R A EVIEW RTICLE World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow’s Milk Allergy (DRACMA) Guidelines Alessandro Fiocchi, (Chair), Jan Brozek, Holger Schu¨nemann, (Chair), Sami L. Bahna, Andrea von Berg, Kirsten Beyer, Martin Bozzola, Julia Bradsher, Enrico Compalati, Motohiro Ebisawa, Maria Antonieta Guzman, Haiqi Li, Ralf G. Heine, Paul Keith, Gideon Lack, Massimo Landi, Alberto Martelli, Fabienne Rancé, Hugh Sampson, Airton Stein, Luigi Terracciano, and Stefan Vieths Keywords:Cowmilkallergy;oralfoodchallenge;epidemiology; HaiqiLi,MD,ProfessorofPediatricDivision,Departmentof DBPCFC;aminoacidformula;hydrolyzedmilkformula; PrimaryChildCare,Children’sHospital,ChongqingMed- hydrolyzedriceformula;hydrolyzedsoyformula;skinpricktest; ical University, China, 400014. specificIgE;OIT;SOTI;GRADE Ralf G. Heine, MD, FRACP, Department of Allergy & Immunology, Royal Children’s Hospital, University of Authorship Melbourne, Murdoch Children’s Research Institute, Mel- bourne, Australia. Alessandro Fiocchi, MD, Pediatric Division, Department of PaulKeith,MD,AllergyandClinicalImmunologyDivision, ChildandMaternalMedicine,UniversityofMilanMedical DepartmentofMedicine,McMasterUniversity,Hamilton, School at the Melloni Hospital, Milan 20129, Italy. Ontario, Canada. HolgerSchu¨nemann,MD,a DepartmentofClinicalEpidemiology Gideon Lack, MD, King’s College London, Asthma-UK & Biostatistics, McMaster University Health Sciences Centre, CentreinAllergicMechanismsofAsthma,Departmentof 1200MainStreetWestHamilton,ONL8N3Z5,Canada. PediatricAllergy,StThomas’Hospital,LondonSE17EH, Sami L. Bahna, MD, Pediatrics & Medicine, Allergy & United Kingdom. Immunology, Louisiana State University Health Sciences Massimo Landi, MD, National Pediatric Healthcare System, Center, Shreveport, LA 71130. ItalianFederationofPediatricMedicine,TerritorialPediat- AndreaVonBerg,MD,ResearchInstitute,Children(cid:1)sdepart- ricPrimaryCareGroup,Turin,Italy. ment , Marien-Hospital, Wesel, Germany. Alberto Martelli, MD, Pediatric Division, Department of Kirsten Beyer, MD, Charite´ Klinik fu¨r Pa¨diatrie m.S. Pneu- ChildandMaternalMedicine,UniversityofMilanMedical mologie und Immunologie, Augustenburger Platz 1, School at the Melloni Hospital, Milan 20129, Italy. D-13353 Berlin, Germany. FabienneRance´,MD,Allergologie,HoˆpitaldesEnfants,Poˆle Martin Bozzola, MD, Department of Pediatrics, British Hos- Me´dicochirurgical de Pe´diatrie, 330 av. de Grande Bret- pital-Perdriel74-CABA-BuenosAires,Argentina. agne, TSA 70034, 31059 Toulouse CEDEX, France. Julia Bradsher, PhD, Food Allergy & Anaphylaxis Network, Hugh Sampson, MD, Jaffe Food Allergy Institute, Mount 11781LeeJacksonHighway,Suite160,Fairfax,VA22033. SinaiSchoolofMedicine,OneGustaveL.LevyPlace,NY Jan Brozek, MD,a Department of Clinical Epidemiology & 10029-6574. Biostatistics, McMaster University Health Sciences Centre, Airton Stein, MD, Conceicao Hospital, Porto Alegre, Brazil. 1200MainStreetWestHamilton,ONL8N3Z5,Canada. Luigi Terracciano, MD,a Pediatric Division, Department of Enrico Compalati, MD,a Allergy & Respiratory Diseases ChildandMaternalMedicine,UniversityofMilanMedical Clinic, Department of Internal Medicine. University of School at the Melloni Hospital, Milan 20129, Italy. Genoa, 16132, Genoa, Italy. Stefan Vieths, MD, Division of Allergology, Paul-Ehrlich- Motohiro Ebisawa, MD, Department of Allergy, Clinical Institut, Federal Institute for Vaccines and Biomedicines, Research Center for Allergy and Rheumatology, Sagami- Paul-Ehrlich-Str. 51-59, D-63225 Langen, Germany. hara National Hospital, Kanagawa 228-8522, Japan. Maria Antonieta Guzman, MD, Immunology and Allergy aMember of the Grades of Recommendation, Assessment, Division, Clinical Hospital University of Chile, Santiago, Development and Evaluation (GRADE) Working Group Chile. Santos Dumont 999. Revision Panel Correspondence to: Alessandro Fiocchi, MD, Paediatric Division, Depart- Amal Assa’ad, MD, Division of Allergy and Immunology, ment of Child and Maternal Medicine, University of Milan Medical CincinnatiChildren’sHospitalMedicalCenter,Cincinnati, SchoolattheMelloniHospital,Milan20129Italy.E-mail:[email protected]. Ohio, USA. ThisReviewArticleisco-publishedasaSupplementtotheMay2010issue Carlos Baena-Cagnani, MD, LIBRA foundation Argentina, ofPediatricAllergyandImmunology. Copyright©2010byWorldAllergyOrganization Division of Immunology and Respiratory Medicine, De- WAO Journal ● April 2010 57 Fiocchietal WAOJournal•April2010 partment of Pediatric, Infantile Hospital Cordoba, Santa 17:ChoosingtheAppropriateSubstituteFormulainDifferent Rosa 381, 5000 Cordoba, Argentina. Presentations, p. 130. GR Bouygue, MSc, Pediatric Division, Department of Child 18:GradeRecommendationsonImmunotherapyforCMA,p.131. and Maternal Medicine, University of Milan Medical 19: UnmetNeeds,RecommendationsforResearch,Implemen- School at the Melloni Hospital, Milan 20129, Italy. tationofDRACMA,p.133. Walter Canonica, MD, Allergy & Respiratory Diseases Acknowledgements, p. 134 Clinic, Department of Internal Medicine. University of Appendix1:Cow’sMilkAllergyLiteratureSearchAlgorithms, Genoa, 16132, Genoa, Italy. p.135 Christophe Dupont, MD, Service de gastroente´rologie et Appendix 2: Evidence Profiles: Diagnosis of CMA, p. 144 nutrition, Hoˆpital Saint Vincent de Paul, 82, avenue Den- Appendix 3: Evidence Profiles: Treatment of CMA, p. 154 fert-Rochereau, 75674, Paris CEDEX 14, France. Appendix 4: Evidence Profiles: OIT for Treatment of CMA, Yehia El-Gamal, MD, Department of Pediatrics, Faculty of p. 160 Medicine, Ain Shams University, Cairo, Egypt. Matthew Fenton, MD, Asthma, Allergy and Inflammation SECTION 1: INTRODUCTION Branch, National Institute of Allergy and Infectious Dis- Allergy and clinical immunology societies have issued eases, NIH, 6610 Rockledge Dr., Bethesda, MD 20892. guidance for the management of food allergy.1,2 Guide- RosaElenaHuertaHernandez,MD,PediatricAllergyClinic, lines are now regarded as translational research instruments, Mexico City, Mexico. designed to provide cutting-edge benchmarks for good prac- Manuel Martin-Esteban, MD, Allergy Department, Hospital tice and bedside evidence for clinicians to use in an interac- Universitario La Paz, Madrid, Spain. tive learning context with their national or international Anna Nowak-Wegrzyn, MD, Jaffe Food Allergy Institute, scientific communities. In the management of cow’s milk Mount Sinai School of Medicine, One Gustave L. Levy allergy (CMA), both diagnosis and treatment would benefit Place, NY 10029-6574. fromareappraisalofthemorerecentliterature,for“current” Ruby Pawankar, MD, Department of Otolaryngology, Nip- guidelines summarize the achievements of the preceding pon Medical School, 1-1-5 Sendagi, Tokyo, 113 Japan. decade, deal mainly with prevention,3–6 do not always agree Susan Prescott, MD, School of Pediatrics and Child Health, on recommendations and date back to the turn of the centu- University of Western Australia, Princess Margaret Hos- ry.7,8 In 2008, the World Allergy Organization (WAO) Spe- pital for Children, Perth, Australia. cialCommitteeonFoodAllergyidentifiedCMAasanareain Patrizia Restani, PhD, Department of Pharmacological Sci- need of a rationale-based approach, informed by the consen- ences, Universita` degli Studi di