(WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy

125 Pages·2010·0.87 MB·English

PediatrAllergyImmunol2010:21(Suppl.21):1–125 (cid:2)2010JohnWiley&SonsA/S
DOI:10.1111/j.1399-3038.2010.01068.x PEDIATRICALLERGYAND
IMMUNOLOGY
World Allergy Organization (WAO)
Diagnosis and Rationale for Action against
Cow(cid:2)s Milk Allergy (DRACMA) Guidelines
Alessandro Fiocchi, (Chair), Jan
Brozek, Holger Sch(cid:2)nemann, (Chair),
Sami L. Bahna, Andrea von Berg,
Kirsten Beyer, Martin Bozzola, Julia
Bradsher, Enrico Compalati, Motohiro
Ebisawa, Maria Antonieta Guzm(cid:3)n,
Haiqi Li, Ralf G. Heine, Paul Keith,
Gideon Lack, Massimo Landi, Alberto
Martelli, Fabienne Ranc(cid:4), Hugh
Sampson, Airton Stein, Luigi
Terracciano and Stefan Vieths
Keywords:Cowmilkallergy;oralfoodchallenge;
epidemiology;DBPCFC;aminoacidformula;
hydrolyzedmilkformula;hydrolyzedriceformula;
hydrolyzedsoyformula;skinpricktest;specificIgE;
OIT;SOTI;GRADE
Correspondenceto:AlessandroFiocchi,MD,
PaediatricDivision,DepartmentofChildand
MaternalMedicine,UniversityofMilanMedical
SchoolattheMelloniHospital,Milan20129,Italy.
E-mail:[email protected].
Thissupplementisco-publishedasanarticleinthe
April2010issueoftheWorldAllergyOrganization
Journal.FiocchiA,BrozekJ,Sch(cid:2)nemannH,Bahna
S,vonBergAetal.WorldAllergyOrganization
(WAO)DiagnosisandRationaleforActionagainst
Cow'sMilkAllergy(DRACMA)Guidelines.World
Allergy OrganizationJournal2010;3(4):57–161.
Authorship Kirsten Beyer, MD, Charite´ Klinik fu¨r Pa¨diatrie
m.S. Pneumologie und Immunologie, Augu-
Alessandro Fiocchi, MD, Pediatric Division,
stenburgerPlatz1,D-13353Berlin,Germany.
Department of Child and Maternal Medi-
Martin Bozzola, MD, Department of Pediatrics,
cine, University of Milan Medical School at
British Hospital-Perdriel 74-CABA-Buenos
the Melloni Hospital, Milan 20129, Italy.
Aires, Argentina.
Holger J. Schu¨nemann, MD,a Department of
Julia Bradsher, PhD, Food Allergy & Anaphy-
Clinical Epidemiology & Biostatistics,
laxis Network, 11781 Lee Jackson Highway,
McMaster University Health Sciences Cen-
Suite 160, Fairfax, VA 22033.
tre, 1200 Main Street West, Hamilton, ON
Jan Brozek, MD,a Department of Clinical
L8N 3Z5, Canada.
Epidemiology & Biostatistics, McMaster
Sami L. Bahna, MD, Pediatrics & Medicine,
UniversityHealthSciencesCentre,1200Main
Allergy & Immunology, Louisiana State
StreetWest,Hamilton,ONL8N3Z5,Canada.
University Health Sciences Center, Shreve-
Enrico Compalati, MD,a Allergy & Respiratory
port, LA 71130.
Diseases Clinic, Department of Internal
Andrea Von Berg, MD, Research Institute,
Medicine, University of Genoa, 16132,
Children‘s department, Marien-Hospital,
Genoa, Italy.
Wesel, Germany.
1
WAO DRACMA Guidelines
MotohiroEbisawa,MD,DepartmentofAllergy, Revision Panel
Clinical Research Center for Allergy and
Amal Assa(cid:2)ad, MD, Division of Allergy and
Rheumatology, Sagamihara National Hos-
Immunology, Cincinnati Children(cid:2)s Hospital
pital, Kanagawa 228-8522, Japan.
