naturally outgrown an finedasfollows: FAorhasreceivedtherapyandnolongerdevelopsclinicalsymp- d ImmediateGIhypersensitivityrefers toan IgE-mediated tomsfollowingingestionofthefood.Thisabilitytotoleratefood FAinwhichupperGIsymptomsmayoccurwithinminutes doesnotdistinguish2possibleclinicalstates.Individualsmaytol- and lower GI symptoms may occur either immediately or eratefoodonlyforashortterm,perhapsbecausetheyhavebeen witha delay of up toseveral hours.14,15 Thisis commonly desensitizedbyexposuretothefood.Alternatively,theymayde- seenasamanifestationofanaphylaxis.AmongtheGIcon- veloplong-termtolerance.Thespecifictermtoleranceisusedin ditions,acuteimmediatevomitingisthemost commonre- theseGuidelinestomeanthatanindividualissymptomfreeafter action and the one best documented as immunologic and consumption of the food or upon oral food challenge weeks, IgE mediated. months,orevenyearsafterthecessationoftreatment.Theimmu- d Eosinophilic esophagitis (EoE) involveslocalized eosino- nological mechanisms that underlie tolerance in humans are philicinflammationoftheesophagus.16-18Insomepatients, poorlyunderstood. avoidance of specific foods will result in normalization of Although many different foods and food components have histopathology. Although EoE is commonly associated been recognized as food allergens,11 these Guidelines focus on with the presence of food-specific IgE, the precise causal onlythosefoodsthatareresponsibleforthemajorityofobserved role of FA in its etiology is not well defined. Both IgE- adverse allergic or immunologic reactions. Moreover, foods or and non-IgE-mediated mechanisms appear to be involved. food components that elicit reproducible adverse reactions but Inchildren,EoEpresentswithfeedingdisorders,vomiting, do not have established or likely immunologic mechanisms are reflux symptoms, and abdominal pain. In adolescents and not considered food allergens. Instead, these non-immunologic adults,EoEmostoftenpresentswithdysphagiaandesoph- adverse reactions are termed food intolerances. For example, ageal food impactions. anindividualmaybeallergictocow’smilk(henceforthreferred d Eosinophilicgastroenteritis(EG)alsoisbothIgE-andnon- toasmilk)duetoanimmunologicresponsetomilkprotein,oral- IgE-mediatedandcommonlylinkedtoFA.15EGdescribesa ternatively,thatindividualmaybeintoleranttomilkduetoanin- constellationofsymptomsthatvarydependingonthepor- ability to digest the sugar lactose. In the former situation, milk tionoftheGItractinvolvedandapathologicinfiltrationof protein is considered an allergen because it triggers an adverse theGItractbyeosinophils,whichmaybelocalizedorwide- immunologicreaction.Inabilitytodigestlactoseleadstoexcess spread.EoEisacommonmanifestationofEG. fluidproductionintheGItract,resultinginabdominalpainand d Foodprotein-inducedallergicproctocolitis(AP)typically diarrhea.Thisconditionistermedlactoseintolerance,andlactose presentsininfantswhoseemgenerallyhealthybuthavevis- isnotanallergenbecausetheresponseisnotimmunebased. ible specks or streaks of blood mixed with mucus in the Note: The words tolerance and intolerance are unrelated stool.15 IgE to specific foods is generally absent. The lack terms, even though the spelling of the words implies that they ofsystemicsymptoms,vomiting,diarrhea,andgrowthfail- areopposites. urehelpsdifferentiatethisdisorderfromotherGIFAdisor- Adversereactionstofoodcanthereforebestbecategorizedas ders that present with similar stool patterns. Because there those involving immune-mediated or non-immune-mediated are no specific diagnostic laboratory tests, the causal role mechanisms,assummarizedinFig1. S10 BOYCEETAL JALLERGYCLINIMMUNOL DECEMBER2010 FIG1. Typesofadversereactionstofood of food allergens such as those found in milk or soy is in- d Atopicdermatitis (AD),also knownas atopiceczema, is ferred from a characteristic history on exposure. Many in- linked to a complex interaction between skin barrier dys- fantspresentwhilebeingbreast-fed,presumablyasaresult function and environmental factors such as irritants, mi- ofmaternallyingestedproteinsexcretedinbreastmilk. crobes, and