Milano. susreachedthroughanexpertreviewoftheavailableclinical Teresita Sarratud, MD, Department of Pediatrics, University evidence,tomakeinroadsagainstaburdensome,world-wide of Carabobo Medical School at the Carabobo Hospital, public health problem. It is in this context that the WAO Valencia, Venezuela. Diagnosis and Rationale for Action against Cow’s Milk Aline Sprikkelmann, MD, Department of Pediatric Respira- Allergy(DRACMA)Guidelineswasplannedtoprovidephy- tory Medicine and Allergy, Emma Children’s Hospital sicians everywhere with a management tool to deal with Academic Medical Centre, Amsterdam, The Netherlands. CMA from suspicion to treatment. Targeted (and tapped for theirexpertise),bothontheDRACMApanelorasnonsitting reviewers, were allergists, pediatricians (allergists and gen- SECTIONS eralists),gastroenterologists,dermatologists,epidemiologists, methodologists,dieticians,foodchemists,andrepresentatives 1: Introduction, p. 58. of allergic patient organizations. Ultimately, DRACMA is 2: Methodology, p. 59. dedicatedtoourpatients,especiallytheyoungerones,whose 3: Epidemiology of CMA, p. 61. burden of issues we hope to relieve through an ongoing and 4: Allergens of Cow’s Milk, p. 65. collective effort of more interactive debate and integrated 5: Immunological Mechanisms of CMA, p. 71. learning. 6: Clinical History and Symptoms of CMA, p. 76. 7:DiagnosisofCMAAccordingtoPrecedingGuidelines,p.85. Definitions 8: The Elimination Diet in Work-Up of CMA, p. 88. Adversereactionsaftertheingestionofcow’smilkcan 9: Guidelines for Diagnosing CMA, p. 89. occur at any age from birth and even among infants fed 10: Oral Food Challenge Procedures in Diagnosis of CMA, exclusively at the breast, but not all such reactions are of an p. 100. allergic nature. A revision of the allergy nomenclature was 11: Natural History of CMA, p. 108. issued in Europe in 20019 and was later endorsed by the 12:TreatmentofCMAAccordingtoPrecedingGuidelines,p.112. WAO10 under the overarching definition of “milk hypersen- 13:WhenCanMilkProteinsBeEliminatedFromDietWithout sitivity,” to cover nonallergic hypersensitivity (traditionally SubstitutingCow’sMilk?,p.117. termed“cow’smilkintolerance”)andallergicmilkhypersen- 14:GuidelinesforChoosingaReplacementFormula,p.119. sitivity (or “cow’s milk allergy”). The latter definition re- 15: Milks From Different Animals for Substituting Cow’s quirestheactivationofanunderlyingimmunemechanismto Milk, p. 124. fit.InDRACMA,theterm“allergy”willabidebytheWAO 16: NutritionalConsiderationsinCMATreatment,p.128. definition (“allergy is a hypersensitivity reaction initiated by 58 ©2010WorldAllergyOrganization WAOJournal•April2010 WAODRACMAGuidelines specific immunologic mechanisms”). In most children with decided to use a GRADE methodology for defining some CMA, the condition can be immunoglobulin E (IgE)-medi- treatments and diagnostic questions. ated and is thought to manifest as a phenotypical expression The DRACMA worked with the GRADE members on of atopy, together with (or in the absence of) atopic eczema, this panel the clinical questions and their scope after various allergicrhinitisand/orasthma.Asubsetofpatients,however, fine-tuning stages. The GRADE panelists independently have non-IgE mediated (probably cell-mediated) allergy and searched the relevant literature for sections 9, 14, 18. Their presentmainlywithgastro-intestinalsymptomsinreactionto analysiswasindependentoftheotherpanellists.Forquestion the ingestion of cow’s milk. formulation, guideline panel members explicitly rated the importance of all outcomes on a scale from 1–9, where the upper end of the scale (7–9) identifies outcomes of critical REFERENCES, SECTION 1 importance for decision making, ratings of 4–6 represent 1. AmericanCollegeofAllergy,Asthma,&Immunology.Foodallergy:a outcomesthatareimportantbutnotcriticalandratingsof1–3 practiceparameter.AnnAllergyAsthmaImmunol.2006;96(Suppl2):S1– are items of limited importance. Evidence summaries were S68. 2. MukoyamaT,NishimaS,AritaM,ItoS,UrisuA,etal.Guidelinesfor prepared following the GRADE Working Group’s ap- diagnosisandmanagementofpediatricfoodallergyinJapan.Allergol proach1–6 based on systematic reviews done by an indepen- Int.2007;56:349–361. dentteamoftheGRADEWorkingGroupmembers(JLBand 3. Prescott SL. The Australasian Society of Clinical Immunology and HJS supported by 5 research associates). Allergypositionstatement:Summaryofallergypreventioninchildren. MedJAust.2005;182:464–467. TheGRADEapproachsuggeststhatbeforegradingthe 4. MuraroA,DreborgS,HalkenS,HøstA,NiggemannB,etal.Dietary quality of evidence and strength of each recommendation, prevention of allergic diseases in infants and small children. Part III: guideline developers should first identify a recent well-done Criticalreviewofpublishedpeer-reviewedobservationalandinterven- systematic review of the appropriate evidence answering the tional studies and final recommendations. Pediatr Allergy Immunol. 2004;15:291–307. relevant clinical question, or conduct one when none is 5. MuraroA,DreborgS,HalkenS,HøstA,NiggemannB,etal.Dietary available.Thisshouldbefollowedbypreparingatransparent prevention of allergic diseases in infants and small children. Part I: evidence summary, such as creation of GRADE evidence immunologic background and criteria for hypoallergenicity. Pediatr profiles, on which the guideline panel will base their judg- AllergyImmunol.2004;15:103–11. 6. MuraroA,DreborgS,HalkenS,HøstA,NiggemannB,AalberseR,et ments.7 We prepared 3 systematic reviews addressing the al.Dietarypreventionofallergicdiseasesininfantsandsmallchildren. clinical questions covered by the guideline (about the diag- PartII.Evaluationofmethodsinallergypreventionstudiesandsensi- nosis, use of formula and immunotherapy of the CMA). We tizationmarkers.Definitionsanddiagnosticcriteriaofallergicdiseases. searched MEDLINE, EMBASE, and the Cochrane Library PediatrAllergyImmunol.2004;15:196–205. 7. Høst A, Koletzko B, Dreborg S, Muraro A, Wahn U, et al. Dietary (including Cochrane Central Register of Controlled Trials, products used in infants for treatment and prevention of food allergy. DARE,NHSEED)forrelevantstudies.Weincludedstudies JointStatementoftheEuropeanSocietyforPaediatricAllergologyand published up to September 2009. We developed GRADE ClinicalImmunology(ESPACI)CommitteeonHypoallergenicFormu- evidenceprofiles(summaryoffindingstables)fortheclinical lasandtheEuropeanSocietyforPaediatricGastroenterology,Hepatol- questionsbasedonthesystematicreviews.Thesummariesof ogy and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child.1999;81:80–84. evidence were reviewed by the panel members and correc- 8. American Academy of Pediatrics Committee on Nutrition. Hypoaller- tions and comments were incorporated. genicinfantformulae.Pediatrics.2000;106:346–349. We assessed the quality of the evidence according to 9. JohanssonSG,HourihaneJO,BousquetJ.Arevisednomenclaturefor allergy.AnEAACIpositionstatementfromtheEAACInomenclature the methodology described by the GRADE system.1–3,8 In taskforce.Allergy.2001;56:813–824. this system quality of supporting evidence is assessed based 10. JohanssonSG,BieberT,DahlR.Revisednomenclatureforallergyfor on explicit methodological criteria and classified as either globaluse:reportoftheNomenclatureReviewCommitteeoftheWorld “high,” “moderate,” “low,” or “very low.” Allergy Organization, 2003. J Allergy Clin Immunol. 