Medical Center, Cincinnati, Ohio, USA.
Maria Antonieta Guzma´n, MD, Immunology
Carlos Baena-Cagnani, MD, LIBRA foundation
and Allergy Division, Clinical Hospital
Argentina, Division of Immunology and
University of Chile, Santiago, Chile. Santos
Respiratory Medicine, Department of Pedi-
Dumont 999.
atric, Infantile Hospital Cordoba, Santa
Haiqi Li, MD, Professor of Pediatric Division,
Rosa 381, 5000 Cordoba, Argentina.
Department of Primary Child Care, Chil-
GR Bouygue, MSc, Pediatric Division, Depart-
dren(cid:2)s Hospital, Chongqing Medical Uni-
ment of Child and Maternal Medicine,
versity, China, 400014.
University of Milan Medical School at the
Ralf G. Heine, MD, FRACP, Department of
Melloni Hospital, Milan 20129, Italy.
Allergy & Immunology, Royal Children(cid:2)s
Walter Canonica, MD, Allergy & Respiratory
Hospital, University of Melbourne, Mur-
Diseases Clinic, Department of Internal
doch Children(cid:2)s Research Institute, Mel-
Medicine. University of Genoa, 16132,
bourne, Australia.
Genoa, Italy.
Paul Keith, MD, Allergy and Clinical Immu-
Christophe Dupont, MD, Service de gastroente´-
nology Division, Department of Medicine,
rologieetnutrition,Hoˆ pitalSaintVincentde
McMaster University, Hamilton, Ontario,
Paul, 82, avenue Denfert-Rochereau, 75674,
Canada.
Paris CEDEX 14, France.
Gideon Lack, MD, King(cid:2)s College London,
YehiaEl-Gamal,MD,DepartmentofPediatrics,
Asthma-UK Centre in Allergic Mechanisms
Faculty of Medicine, Ain Shams University,
ofAsthma, Departmentof PediatricAllergy,
Cairo, Egypt.
St Thomas(cid:2) Hospital, London SE1 7EH,
Matthew Fenton, MD, Asthma, Allergy and
United Kingdom.
Inflammation Branch, National Institute of
Massimo Landi, MD, National Pediatric
Allergy and Infectious Diseases, NIH, 6610
Healthcare System, Italian Federation of
Rockledge Dr., Bethesda, MD 20892.
Pediatric Medicine, Territorial Pediatric
Rosa Elena Huerta Hernandez, MD, Pediatric
Primary Care Group, Turin, Italy.
Allergy Clinic, Mexico City, Mexico.
Alberto Martelli, MD, Pediatric Division,
Manuel Martin-Esteban, MD, Allergy Depart-
Department of Child and Maternal
ment, Hospital Universitario La Paz, Ma-
Medicine, University of Milan Medical
drid, Spain.
SchoolattheMelloniHospital,Milan20129,
Anna Nowak-Wegrzyn, MD, Jaffe Food
Italy.
Allergy Institute, Mount Sinai School of
Fabienne Rance´, MD, Allergologie, Hoˆpital des
Medicine, One Gustave L. Levy Place, NY
Enfants, Poˆ le Me´dicochirurgical de Pe´diat-
10029-6574.
rie,330 av. deGrande Bretagne,TSA70034,
Ruby Pawankar, MD, Department of Otolar-
31059 Toulouse CEDEX, France.
yngology, Nippon Medical School, 1-1-5
Hugh Sampson, MD, Jaffe Food Allergy Insti-
Sendagi, Tokyo, 113 Japan.
tute, Mount Sinai School of Medicine, One
Susan Prescott, MD, School of Pediatrics and
Gustave L. Levy Place, NY 10029-6574.