allergens.20 Null mutations of the skin barrier d Food protein-induced enterocolitissyndrome (FPIES)is proteinfilaggrinmayincreasetheriskfortranscutaneousal- another non-IgE-mediated disorder that usually occurs in lergen sensitizationandthe developmentofFA insubjects young infants and manifests as chronic emesis, diarrhea, with AD.21-23 Although the EP does not mean to imply and failure to thrive. Upon re-exposure to the offending thatADresultsfromFA,theroleofFAinthepathogenesis food after a period of elimination, a subacute syndrome and severity of this condition remains controversial.24 In can present with repetitive emesis and dehydration.13,15 somesensitizedpatients,particularlyinfantsandyoungchil- Milk and soy protein are the most common causes, al- dren, food allergens can induce urticarial lesions, itching, thoughsomestudiesalsoreportreactionstootherfoods,in- andeczematousflares,allofwhichmayaggravateAD.19 cludingrice,oat,orothercerealgrains.Asimilarcondition d Allergic contact dermatitis (ACD) is a form of eczema alsohasbeenreportedinadults,mostoftenrelatedtocrus- causedbycell-mediatedallergicreactionstochemicalhap- tacean shellfish ingestion. tensthatareadditivestofoodsoroccurnaturallyinfoods, d Oral allergy syndrome (OAS), also referred to as pollen- suchasmango.25Clinicalfeaturesincludemarkedpruritus, associated FA syndrome, is a form of localized IgE- erythema, papules, vesicles, and edema. mediated allergy, usually to raw fruits or vegetables, with d Contact urticaria can be either immunologic (IgE-medi- symptoms confined to the lips, mouth, and throat. OAS ated reactions to proteins) or non-immunologic (caused mostcommonlyaffectspatientswhoareallergictopollens. by direct histamine release). Symptoms include itching of the lips, tongue, roof of the Respiratory manifestations of IgE-mediated FA occur fre- mouth,andthroat,withorwithoutswelling,and/ortingling quently during systemic allergic reactions and are an important of the lips, tongue, roof of the mouth, and throat. indicatorofsevereanaphylaxis.26However,FAisanuncommon causeofisolatedrespiratorysymptoms,namelythoseofrhinitis Cutaneous reactions tofoods are some of the most common andasthma. presentationsofFAandincludeIgE-mediated(urticaria,angioe- Heinersyndromeisararediseaseininfantsandyoungchil- dema,flushing,pruritus),cell-mediated(contactdermatitis,der- dren.Causedprimarilybytheingestionofmilk,itischaracterized matitis herpetiformis), and mixed IgE- and cell-mediated bychronicorrecurrentlowerrespiratorysymptomsoftenassoci- (atopicdermatitis)reactions.Thesearedefinedasfollows: atedwith27,28: d AcuteurticariaisacommonmanifestationofIgE-mediated FA,althoughFAisnotthemostcommoncauseofacuteur- d Pulmonary infiltrates ticariaandisrarelyacauseofchronicurticaria.19Lesionsde- d Upper respiratory symptoms veloprapidlyafteringestingtheproblemfoodandappearas d GI symptoms polymorphic, round, or irregular-shaped pruritic wheals, d Failure to thrive ranginginsizefromafewmillimeterstoseveralcentimeters. d Iron-deficiency anemia d Angioedema most often occurs in combination with urti- The syndrome is associated with non-IgE-mediated immune caria and, if food induced, is typically IgE mediated. It is responses, such as precipitating antibodies to milk protein characterized by nonpitting, nonpruritic, well-defined fractions. Evidence often exists of peripheral eosinophilia, iron edematous swelling that involves subcutaneous tissues deficiency, and deposits of immunoglobulins and C3 in lung (forexample,face,hands,buttocks,andgenitals),abdomi- biopsies in some cases. Milk elimination leads to marked nalorgans,ortheupperairway.19Whentheupperairwayis improvement in symptoms within days and clearing of pulmo- involved,laryngealangioedemaisamedicalemergencyre- naryinfiltrateswithinweeks.28Theimmunopathogenesisofthis quiringpromptassessment.Bothacuteangioedemaandur- disorder is not understood, but seems to combine cellular and ticaria are common features of anaphylaxis. immune-complexreactions,causingalveolarvasculitis.Insevere
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