2004;113:832– The DRACMA guideline panel reviewed the evidence 836. summaries and the draft guidelines, and made recommenda- tions. We reached consensus on all recommendations. For- SECTION 2: METHODOLOGY mulating the recommendations included explicit consider- Theoutlineoftheconsensusguidelinewastheresultofthe ationofthequalityofevidence,benefits,harms,burden,cost, considered opinion of the whole panel. Narrative parts, and values and preferences described as the “Underlying that is, sections 1–8, 9–13, 15–17, and 19 included the valuesandpreferences”orinthe“Remarks”sectionsofeach relevant CMA literature as searched using the algorithms recommendation as outlined earlier.9 Statements about the reported in Appendix 1. For these sections, the relative underlying values and preferences and the remarks are inte- weight of the suggestions retained for the purpose of gral parts of the recommendations and serve to facilitate DRACMAreflectstheexpertopinionofthepanel.Theymay accurateinterpretationoftherecommendations.Theycannot contain general indications, but no evidence-based recom- be omitted when citing or translating DRACMA guidelines. mendations. The consensus on these indications was ex- In this document, the expression “values and preferences” pressed by the panelists using a checklist itemizing the refers to the relative weight one attributes to particular ben- clinical questions considered relevant after analysis of the efits, harms, burdens, and costs to determine their balance. literature. The collective judgment of the panel is expressed We used the decision framework described previously to as a percentage of agreement among panelists. The panel determine the strength of recommendations.1,10 ©2010WorldAllergyOrganization 59 Fiocchietal WAOJournal•April2010 Little information about costs of diagnosis and treat- interpretationofthese2grades(strongorconditional)ofthe mentofIgE-mediatedcow’smilkallergywasavailabletothe strengthofrecommendationsisessentialforclinicaldecision panel and it is very likely that it varies considerably across making. geographical areas and jurisdictions. Cost, therefore, plays a limited role in these recommendations. However, whenever How to Use These Recommendations weconsideredcostandresourceexpenditure,weusedhealth systemperspective.11Forindividualpatients,costmaynotbe TheDRACMAguidelinesarenotintendedtoimposea an issue if the service or treatment strategy is provided at standard of care for individual countries and jurisdictions. reducedpriceorfreeofcharge.Cliniciansandpatientsshould They should, as any guideline, provide a basis for rational consider their local resource implications when interpreting decisions for clinicians and their patients about the manage- these recommendations. ment of cow’s milk allergy. Clinicians, patients, third-party After the GRADE approach we classified recommen- payers, institutional review committees, other stakeholders, dationsintheseguidelinesaseither“strong”or“conditional” or the courts should never view these recommendations as (also known as weak)/weak. The strength of recommenda- dictates. Strong recommendations based on high quality ev- tions depends on a balance between all desirable and all idence will apply to most patients for whom these recom- undesirableeffectsofanintervention(ie,netclinicalbenefit), mendations are made, but they may not apply to all patients quality of available evidence, values and preferences, and in all circumstances. No recommendation can take into ac- cost (resource utilization).1 In general, the higher the quality count all of the often-compelling unique features of individ- of the supporting evidence, the more likely it is for the ual clinical circumstances. Therefore, nobody charged with recommendationtobestrong.Strongrecommendationsbased evaluating clinicians’ actions should attempt to apply the on low or very low quality evidence are rare, but possible.12 recommendationsfromtheDRACMAguidelinesasroteorin For strong recommendations we used words “we rec- a blanket fashion. ommend” and for conditional recommendations, “we sug- gest.” We offer the suggested interpretation of “strong” and “weak” recommendations in Table 2-1. Understanding the REFERENCES, SECTION 2 1. GuyattGH,OxmanAD,KunzR,Falck-YtterY,VistGE,LiberatiA, SchunemannHJ.GoingfromevidencetorecommendationsBMJ.2008; 336:1049–1051. TABLE2-1. Interpretationof“Strong”and“Weak” 2. GuyattGH,OxmanAD,KunzR,VistGE,Falck-YtterY,Schunemann HJ.Whatis“qualityofevidence”andwhyisitimportanttoclinicians? Recommendations BMJ.2008;336:995–998. Strong 3. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso- Implications Recommendation WeakRecommendation CoelloP,SchunemannHJ.GRADE:anemergingconsensusonrating quality of evidence and strength of recommendations BMJ. 2008;336: For Mostindividualsinthis Themajorityofindividuals 924–926. patients situationwouldwant inthissituationwould 4. Schu¨nemannHJ,FretheimA,OxmanAD.Improvingtheuseofresearch therecommended wantthesuggestedcourse evidenceinguidelinedevelopment:9.Gradingevidenceandrecommen- courseofactionand ofaction,butmanywould dations.HealthResPolicySyst.2006;4:21. onlyasmall not. 5. Schu¨nemannHJ,OxmanAD,FretheimA.Improvingtheuseofresearch proportionwouldnot. evidenceinguidelinedevelopment:6.Determiningwhichoutcomesare Formaldecisionaids important.HealthResPolicySyst.2006;4:18. arenotlikelytobe 6. WorldHealthOrganization.GlobalProgrammeonEvidenceforHealth neededtohelp Policy. Guidelines for WHO Guidelines. EIP/GPE/EQC/2003.1. Ge- individualsmake neva,2003. decisionsconsistent 7. Schu¨nemann HJ, Hill SR, Kakad M, Vist GE, Bellamy R, et al. withtheirvaluesand Transparent development of the WHO rapid advice guidelines. PLoS preferences. Med.2007;4:e119. 8. Schu¨nemannHJ,OxmanAD,BrozekJ,GlasziouP,JaeschkeR,etal. For Mostindividualsshould Recognizethatdifferent Grading quality of evidence and strength of recommendations for clinicians receivethe choiceswillbeappropriate diagnostictestsandstrategies.BMJ.2008;336:1106–1110. intervention. forindividualpatients,and 9. Schu¨nemann HJ, Munger H, Brower S, O’Donnell M, Crowther M, Adherencetothis thatyoumusthelpeach Cook D, Guyatt G. Methodology for guideline development for the recommendation patientarriveata Seventh American College of Chest Physicians Conference on Anti- accordingtothe managementdecision thromboticandThrombolyticTherapy:theSeventhACCPConference guidelinecouldbe consistentwithhisorher usedasaquality valuesandpreferences. onAntithromboticandThrombolyticTherapy.Chest.2004;126:174S– criterionor Decisionaidsmaybe 178S. performanceindicator. usefulhelpingindividuals 10. Schu¨nemannHJ,JaeschkeR,CookDJ,BriaWF,El-SolhAA,etal.An makingdecisions officialATSstatement:gradingthequalityofevidenceandstrengthof consistentwiththeir recommendationsinATSguidelinesandrecommendations.AmJRespir valuesandpreferences. CritCareMed.2006;174:605–614. 11. GuyattGH,OxmanAD,KunzR,JaeschkeR,HelfandM,LiberatiA, Forpolicy Therecommendationcan Policymakingwillrequire VistGE,SchunemannHJ.Incorporatingconsiderationsofresourcesuse makers beadaptedaspolicy substantialdebatesand intogradingrecommendations.BMJ.2008;336:1170–1173. inmostsituations. involvementofvarious 12. BrozekJL,Baena-CagnaniCE,BoniniS,CanonicaGW,RasiG,etal. stakeholders. MethodologyfordevelopmentoftheAllergicRhinitisanditsImpacton Asthmaguideline2008update.Allergy.2008;63:38–46. 