Child Health, University of Western Aus-
Airton Stein, MD, Conceicao Hospital, Porto
tralia, Princess Margaret Hospital for Chil-
Alegre, Brazil.
dren, Perth, Australia.
Luigi Terracciano, MD,a Pediatric Division,
Patrizia Restani, PhD, Department of Pharma-
Department of Child and Maternal Medi-
cological Sciences, Universita` degli Studi di
cine, University of Milan Medical School
Milano.
at the Melloni Hospital, Milan 20129,
Teresita Sarratud, MD, Department of Pediat-
Italy.
rics,University of CaraboboMedicalSchool
Stefan Vieths, MD, Division of Allergology,
at the Carabobo Hospital, Valencia, Vene-
Paul-Ehrlich-Institut, Federal Institute for
zuela.
Vaccines and Biomedicines, Paul-Ehrlich-
Aline Sprikkelmann, MD, Department of Pedi-
Str. 51-59, d-63225 Langen, Germany.
atric Respiratory Medicine and Allergy,
aMember of the Grades of Recommendation,
Emma Children(cid:2)s Hospital Academic Medi-
Assessment, Development and Evaluation
cal Centre, Amsterdam, The Netherlands.
(GRADE) Working Group
2
WAO DRACMA Guidelines
Sections tions and date back to the turn of the century (7,
8). In 2008, the World Allergy Organization
1: Introduction, p. 3
(WAO) Special Committee on Food Allergy
2: Methodology, p. 4
identifiedCMAasanareainneedofarationale-
3: Epidemiology of CMA, p. 6
based approach, informed by the consensus
4: Allergens of Cow(cid:2)s Milk, p. 12
reachedthroughanexpertreviewoftheavailable
5: Immunological Mechanisms of CMA, p. 18
clinical evidence, to make inroads against a
6: ClinicalHistoryandSymptomsofCMA,p.25
burdensome, world-wide public health problem.
7: Diagnosis of CMA According to Preceding
It is in this context that the WAO Diagnosis and
Guidelines, p. 37
Rationale for Action against Cow(cid:2)s Milk Allergy
8: TheEliminationDietinWork-UpofCMA,p.41
(DRACMA) Guidelines was planned to provide
9: Guidelines for Diagnosing CMA, p. 42
physicianseverywherewithamanagementtoolto
10: Oral Food Challenge Procedures in Diagno-
deal with CMA from suspicion to treatment.
sis of CMA, p. 56
Targeted(andtappedfortheirexpertise),bothon
11: Natural History of CMA, p. 66
the DRACMA panel or as nonsitting reviewers,
12: Treatment of CMA According to Preceding
wereallergists,pediatricians(allergistsandgener-
Guidelines, p. 71
alists), gastroenterologists, dermatologists, epi-
13: WhenCanMilkProteinsBeEliminatedFrom
demiologists, methodologists, dieticians, food
DietWithoutSubstitutingCow(cid:2)sMilk?,p.75
chemists, and representatives of allergic patient
14: Guidelines for Choosing a Replacement
organizations. Ultimately, DRACMA is dedi-
Formula, p. 79
catedtoourpatients,especiallytheyoungerones,
15: Milks From Different Animals for Substi-
whoseburdenofissueswehopetorelievethrough
tuting Cow(cid:2)s Milk, p. 84
an ongoing and collective effort of more interac-
16: Nutritional Considerations in CMA Treat-
tivedebateandintegratedlearning.