60 ©2010WorldAllergyOrganization WAOJournal•April2010 WAODRACMAGuidelines SECTION 3: EPIDEMIOLOGY OF CMA reported between 174 and 27.5%.5 Thirty percent of women reported that they or some member of their family were Overview allergic to some food product.6 In the after decade, a British study using a food allergy questionnaire reported a 19.9% incidenceoffoodallergy.7Fromthemid-1990sonwards,self There are no surveys of population and geographical reports began to be compared with challenge-confirmed di- trendsinfoodallergyinadultsorchildren(thoughthe agnoses; reported incidence data of between 12.4 and 25% situation is different in pediatric asthma and rhinitis) and couldbeconfirmedbyoralfoodchallengeinonly1.5to3.5% thisunmetneedisparticularlyfeltforCMA.Thepercep- of cases, illustrating how reports of adverse reactions over- tion of milk allergy is far more frequent than confirmed estimate true food allergy.8,9 This was further confirmed CMA. Patient reports of CMA range between 1 and when prevalence figures of 2.3 to 3.6% were confirmed by 17.5%, 1 and 13.5%, and 1 to 4% in preschoolers, at challengeproceduresinunselectedpatientpopulations.10,11In children 5 to 16 years of age and adults respectively. the 1990s, it was also confirmed that only a minority of Cow’s milk-specific IgE sensitization point prevalence subjects who report food-related illness also test positive by progressively decreased from about 4% at 2 years to less skin prick test using the same food.12 than 1% at 10 years of age in the German Multi-Centre Thus, 2 separate “food allergy epidemiologies” can be AllergyStudy.Themostreliabledatainepidemiologyare distinguished: those from birth cohorts that are free from selection bias. a. Self-reported food allergy; although this does not rep- There are 5 such challenge-confirmed studies. The CMA resentactualfoodallergyepidemiology,itisusefulasa prevalence during infancy ranged from 1.9% in a Finnish proxy measure of the potential demand for allergy study, 2.16% in the Isle of Wight, 2.22% in a study from medical services, and may guide public health allergy Denmark, 2.24% in the Netherlands, and up to 4.9% in serviceusersbetweengeneralandspecialistmedicine,13 Norway. and more generally for public health planning. Patients with CMA develop gastrointestinal symp- toms in 32 to 60% of cases, skin symptoms in 5 to 90%, b. Actual food allergy (ie, confirmed by a positive oral and anaphylaxis in 0.8 to 9% of cases. This frequency of foodchallenge)representstherealextentofthisclinical anaphylaxisisthemainconcernpointedoutinmanyCMA problem. studies. In a review, nearly one third of children with In general, food allergy is more frequent in the pediat- atopicdermatitis(AD)receivedadiagnosisofCMAafter ric, rather than the adult, population. According to a recent an elimination diet and an oral food challenge, and about Japanese multicenter trial, the prevalence of CMA is 0.21% 40 to 50% of children less than a year of age with CMA in newborns and 0.35% amid extremely premature babies also had AD. Finally, with actual population and geo- ((cid:2)1000g).14Foodallergiesareacauseofparticularconcern graphicaltrendsremainingunknown,allergistsareprimar- for children. Incidence is estimated to be greater in toddlers ilyinneedofmoredetailedepidemiologicalsurveysona (5–8%) than it is in adults (1–2%).15–17 Earlier prospective global scale. One large such epidemiological study sup- challenge-based studies have shown that in a population of ported by the European Commission is ongoing and aims 480 newborns followed up in the setting of a U.S. general tofurnishthefirstprevalencedataregardingthesuspicion pediatric practice through their third birthday, a parental of CMA, sensitization to cow’s milk, and oral food chal- report of 28% food allergy translates into a challenge-con- lenge-confirmed diagnosis in 10 European birth cohorts. firmed CMA rate of 8%,18,19 with 2.27 to 2.5% occurring in the first 2 years of life. Introduction Perceived Cow’s Milk Allergy Around 11–26 million of the European population are Similar considerations can be applied to cow’s milk estimatedtosufferfromfoodallergy.1Ifthisprevalencewas allergy perception. Self-report is common. In a large Euro- consistent around the world and projected to the pean survey of above 44,000 telephone contacts, 5 million 6,659,040,000peopleoftheworld’spopulation,2ittranslates Europeanrespondentsclaimedtobemilk-allergic,withadult into 220–520 million people and represents a major global womenasthegroupmakingmostoftheseclaims.Therewere health burden. Although there are surveys on the natural alsowidenationaldifferencesrangingfrom13.8%ofreports historyandprevalencetrendsforsymptomsofasthma,aller- fromGreeceto52.3%fromFinland.Inthissurveymilkwas gicrhinoconjunctivitis,andeczemainchildhood,3wedonot themostoftenreportedoffendingfoodinchildren(38.5%of haveastudyassessingtheprevalenceoffoodallergyandits reports)andthesecondfoodmostoftenimplicatedbyadults time-trends. The problem is complicated by the fact that (26%).20 In a group of 600 children less than 4 years, CMA perceived food allergy (ie, the self-reported feeling that a was reported by the parents of 18 children (3%).21 Milk particular food negatively influences health status) is not reactions were reported by the parents of 2% of children actualfoodallergy.Allergyprevalenceismuchgreaterinthe without wheeze and by 16% of wheezers.22 public’sbeliefthanithaseverbeenreportedbydouble-blind In the literature, the bulk of studies based only on studies.Backinthe1980s,theperceivedincidenceofallergy self-reportsofCMAisstaggering,comparedwithreportsthat tofoodorfoodadditivesinmotherswithyoungchildrenwas include an objective measure to assess the condition.23 Cur- ©2010WorldAllergyOrganization 61 Fiocchietal WAOJournal•April2010 rently, at least a score of studies have evaluated the self- e. InanewborncohortfromtheNetherlands1,158infants perception of CMA over the last 20 years in preschool- prospectively followed through 12 months of age re- ers,24–33 school-age children (5–16 years),20,34–38 and young porting “cow’s milk protein intolerance” (defined as adults.20,39–45Fromthesestudies,reviewedintheonlymeta- two positive cow’s milk elimination/challenge tests) analysis in the field,35 the prevalence of self-reports varies reported 26 allergic children (or 2.24%) of 211 (or between 1 to 17.5% in preschoolers, 1 and 13.5% in 5 to 18.2%) suspected cases.33 16-year-olds, and between 1 and 4% in adults. Thechildrenfromthesestudiesneitherunderwentsensi- In this series of challenge-based studies, the Danish study tization testing nor oral food challenge. In a population of furthersuggestedthatreproducibleclinicalreactionstoCMP 6-year-olds,1outof7caseswasbasedonself-reportswhereas in human milk were reported in (cid:3)0.5% of breast-fed in- less than one out of 2 children with a positive cow’s milk fants.55 Data from cross-sectional studies (analyzed by Rona specific skin prick test was confirmed allergic by DBPCFC, and coworkers2) demonstrated a rate of 0.6 to 2.5% preva- thereby confirming that most parent-reported symptoms of