ment, p. 89
17: Choosing the Appropriate Substitute For-
mula in Different Presentations, p. 92 Definitions
18: Grade Recommendations on Immuno-
Adversereactionsaftertheingestionofcow(cid:2)smilk
therapy for CMA, p. 93
can occur at any age from birth and even among
19: Unmet Needs, Recommendations for Re-
infants fed exclusively at the breast, but not all
search, Implementation of DRACMA, p. 95
suchreactionsareofanallergicnature.Arevision
Acknowledgements, p. 97
oftheallergynomenclaturewasissuedinEurope
Appendix 1: Cow(cid:2)s Milk Allergy Literature
in 2001 (9) and was later endorsed by the WAO
Search Algorithms, p. 98
(10) under the overarching definition of ‘‘milk
Appendix 2: Evidence Profiles: Diagnosis of
hypersensitivity,’’ to cover nonallergic hypersen-
CMA, p. 104
sitivity (traditionally termed ‘‘cow(cid:2)s milk intoler-
Appendix 3: Evidence Profiles: Treatment of
ance’’) and allergic milk hypersensitivity (or
CMA, p. 114
‘‘cow(cid:2)s milk allergy’’). The latter definition re-
Appendix4: EvidenceProfiles:OITforTreatment
quires the activation of an underlying immune
ofCMA,p.123
mechanism to fit. In DRACMA, the term
‘‘allergy’’ will abide by the WAO definition
(‘‘allergy is a hypersensitivity reaction initiated by
Section 1: Introduction
specific immunologic mechanisms’’). In most chil-
Allergy and clinical immunology societies dren with CMA, the condition can be immuno-
have issued guidance for the management globulin E (IgE)-mediated and is thought to
of food allergy.1,2 Guidelines are now regarded manifest as a phenotypical expression of atopy,
astranslationalresearchinstruments,designedto togetherwith(orintheabsenceof)atopiceczema,
provide cutting-edge benchmarks for good prac- allergic rhinitis and/or asthma. A subset of
ticeandbedsideevidenceforclinicianstouseinan patients,however,havenon-IgEmediated(prob-
interactivelearningcontextwiththeirnationalor ably cell-mediated) allergy and present mainly
international scientific communities. In the man- withgastro-intestinalsymptomsinreactiontothe
agement of cow(cid:2)s milk allergy (CMA), both ingestionofcow(cid:2)smilk.
diagnosis and treatment would benefit from a
reappraisal of the more recent literature, for References, Section 1
‘‘current’’guidelinessummarizetheachievements 1. American College of Allergy, Asthma, &
oftheprecedingdecade,dealmainlywithpreven- Immunology.Foodallergy:apracticeparameter.Ann
tion (3–6), do not always agree on recommenda- AllergyAsthma Immunol.2006;96(Suppl 2):S1–S68.
3
WAO DRACMA Guidelines
2. MukoyamaT,NishimaS,AritaM,ItoS,UrisuA, ature. The panel decided to use a GRADE
et al. Guidelines for diagnosis and management of methodology for defining some treatments and
pediatricfoodallergyinJapan.AllergolInt.2007:56:
diagnostic questions.
349–361.
The DRACMA worked with the GRADE
3. Prescott SL. The Australasian Society of Clinical
members on this panel the clinical questions
Immunology and Allergy position statement: Sum-
mary of allergy prevention in children. Med J Aust. and their scope after various fine-tuning stages.
2005:182: 464–467. The GRADE panelists independently searched
4. Muraro A, Dreborg S, Halken S, Høst A, Nigge- the relevant literature for sections 9, 14, 18.
mannB,etal.Dietarypreventionofallergicdiseasesin
Their analysis was independent of the other
infants and small children. Part III: Critical review of
panel lists. For question formulation, guideline
published peer-reviewed observational and interven-
tional studies and final recommendations. Pediatr Al- panel members explicitly rated the importance
lergyImmunol. 2004: 15:291–307. of all outcomes on a scale from 1-9, where the
5. Muraro A, Dreborg S, Halken S, Høst A, Nigge- upper end of the scale (7–9) identifies outcomes
mannB,etal.Dietarypreventionofallergicdiseasesin of critical importance for decision making,
infants and small children. Part I: immunologic back-
ratings of 4-6 represent outcomes that are
ground and criteria for hypoallergenicity. Pediatr Al-
important but not critical and ratings of 1-3
lergyImmunol. 2004: 15:103–11.