lenceinpreschoolers,0.3%at5to16yearsofage,andofless CMA are unreliable.46 Not only parents, but also health care than 0.5% in adults.23,56–58 professionals,allergists,andnonallergistsalike,citecow’smilk- While most of our information on cow’s milk allergy induced reactions as the most common food allergy affecting prevalencecomesfromnorthernEuropeanandSpanishstud- children.47Thus,theincidenceofself-reportsofCMAremains ies,therearemethodologicalandgeographicaldifferencesin of interest for public health authorities, health maintenance clinicalevaluation,whichmustbeconsideredinassessingthe organizations and the processed food industry as a metric for epidemiological features we discuss here. Some studies may policyplanning,planningdiagnosticservices;48tablinglabeling consider only immediate reactions, while others include de- legislationandevenmeetingthedemandformilk-freeproducts. layed reactions; not all studies include IgE sensitization However,assuch,thisproxycannotrepresentthefullextentof assessments; some studies are based on open oral food theclinicalissuesatstake. challenges,someperformedblindedoralfoodchallengetests. Methods used across studies in this literature of oral food challenges with59 cow’s milk are not standardized (see sec- Sensitization to Cow’s Milk Proteins tion on Diagnosis). ThenumberofstudiesonCMsensitizationinunselected Thus, among the unmet needs of epidemiological re- populations is limited. The meta-analysis carried out by Rona searchinthisfieldarehigh-qualitycommunitystudiesbased andcolleagues23identified7studiesreportingasensitizationrate on patient data objectively confirmed by DBPCFC to close of0.5to2%ofpreschoolers,of0.5%at5to16yearsofage,and the current knowledge gap on the prevalence of CMA in the in less than 0.5% of adults.23,25–33 In a later cohort of 543 population. To address this, the European Commission children from the Isle of Wight followed-up from birth and launched the EuroPrevall Project (www.europrevall.org) in testedat1,2,and3yearsofage,apositivemilksensitizationtest 2005inconcertwithmorethan60partnersincludingpatient was found in 2 infants at 12 months (0.37%), in 5 at 2 years organizations, the food industry and research institutions (0.92%), and in 3 at 3 years (0.55%).49 In the German Multi- from across Europe, Russia, Ghana, India, and China. This center Allergy Study, 1314 children initially recruited were translational endeavor involves basic and clinical research followed from birth for 13 years. The longitudinal data were components, and large epidemiological studies of both chil- analyzedfor273childrentestingpositiveforserumcow’smilk dren and adults.60 The first results, will include data on specificIgEantibodyandwereobtainedatage2,5,7,and10. suspicionofCMA,onsensitizationtocow’smilkandoforal The point prevalence of sensitization to cow’s milk progres- food challenge-confirmed diagnosis from 10 birth cohorts.61 sivelydecreasedfromabout4%at2yearstolessthan1%at10 years.50 Different Clinical Presentations of CMA In a Danish birth cohort, 60% of children with CMA Epidemiology of Challenge-Confirmed CMA presented with gastrointestinal symptoms, 50 to 60% with The epidemiology of oral food challenge-confirmed skin issues, and respiratory symptoms present in 20 to 30% CMAofthelast10yearsconsistsofthefollowing5studies: while 9% developed anaphylaxis.62,63 In the Norwegian co- hort noted above, young infants experienced pain (48%), a. In a Danish study of 1,749 newborns followed for 12 gastrointestinal symptoms (32%), respiratory problems months, 39 (or 2.22%) were confirmed allergic51 (27%), and atopic dermatitis (4.5%).53 In the Finnish cohort, b. InastudyfromFinland6,209newbornsfollowedfor15 presentation symptoms included urticaria (45.76%), atopic months, 118 (1.9%) had positive DBPCFC52 dermatitis (89.83%), vomiting and/or diarrhea (51.69%), re- c. In a Norwegian study of 193 premature and 416 full- spiratorysymptoms(30.50%),andanaphylaxis(2.54%).The term infants, 27 of 555 (or 4.9%) were diagnosed with same children reacted at oral food challenge with symptoms an allergic reaction to cow’s milk on the basis of an of urticaria (51.69%), atopic dermatitis (44.06%), vomiting open challenge but not all children were tested; inter- and/or diarrhea (20.33%), respiratory symptoms (15.25%), estingly, all had symptoms before 6 months of age53 andanaphylaxis(0.84%).52IntheBritishstudyquotedabove, d. InanIsleofWightcohortof969newbornsfollowedfor infants reacted to oral food challenges with eczema (33%), 12 months, 21 (2.16%) reported CMA but only 2 diarrhea(33%),vomiting(23.8%),andurticariain2children (0.21%) were actually with IgE-mediated CMA54 who immediately reacted to the challenge meal (one with 62 ©2010WorldAllergyOrganization WAOJournal•April2010 WAODRACMAGuidelines wheeze and the other with excessive crying).54 Dutch TABLE3-1. ComparisonoftheThreeMainFoodAllergens infants with CMA from the study noted above developed InChildrenStudies75 gastrointestinal (50%), skin (31%), and respiratory (19%) symptoms.33 Country 1st 2nd 3rd Several other studies have assessed the incidence of USA Egg Cow’smilk Peanuts CMAinpopulationsselectedforreferralbyothercaregivers Germany Egg Cow’smilk Wheat to a tertiary institution for specialist assessment of their Spain Egg Cow’smilk Fish symptoms and therefore requires caution in generalizing the Switzerland Egg Cow’smilk Peanuts results of such studies. As a case in point, in a long-term Israel Egg Cow’smilk Sesame study of 97 children with challenge-confirmed CMA, 21% Japan Egg Cow’smilk Wheat had atopic dermatitis at the final follow-up evaluation (at 8 years).62 In another follow-up study of 42 infants with IgE- mediated CMA, 57% of children had developed atopic der- identified across studies regarding time variations in CMA matitis at the median age of 3.7 years.63 frequency.72IsCMAprevalenceontherise?Utilizingsurro- Thus,CMAappearswithGIsymptomsin32to60%of gate indicators, we can only infer changes in CMA preva- cases,cutaneoussymptomsin5to90%,anaphylaxisin0.8to lencebasedonstudiesofgeneralfoodallergy.Amongthose, 9% of cases. Respiratory complaints, including asthma, are a British study found that the admission rates per million notrare.Clearly,inmostofthepopulationsstudied,thereare population between 1990 and 2004 rose form 5 to 26 for overlappingpresentingsymptomsandmultiplesymptomsare anaphylaxis,from5to26forfoodallergy,andfrom16to107 often confirmed during challenge. specificallyforpediatricfoodallergy.73Reinforcingthispicture, eczemarosefrom13%in1991to16%in2003.3 CMA in Different Clinical Conditions Reversing the point of view, milk sensitization and Geographical Trends in CMA CMA are reported with different frequencies in different Is milk the most important offender in food allergy in clinical presentations. In 2184 young children aged 13–24 children? From self-reports, it appears that this may be the months with atopic dermatitis, the frequency of positive case.However,giventhepaucityofepidemiologicalstudies, serum IgE responses against cow’s milk protein was 3%.64 we do not have sufficient information to argue the relative Among 59 breast-fed children with moderate-severe AD, 5 importance of CMA in different parts of the world. The (8,5%) were SPT-positive with milk extracts.65 In a consec- maximum information comes from Spain, Scandinavian utive series with moderate atopic eczema referred to a Uni- countries, the UK, and Germany. Inadequate information versity-affiliated dermatology department, SPT showed 16% from different areas in the world are available, including of infants with IgE against CMP.66 In a group of infants and Italy, Australia and North America where many cross-sec- children (mean age 17.6 months) with AD and no other tional and referral studies come from. Table 3-1 shows the allergicmanifestations,20/54children(37%)hadadiagnosis comparisonofthe3mainfoodallergensinthechildstudies. of CMA.67 Among 90 children with IgE-mediated food al- Thepan-EuropeanRedAllsurveyestimatedmilkasthemost lergy, 17% were allergic to cow’s milk.68 Thus, as reviewed frequently reported offender in children (38.5% of reports) some years ago, nearly one third of AD children have a andthesecondinadults(26.2%).20InFrance,29/182school- diagnosis of CMA according to elimination diet and chal- aged children with reported food allergy are milk-allergic in lenge tests, and about 40–50% of children (cid:2)1 year of age 11.9% of cases.24 Accordingly, the Rona23 metanalysis indi- with CMA have AD.67 cates milk as the major food offender in challenge-based An exception to the uncertainty of information about studies, followed by egg and fish. However, cow’s milk epidemiology of CMA is anaphylaxis. In a prospective sur- accounts for less than one third of any food that can be vey of hospital admissions for food-allergic reactions, con- blamedforfoodallergyamongthestudiessignificantlycom- ducted through the British Pediatric Surveillance Unit, cov- bined(P(cid:2)0.001).74Similarlyareviewofstudiesofvarious ering the 13 million children in the United Kingdom and designs (surveys, reviews, clinico-epidemiological studies) Ireland, 229 cases were reported by 176 physicians in 133 indicated egg as the most frequently found allergen in chil- departments, yielding a rate of 0.89 hospital admissions per dren.75ThepatternisrepeatedinJapan,whereCMaccounts 100,000 children per year. With a 10% rate, milk was the for22.6%ofchildrenwithfoodallergy.76Thesamemaynot thirdmostfrequentallergenictrigger,afterpeanut(21%)and betrueinotherpartsoftheworld,wheretheprevalencewill treenuts(16%).69IntheUK,thereare13millionindividuals largely reflect local factors such as exposure to foods, mode lessthan16yearsofage,andoverthepast10years8children ofpreparation,andculturalattitudes.Asanexample,inIsrael died of anaphylaxis (incidence of 0.006 deaths per 100 000 sesame is the third most frequently implicated offending children 0–15 years per year). Milk caused the greatest food, probably because of its widespread consumption. numberoffatalreactions(fourofeight),70inlinewithreports Among young Australian adults, the major offender was of both the frequency and severity71 of reactions to milk. peanut, followed by shrimp, wheat, egg, and milk.44 In Iranian children CM is the most common offender identified Secular Trends of CMA during diagnostic provocation challenge.77 Thus, it may be In such a leopard-skin epidemiological context, it is saidthatthemostrepresentativeallergenisahand-maidento hardly surprising that there is no continuum that can be local customs. ©2010WorldAllergyOrganization 63 Fiocchietal WAOJournal•April2010 REFERENCES, SECTION 3 asamajorcauseofsevereIgE-mediatedfoodallergicreactionsamong infantsandyoungchildreninIsrael.Allergy.2002;57:362–365. 1. Eigenmann PA. Future therapeutic options in food allergy. Allergy. 26. Tariq SM, Matthews SM. Egg allergy in infancy predicts respiratory 2003;58:1217–1223. allergicdiseaseby4yearsofage.PediatrAllergyImmunol.2000;11: 2. WHO, World Health Statistics 2009. Available at http://www.who.int/ 162–167. whosis/whostat/2009/en/print.html,accessedJune30,2009. 27. Garcia Ara MC, Boyano Martinez MT. Incidence of allergy to cow’s 3. ISAACPhaseThreeStudyGroup.Worldwidetimetrendsintheprev- milk protein in the first year of life and its effect on consumption of alenceofsymptomsofasthma,allergicrhinoconjunctivitis,andeczema hydrolyzedformulae.AnnPediatr(Barc).2003;58:100–105. inchildhood:ISAACPhasesOneandThreerepeatmulticountrycross- 28. KristjanssonI,ArdalB,JonssonJS,SigurdssonJA,FoldeviM,Bjork- sectionalsurveys.Lancet.2006;368:733–743. stenB.Adversereactionstofoodandfoodallergyinyoungchildrenin 4. GoodHousekeepingInstitute,ConsumerResearchDepartment.Child- IcelandandSweden.ScandJPrimHealthCare.1999;17:30–34. carefindingsV,ChildrenandFood.NewYork:AGoodHousekeeping 29. EggesbøM,HalvorsenR,TambsK,BottenG.Prevalenceofparentally Report.1989. perceivedadversereactionstofoodinyoungchildren.PediatrAllergy 5. GoodHousekeepingInstitute,ConsumerResearchDepartment.Wom- Immunol.1999;10:122–132. en’s opinions of food allergens. New York: A Good Housekeeping 30. HøstA,HalkenSA.AprospectivestudyofcowmilkallergyinDanish InstitutePublication.1984. infantsduringthefirstyearoflife.Allergy.1990;45:587–596. 6. SloanAE,PowersME,SloanAE,PowersMD.Aperspectiveonpopular 31. Bival’kevich VG. Allergic diathesis in infants in the first year of life. perceptions on adverse reaction to food. J Allergy Clin Immunol. VestnDermatolVenerol.1990;4:49–52. 1986;78:128–133. 32. FrongiaO,BellomoAR.Foodallergiesandintoleranceininfantsand 7. YoungE,StonehamMD,PetruckeirtchA,etal.Apopulationstudyof children.MedicoBambino.2005;24:533–538. foodintolerance.Lancet.1994;343:1127–31. 33. Schrander JJ, Van Den Bogart JP. Cow’s milk protein intolerance in 8. JansenJJ,KardinnalAF,HuijbersG,Vlieg-BoerstraBJ,MartensBP, infants under 1 year of age: a prospective epidemiological study. Eur Ockhuizen T. Prevalence of food allergy and intolerance in the adult JPediatr.1993;152:640–644. Dutchpopulation.JAllergyClinImmunol.1994;93:446–456. 34. Penard-MorandC,RaherisonC,KopferschmittC,CaillaudD,LavaudF, 9. BjornssonEJansonC,PlaschkeP,NorrmanE,Sjo¨bergO.Prevalenceof et al. Prevalence of food allergy and its relationship to asthma and sensitization to food allergens in adult Swedes. Ann Allergy, Asthma allergicrhinitisinschoolchildren.Allergy.2005;60:1165–1171. Immunol.1996;77:327–332. 35. Roehr CC, Edenharter G, Reimann S, Ehlers I, Worm M, et al. Food 10. Osterballe M. The clinical relevance of sensitization to pollen-related allergy and non-allergic food hypersensitivity in children and adoles- fruits and vegetables in unselected pollen-sensitized adults. Allergy. cents.ClinExpAllergy.2004;34:1534–1541. 2005;60:218–225. 36. Santadusit S, Atthapaisalsarudee S, Vichyanond P. Prevalence of ad- 11. Zuberbier T. Prevalence of adverse reactions to food in Germany. versefoodreactionsandfoodallergyamongThaichildren.JMedAssoc Allergy.2004;59:338–345. Thai.2005;88(Suppl8):S27–S32. 12. WoodsRK,StoneyRM,RavenJ,WaltersEH,AbramsonM,ThienFC. 37. IsolauriE,HuurreA.Theallergyepidemicextendsbeyondthepastfew Reportedadversereactionsoverestimatetruefoodallergyinthecom- decades.ClinExpAllergy.2004;34:1007–1010. munity.EurJClinNutr.2002;56:31–36. 38. van Bockel-Geelkerken M, Meulmeester JF. Prevalence of putative 13. Fiocchi A, Bouygue GR, Terracciano L, Sarratud T, Martelli A. The hypersensitivity in young children. Ned Tijdschr Geneeskd. 1992;136: march of allergic children - excluding allergy in paediatric practice. 1351–1356. AllergyAsthmaProc.2006;27:306–311. 