6. Muraro A, Dreborg S, Halken S, Høst A, Nigge- are items of limited importance. Evidence
mann B, Aalberse R, et al. Dietary prevention of summaries were prepared following the
allergic diseases in infants and small children. Part II. GRADE Working Group(cid:2)s approach (1–6)
Evaluation of methods in allergy prevention studies
based on systematic reviews done by an inde-
and sensitization markers. Definitions and diagnostic
pendent team of the GRADE Working Group
criteria of allergic diseases. Pediatr Allergy Immunol.
members (JLB and HJS supported by 5
2004:15: 196–205.
7. HøstA,KoletzkoB,DreborgS,MuraroA,Wahn research associates).
U,etal.Dietaryproductsusedininfantsfortreatment The GRADE approach suggests that before
andpreventionoffoodallergy.JointStatementofthe grading the quality of evidence and strength of
European Society for Paediatric Allergology and
each recommendation, guideline developers
Clinical Immunology (ESPACI) Committee on
should first identify a recent well-done system-
Hypoallergenic Formulas and the European Society
for Paediatric Gastroenterology, Hepatology and atic review of the appropriate evidence answer-
Nutrition(ESPGHAN)CommitteeonNutrition.Arch ing the relevant clinical question, or conduct
DisChild. 1999:81: 80–84. one when none is available. This should be
8. American Academy of Pediatrics Committee on followed by preparing a transparent evidence
Nutrition. Hypoallergenic infant formulae. Pediat-
summary, such as creation of GRADE evi-
rics.2000: 106:346–349.
9. JohanssonSG,HourihaneJO,BousquetJ.Arevised dence profiles, on which the guideline panel will
nomenclature for allergy. An EAACI position state- base their judgments (7). We prepared 3
ment from the EAACI nomenclature task force. Al- systematic reviews addressing the clinical ques-
lergy.2001: 56: 813–824. tions covered by the guideline (about the
10. Johansson SG, Bieber T, Dahl R. Revised nomen- diagnosis, use of formula and immunotherapy
clature for allergy for global use: report of the
of the CMA). We searched MEDLINE, EM-
Nomenclature Review Committee of the World Al-
BASE, and the Cochrane Library (including
lergy Organization, 2003. J Allergy Clin Immunol.
2004:113: 832–836. Cochrane Central Register of Controlled Trials,
DARE, NHS EED) for relevant studies. We
included studies published up to September
Section 2: Methodology
2009. We developed GRADE evidence profiles
The outline of the consensus guideline was the (summary of findings tables) for the clinical
result of the considered opinion of the whole questions based on the systematic reviews. The
panel. Narrative parts, that is, sections 1-8, 9- summaries of evidence were reviewed by the
13, 15-17, and 19 included the relevant CMA panel members and corrections and comments
literature as searched using the algorithms were incorporated.
reported in Appendix 1. For these sections, We assessed the quality of the evidence
the relative weight of the suggestions retained according to the methodology described by the
for the purpose of DRACMA reflects the GRADE system (1–3, 8). In this system quality
expert opinion of the panel. They may contain of supporting evidence is assessed based on
general indications, but no evidence-based explicit methodological criteria and classified as
recommendations. The consensus on these either ‘‘high,’’ ‘‘moderate,’’ ‘‘low,’’ or ‘‘very
indications was expressed by the panelists using low.’’
a checklist itemizing the clinical questions The DRACMA guideline panel reviewed the
considered relevant after analysis of the liter- evidence summaries and the draft guidelines,
4
WAO DRACMA Guidelines
and made recommendations. We reached con- Table2-1. Interpretationof''Strong''and''Weak''Recommendations
sensus on all recommendations. Formulating
Implications StrongRecommendation WeakRecommendation
the recommendations included explicit consid-
eration of the quality of evidence, benefits,
Forpatients Mostindividualsinthissit- Themajorityofindividualsin
harms, burden, cost, and values and prefer- uationwouldwanttherec- thissituationwouldwantthe
ences described as the ‘‘Underlying values and ommendedcourseofaction suggestedcourseofaction,
preferences’’ or in the ‘‘Remarks’’ sections of andonlyasmallproportion butmanywouldnot.