39. Pereira B, Venter C, Grundy J, Clayton CB, Arshad SH, Dean T. 14. MiyazawaT,ItahashiK,ImaiT.Managementofneonatalcow’smilk Prevalenceofsensitizationtofoodallergens,reportedadversereaction allergyinhigh-riskneonates.PediatrInt.2009;51:544–547. tofoods,foodavoidance,andfoodhypersensitivityamongteenagers.J 15. BrugmanE,MeulmeesterJF,Spee-vanderWA,BeukerRJ,RadderJJ, AllergyClinImmunol.2005;116:884–892. Verloove-VanhorickSP.Prevalenceofself-reportedfoodhypersensitiv- 40. GislasonD,BjornssonE,GislasonS.Allergyandintolerancetofoodin ityamongschoolchildreninTheNetherlands.EurJClinNutr.1998; an Icelandic urban population 20–44 years of age. Icelandic Med J. 52:577–581. 2000;86:851–857. 16. Eggesbo M, Botten G, Halvorsen R, Magnus P. The prevalence of 41. Woods RK, Abramson M, Bailey M, Walters EH, on behalf of the allergy to egg: a population-based study in young children. Allergy. European Community Respiratory Health Survey (ECRHS). Interna- 2001;56:403–411. tionalprevalenceofreportedfoodallergiesandintolerances:compari- 17. HalmerbauerG,GartnerC,SchierlM,ArshadH,DeanT,etal.Studyon sonsarisingfromtheEuropeanCommunityRespiratoryHealthSurvey the Prevention of Allergy in Children in Europe (SPACE): Allergic (ECRHS)1991–1994.EurRespirJ.2001;55:298–304. sensitizationinchildrenat1yearofageinacontrolledtrialofallergen 42. Falcao H, Lunet N, Lopes C, Barros H. Food hypersensitivity in avoidancefrombirth.PediatrAllergyImmunol.2002;13(s15):47–54. Portugueseadults.EurJClinNutr.2004;58:1621–1625. 18. BockSA.Thenaturalhistoryoffoodsensitivity.JAllergyClinImmu- 43. Altman DR, Chiaramonte LT. Public perception of food allergy. J nol.1982;69:173–177. AllergyClinImmunol.1996;97:1247–1251. 19. Bock SA. Prospective appraisal of complaints of adverse reactions to 44. WoodsRK,ThienF,RavenJ,WaltersH,AbramsonM.Prevalenceof foods in children during the first three years of life. Pediatrics. 1987; food allergies in young adults and their relationship to asthma, nasal 79:683–688. allergies,andeczema.AnnAllergyAsthmaImmunol.2002;88:183–189. 20. SteinkeM,FiocchiA,theREDALLgroup.PerceivedFoodallergyin 45. Marklund B, Ahlstedt S, Nordstrom G. Health-related quality of life children.Areportonarepresentativetelephonesurveyin10European amongadolescentswithallergy-likeconditions:withemphasisonfood countries.IntArchAllergyAsthmaImmunol.2007;143:290–295. hypersensitivity.HealthQualLifeOutcomes.2004;2:65. 21. KilgallenI,GibneyMJ.Parentalperceptionoffoodallergyorintoler- 46. VenterC.Prevalenceofsensitizationreportedandobjectivelyassessed anceinchildrenunder4yearsofage.JHumNutrDiet.1996;9:473–478. foodhypersensitivityamongstsix-year-oldchildren:apopulation-based 22. SandinA,AnnusT,Bjo¨rkste´nB,NilssonL,Riikja¨rvMA,vanHage- study.PediatrAllergyImmunol.2006;17:356–363. HamstenM,Bråba¨ckL.Prevalenceofself-reportedfoodallergyandIgE 47. Wilson BG, Cruz NV, Fiocchi A, Bahna SL; American College of antibodies to food allergens in Swedish and Estonian schoolchildren. Allergy,Asthma&ImmunologyAdverseReactionstoFoodCommittee. EurJClinNutr.2005;59:399–403. Survey of physicians’ approach to food allergy, Part 2: Allergens, 23. Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, et al. The diagnosis, treatment, and prevention. Ann Allergy Asthma Immunol. prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol. 2008;100:250–255. 2007;120:638–646. 48. Hourihane JO’B. Prevalence and severity of food allergy: need for 24. Rance´F,GrandmottetX,GrandjeanH.Prevalenceandmaincharacter- control.Allergy.1998;53(Suppl48):84–88. istics of schoolchildren diagnosed with food allergies in France. Clin 49. Dean T, Venter C, Pereira B, Arshad SH, Grundy J, Clayton CB, ExpAllergy.2005;35:167–172. HigginsB.Patternsofsensitizationtofoodandaeroallergensinthefirst 25. DalalI,BinsonI.Foodallergyisamatterofgeographyafterall:sesame 3yearsoflife.JAllergyClinImmunol.2007;120:1166–1171. 64 ©2010WorldAllergyOrganization WAOJournal•April2010 WAODRACMAGuidelines 50. MatricardiPM,BockelbrinkA,BeyerK,KeilT,NiggemannB,Gru¨ber 77. PourpakZ,FarhoudiA,ArshiS,MovahediM,GharegozlouM,Yazdani C, Wahn U, Lau S. Primary versus secondary immunoglobulin E F, Mesdaghi M. Common Food Allergens in Iranian Children. IJMS. sensitizationtosoyandwheatintheMulti-CentreAllergyStudycohort. 2003;28:17–22. ClinExpAllergy.2008;38:493–500. 51. HøstA,HalkenS,JacobsenHP,ChristensenAE,HerskindAM,PlesnerK. Clinicalcourseofcow’smilkproteinallergy/intoleranceandatopicdiseases SECTION 4: ALLERGENS OF COW’S MILK inchildhood.PediatrAllergyImmunol.2002;13(Suppl15):23–28. 52. SaarinenKM,Juntunen-BackmanK,Ja¨rvenpa¨a¨ AL,KuitunenP,etal. Supplementaryfeedinginmaternityhospitalsandtheriskofcow’smilk Overview allergy: a prospective study of 6209 infants. J Allergy Clin Immunol. 1999;104:457–461. 53. KvenshagenB,HalvorsenR,JacobsenM.Adversereactionstomilkin Themainallergensofcow’smilkaredistributedamong infants.ActaPaediatr.2008;97:196–200. the whey and casein fractions. 54. VenterC,PereiraB,GrundyJ,ClaytonCB,RobertsG,HigginsB,Dean The whey allergens include: T.Incidenceofparentallyreportedandclinicallydiagnosedfoodhyper- sensitivity in the first year of life. J Allergy Clin Immunol. 2006;117: a. Alpha-lactalbumin(Bosd4):itsroleinmilkallergyis 1118–1124. 55. Høst A. Frequency of cow’s milk allergy in childhood. Ann Allergy controversial and prevalence data across studies vary AsthmaImmunol.2002;89(Suppl1):33–37. between0and80%ofpatientsreactingtothisprotein. 56. OsterballeM,HansenTK,MortzCG,HøstA,Bindslev-JensenC.The b. Beta-lactoglobulin(Bosd5),themostabundantcow’s prevalence of food hypersensitivity in an unselected population of milkwheyprotein;itoccursinthemilkofmanyother childrenandadults.PediatrAllergyImmunol.2005;16:567–573. 57. MadrigalBI,AlfaroAN.Adversereactionstofoodindaycarechildren. species but is not present in human milk. Thirteen to RevAlergMex.1996;43:41–44. 76% of patients are found to react to this protein. 58. AltintasD.Aprospectivestudyofcow’smilkallergyinTurkishinfants. c. Bovine serum albumin (Bos d 6): involved in other ActaPaediatr.1995;84:1320–1321. allergies such as beef; it accounts for between 0 and 59. MartelliA,BouygueGR,FiocchiA,RestaniP,SarratudT,Terracciano L.OralfoodchallengesinchildreninItaly.Allergy2005;60:907–911. 88% of sensitization events, while clinical symptoms 60. ClareMillsEN,MackieAR,BurneyP,BeyerK,FrewerL,MadsenC, occur in up to 20% of patients. et al. The prevalence, cost and basis of food allergy across Europe. d. Bovine immunoglobulins (Bos d 7): are seldom held Allergy.2007;62:717–722. responsible for clinical symptoms in CMA. 61. KeilT,McBrideD,GrimshawK,NiggemannB,XepapadakiP,etal. The multinational birth cohort of EuroPrevall: background, aims and The casein allergens (collectively known as Bos d 8) methods.Allergy,2010;65:482–490. 62. BishopJM,HillDG,HoskingCS.Naturalhistoryofcowmilkallergy. consist of 4 different proteins (alpha , alpha , beta, and s1 s2 Clinicaloutcome.JPediatr.1990;116:862–867. kappa casein) which share little sequential homology. 63. Hill DJ, Bannister DG, Hosking CS, Kemp AS. Cow milk allergy Despitethis,simultaneoussensitizationtothesecaseinsis within the spectrum of atopic disorders. Clin Exp Allergy. 1994;24: frequently observed. Patients are more often sensitized to 1137–1143. 