wouldnot.Formaldecision
each recommendation as outlined earlier (9).
aidsarenotlikelytobe
Statements about the underlying values and
neededtohelpindividuals
preferences and the remarks are integral parts makedecisionsconsistent
of the recommendations and serve to facilitate withtheirvaluesandpref-
accurate interpretation of the recommenda- erences.
Forclinicians Mostindividualsshouldre- Recognizethatdifferentchoi-
tions. They cannot be omitted when citing or
ceivetheintervention. ceswillbeappropriatefor
translating DRACMA guidelines. In this doc-
Adherencetothisrecom- individualpatients,andthat
ument, the expression ‘‘values and preferences’’ mendationaccordingtothe youmusthelpeachpatient
refers to the relative weight one attributes to guidelinecouldbeusedasa arriveatamanagementdeci-
particular benefits, harms, burdens, and costs qualitycriterionorperfor- sionconsistentwithhisorher
manceindicator. valuesandpreferences.Deci-
to determine their balance. We used the
sionaidsmaybeusefulhelp-
decision framework described previously to
ingindividualsmaking
determine the strength of recommendations decisionsconsistentwiththeir
(1, 10). valuesandpreferences.
Littleinformationaboutcostsofdiagnosisand Forpolicy Therecommendationcanbe Policymakingwillrequire
makers adaptedaspolicyinmost substantialdebatesand
treatmentofIgE-mediatedcow(cid:2)smilkallergywas
situations. involvementofvariousstake-
available to the panel and it is very likely that it
holders.
varies considerably across geographical areas
and jurisdictions. Cost, therefore, plays a limited
role in these recommendations. However, when- How to Use These Recommendations
ever we considered cost and resource expendi-
The DRACMA guidelines are not intended to
ture, we used health system perspective (11). For
impose a standard of care for individual coun-
individual patients, cost may not be an issue if
tries and jurisdictions. They should, as any
the service or treatment strategy is provided at
guideline, provide a basis for rational decisions
reduced price or free of charge. Clinicians and
for clinicians and their patients about the man-
patients should consider their local resource
agement of cow(cid:2)s milk allergy. Clinicians,
implications when interpreting these recommen-
patients, third-party payers, institutional review
dations.
committees, other stakeholders, or the courts
After the GRADE approach we classified
should never view these recommendations as
recommendations in these guidelines as either
dictates. Strong recommendations based on high
‘‘strong’’ or ‘‘conditional’’ (also known as
quality evidence will apply to most patients for
weak)/weak. The strength of recommendations
whom these recommendations are made, but
depends on a balance between all desirable and
they may not apply to all patients in all
all undesirable effects of an intervention (ie, net
circumstances. No recommendation can take
clinical benefit), quality of available evidence,
into account all of the often-compelling unique
values and preferences, and cost (resource
features of individual clinical circumstances.
utilization) (1). In general, the higher the
Therefore, nobody charged with evaluating cli-
quality of the supporting evidence, the more
nicians(cid:2) actions should attempt to apply the
likely it is for the recommendation to be
recommendations from the DRACMA guide-
strong. Strong recommendations based on low
lines as rote or in a blanket fashion.
or very low quality evidence are rare, but
possible (12).
References, Section 2
For strong recommendations we used words
1. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y,
‘‘we recommend’’ and for conditional recom- Vist GE, Liberati A, Schunemann HJ. Going from
mendations, ‘‘we suggest.’’ We offer the sug- evidence to recommendations. BMJ. 2008: 336: 1049–
gested interpretation of ‘‘strong’’ and ‘‘weak’’ 1051.
recommendations in Table 2-1. Understanding 2. GuyattGH,OxmanAD,KunzR,VistGE,Falck-
the interpretation of these 2 grades (strong or Ytter Y, Schunemann HJ. What is ‘‘quality of evi-
dence’’ and why is it important to clinicians? BMJ.
conditional) of the strength of recommendations
2008: 336:995–998.
is essential for clinical decision making.
5
WAO DRACMA Guidelines
3. GuyattGH,OxmanAD,VistGE,KunzR,Falck-
Ytter Y, Alonso-Coello P, Schunemann HJ. the German Multi-Centre Allergy Study. The
GRADE: an emerging consensus on rating quality of most reliable data in epidemiology are those
evidence and strength of recommendations. BMJ. from birth cohorts thatare free from selection
2008:336: 924–926. bias. There are 5 such challenge-confirmed
4. Schu¨nemann HJ, Fretheim A, Oxman AD. Improv-
studies. The CMA prevalence during infancy
ing the use of research evidence in guideline develop-
ranged from 1.9% in a Finnish study, 2.16%
ment: 9. Grading evidence and recommendations.
HealthRes Policy Syst.2006: 4: 21. in the Isle of Wight, 2.22% in a study from
5. Schu¨nemann HJ, Oxman AD, Fretheim A. Improv- Denmark, 2.24% in the Netherlands, and up
ing the use of research evidence in guideline develop- to 4.9% in Norway.
ment: 6. Determining which outcomes are important.
Patients with CMA develop gastrointestinal
HealthRes Policy Syst.2006: 4: 18.
symptoms in 32 to 60% of cases, skin symp-
6. World Health Organization. Global Programme
toms in 5 to 90%, and anaphylaxis in 0.8 to
on Evidence for Health Policy. Guidelines for WHO
Guidelines. EIP/GPE/EQC/2003.1.Geneva, 2003. 9% of cases. This frequency of anaphylaxis is
7. Schu¨nemann HJ, Hill SR, Kakad M, Vist GE, the main concern pointed out in many CMA
Bellamy R, et al. Transparent development of the studies. In a review, nearly one third of
WHO rapid advice guidelines. PLoS Med. 2007: 4:
children with atopic dermatitis (AD) received
e119.
8. Schu¨nemannHJ,OxmanAD,BrozekJ,GlasziouP, a diagnosis of CMA after an elimination diet
Jaeschke R, et al. Grading quality of evidence and and an oral food challenge, and about 40 to
strength of recommendations for diagnostic tests and 50% of children less than a year of age with
strategies. BMJ.2008: 336: 1106–1110. CMA also had AD. Finally, with actual
9. Schu¨nemannHJ,MungerH,BrowerS,O(cid:2)Donnell populationandgeographicaltrendsremaining
M,CrowtherM,CookD,GuyattG.Methodology
unknown, allergists are primarily in need of
for guideline development for the Seventh American
more detailed epidemiological surveys on a
College of Chest Physicians Conference on Anti-
thrombotic and Thrombolytic Therapy: the Seventh global scale. One large such epidemiological
ACCP Conference on Antithrombotic and Thrombo- studysupportedbytheEuropeanCommission
lyticTherapy. Chest.2004: 126:174S–178S. is ongoing and aims to furnish the first
10. Schu¨nemann HJ, Jaeschke R, Cook DJ, Bria WF,
prevalence data regarding the suspicion of
El-SolhAA,etal.AnofficialATSstatement:grading
CMA, sensitization to cow(cid:2)s milk, and oral
the quality of evidence and strength of recommenda-
food challenge-confirmed diagnosis in 10
tions in ATS guidelines and recommendations. Am J
RespirCrit Care Med.2006: 174: 605–614. European birth cohorts.
11. Guyatt GH, Oxman AD, Kunz R, Jaeschke R,
HelfandM,LiberatiA,VistGE, SchunemannHJ.
Incorporating considerations of resources use into
grading recommendations. BMJ. 2008: 336: 1170–
Introduction
1173.