64. WahnU,WarnerJ,SimonsFE,deBenedictisFM,DiepgenTL,etal. alpha (100%) and kappa caseins (91.7%). IgEantibodyresponsesinyoungchildrenwithatopicdermatitis.Pediatr Of clinical relevance, milk allergens of various AllergyImmunol.2008;19:332–336. mammalian species cross-react. The greatest homology is 65. RennickGJ,MooreE,OrchardDC.Skinpricktestingtofoodallergens among cow’s, sheep’s and goat’s milks protein as Bos in breast-fed young infants with moderate to severe atopic dermatitis. AustralasJDermatol.2006;47:41–45. (oxen),Ovis(sheep),andCapra(goat)aregenerabelong- 66. Hill DJ, Heine RG, Hosking CS, Brown J, Thiele L, et al. IgE food ing to the Bovidae family of ruminants. Proteins in their sensitizationininfantswitheczemaattendingadermatologydepartment. milks have less structural similarity with those from the JPediatr.2007;151:359–363. Suidae (pig), Equidae (horse and donkey), andCamelidae 67. NovembreE,VierucciA.Milkallergy/intoleranceandatopicdermatitis (camel and dromedary) families and also from those of ininfancyandchildhood.Allergy.2001;56(Suppl67):105–108. 68. HillDJ,HoskingCS.Foodallergyandatopicdermatitisininfancy:an humans. Its noteworthy that the milks of camels and drom- epidemiologicstudy.PediatrAllergyImmunol.2004;15:421–427. edaries(andhumanmilk)donotcontainBosd5.Allthisis 69. ColverAF,NevantausH,MacdougallCF,CantAJ.Severefood-allergic relevantforlaterconsiderationsonformula(section13). reactions in children across the UK and Ireland, 1998–2000. Acta There is no clear relationship between digestibility Paediatr.2005;94:689–695. 70. MacdougallCF,CantAJ,ColverAF.Howdangerousisfoodallergyin and protein allergenicity. Milk allergens are known to childhood?Theincidenceofsevereandfatalallergicreactionsacrossthe preservetheirbiologicactivityevenafterboiling,pasteur- UKandIreland.ArchDisChild.2002;86:236–239. ization, ultra-high-temperature processing, or evaporation 71. Stewart AG, Ewan PW. The incidence, aetiology and management of for the production of powdered infant formula. To obtain anaphylaxispresentingtoanaccidentandemergencydepartment.QJM. 1996;89:859–864. hypoallergenic formulas, extensive hydrolysis and further 72. MadsenCH.Prevalenceoffoodallergy:anoverview.ProcNutrSoc. processing, such as heat treatment, ultrafiltration, and appli- 2005;64:413–417. cation of high pressure are necessary. Attempts have been 73. GuptaR.TimetrendsinallergicdisordersintheUK.Thorax.2007;62: madetoclassifyformulasintopartialandextensivelyhydro- 91–96. 74. ThongBY,HourihaneJO.MonitoringofIgE-mediatedfoodallergyin lyzedproductsaccordingtotheirdegreeofproteinfragmen- childhood.ActaPaediatr.2004;93:759–764. tation,butthereisnoagreementonthecriteriaonwhichto 75. EbisawaM,IkematsuK,TakanoriI,TachimotoH.FoodallergyinJapan. base this classification. Nevertheless, hydrolyzed formulas AllergyClinImmunolInt–JWorldAllergyOrg.2003;15:214–217. haveuntilnowproventobeausefulandwidelyusedprotein 76. Iikura Y, Imai Y, Imai T, Akasawa A, Fujita K, et al. Frequency of sourceforinfantssufferingfromCMA(section12). immediate-type food allergy in children in Japan. Int Arch Allergy Immunol.1999;118:251–252. ©2010WorldAllergyOrganization 65 Fiocchietal WAOJournal•April2010 TABLE4-1. TheProteinsofCow’sMilk Fraction Protein Allergen10 g/L %TotalProtein MW(kDa) #AA pI Caseins Bosd8 (cid:3)30 80 (cid:1) -casein 12–15 29 23.6 199 4.9–5.0 s1 (cid:1) -casein 3–4 8 25.2 207 5.2–5.4 s2 (cid:2)-casein 9–11 27 24.0 209 5.1–5.4 (cid:3)-casein 20.6 180 5.5 1 (cid:3)-casein 1–2 6 11.8 104 6.4 2 (cid:3)-casein 11.6 102 5.8 3 (cid:4)-casein 3–4 10 19.0 169 5.4–5.6 Wheyproteins (cid:3)5.0 20 Alpha-lactalbumin Bosd4 1–1.5 5 14.2 123 4.8 Beta-lactoglobulin Bosd5 3–4 10 18.3 162 5.3 Immunoglobulin Bosd7 0.6–1.0 3 160.0 — — BSA* Bosd6 0.1–0.4 1 67.0 583 4.9–5.1 Lactoferrin — 0.09 Traces 800.0 703 8.7 *Bovineserumalbumin. Introduction (BLG)accountsfor50%ofthisfraction.BecauseBLGisnot Milk can give rise to several food hypersensitivities, present in human milk, this protein was previously consid- usually classified as milk allergy or milk intolerance.1 The eredthemostimportantcow’smilkallergen,butithassince mechanismofintolerancetocow’smilkisnotIgEantibody- been shown that other proteins, such as the caseins, are also mediated and has been blamed on the functionality of a critically involved in the etiology of the disease. specific enzyme deficiency, commonly lactose intolerance, Byconvention,allergensintheinternationalnomencla- attributable to beta-galactosidase (lactase) deficiency. ture are designated by an abbreviation formed by the genus DRACMAwillnotaddresslactasedeficiencyorothercow’s (capitalized; abbreviated to the first 3 letters) and species milk-induced hypersensitivity not mediated by immune (reduced to one letter) names of the Linnaean taxonomical mechanisms, which have been described in detail else- system in italics, followed by an Arabic numeral reflecting where.2–5 Cow’s milk allergy is an adverse clinical reaction the chronological order in which the allergen was identified associated with the binding of immunoglobulin (IgE) to and characterized (eg, Bos d[omesticus] 4).10 antigens capable of eliciting an immune response.6 Where Alpha-Lactalbumin (Bos d 4) allergyisnotmediatedbyIgE,otherclassesofimmunoglob- Alpha-lactalbumin(A-LA)isawheyproteinbelongingto ulin, immune complexes, or a cell-mediated reaction have the lysozyme superfamily. It is a regulatory subunit of lactose been proposed to be involved. In IgE-mediated allergy, cir- synthase and is, able to modify the substrate specificity of culating antibodies recognize specific molecular regions on galactosyl-transferaseinthemammarygland,makingglucosea theantigensurface(epitopes),whichareclassifiedaccording good acceptor substrate for this enzyme and allowing lactose totheirspecificaminoacidsequence(sequentialepitopes)or synthase to synthesize lactose.11,12 A-LA is produced by the thefoldingandconfigurationoftheirproteinchains(confor- mammaryglandandhasbeenfoundinallmilksanalyzedsofar. mational epitopes). In this section, we describe the chemical Table4-2showsitsmainchemicalcharacteristics. characteristicsofcow’smilkallergens,howtheyareinvolved in cross-reactivity among mammalian species, their resis- tance to digestion and proteolysis and their response to TABLE4-2. CharacteristicsofAlpha-Lactalbumin(Bosd4) technological processing. Parameter Description Chemical Characterization of Cow’s Allergennomenclature Bosd4 Milk Allergens Entryname LALBA_BOVIN Cow’smilkcontainsseveralproteinsthatcouldeachin Synonyms LactoseSynthaseBprotein principle elicit an allergic reaction in a sensitized individual. Sequencedatabases Genbank:M18780 Someoftheseproteinsareconsideredmajorallergens,some PIR:A27360,LABO minorones,whileothershaverarelyorneverbeenassociated Swiss-Prot:P00711 with reports of clinical reactions. The casein and whey Numberofaminoacids 123residues proteins of cow’s milk are listed in Table 4-1. Each of these Molecularweight 14.2kDa 2fractionscontains5majorcomponents.7–9Thecaseinfrac- Isoelectricpoint 4.8 tion contains 80% of the total protein of cow’s milk while Involvementinallergicsensitization 0–80%CMallergicsubjects alpha and beta-casein make up for 70% of this fraction. s1 tocow’smilk 75%CMallergicchildrenbySPT Whey proteins are less abundant, and beta-lactoglobulin 66 ©2010WorldAllergyOrganization