12. BrozekJL,Baena-CagnaniCE,BoniniS,Canonica Around 11–26 million of the European popula-
GW, Rasi G, et al. Methodology for development of tion areestimatedto suffer fromfoodallergy(1).
the Allergic Rhinitis and its Impact on Asthma
If this prevalence was consistent around the
guideline2008update.Allergy. 2008:63: 38–46.
world and projected to the 6,659,040,000 people
of the world(cid:2)s population (2), it translates into
Section 3: Epidemiology of CMA 220–520 million people and represents a major
globalhealthburden. Althoughtherearesurveys
Overview on the natural history and prevalence trends for
symptomsofasthma,allergicrhinoconjunctivitis,
There are no surveys of population and
and eczema in childhood (3), we do not have a
geographical trends in food allergy in adults
study assessing the prevalence of food allergy
orchildren(thoughthesituationisdifferentin
and its time-trends. The problem is complicated
pediatric asthma and rhinitis) and this unmet
by the fact that perceived food allergy (ie, the
need is particularly felt for CMA. The per-
self-reported feeling that a particular food neg-
ception of milk allergy is far more frequent
ativelyinfluenceshealthstatus)isnotactualfood
thanconfirmedCMA.PatientreportsofCMA
allergy. Allergy prevalence is much greater in the
rangebetween1and17.5%,1and13.5%,and
public(cid:2)s belief than it has ever been reported by
1 to 4% in preschoolers, at children 5 to
double-blind studies. Back in the 1980s, the
16 years of age and adults respectively. Cow(cid:2)s
perceived incidence of allergy to food or food
milk-specific IgE sensitization point preva-
additives in mothers with young children was
lence progressively decreased from about 4%
reported between 17 (4) and 27.5% (5). Thirty
at2 yearstolessthan1%at10 yearsofagein
percent of women reported that they or some
6
WAO DRACMA Guidelines
member of their family were allergic to some reports from Greece to 52.3% from Finland. In
food product (6). In the after decade, a British this survey milk was the most often reported
studyusingafoodallergyquestionnairereported offendingfoodinchildren(38.5%ofreports)and
a 19.9% incidence of food allergy (7). From the the second food most often implicated by adults
mid-1990s onwards, self reports began to be (26%) (20). In a group of 600 children less than
compared with challenge-confirmed diagnoses; 4 years, CMA was reported by the parents of 18
reportedincidencedataofbetween12.4and25% children (3%) (21). Milk reactions were reported
couldbeconfirmedbyoralfoodchallengeinonly by the parents of 2% of children without wheeze
1.5 to 3.5% of cases, illustrating how reports of andby16%ofwheezers(22).
adverse reactions overestimate true food allergy Intheliterature,thebulkofstudiesbasedonly
(8, 9). This was further confirmed when preva- on self-reports of CMA is staggering, compared
lence figures of 2.3 to 3.6% were confirmed by with reports that include an objective measure to
challenge procedures in unselected patient pop- assess the condition (23). Currently, at least a
ulations (10, 11). In the 1990s, it was also score of studies have evaluated the self-percep-
confirmed that only a minority of subjects who tion of CMA over the last 20 years in preschool-
report food-related illness also test positive by ers (24–33), school-agechildren (5-16 years), (20,
skin prick test using the same food (12). 34–38),andyoungadults(20,39–45).Fromthese
Thus,2separate‘‘foodallergyepidemiologies’’ studies, reviewed in the only meta-analysis in the
can be distinguished: field,35 the prevalence of self-reports varies
between 1 to 17.5% in preschoolers, 1 and
a. Self-reported food allergy; although this does 13.5% in 5 to 16-year-olds, and between 1 and
notrepresentactualfoodallergyepidemiology, 4% in adults.
itis useful asa proxymeasure of thepotential The children from these studies neither under-
demand for allergy medical services, and may went sensitization testing nor oral food chal-
guide public health allergy service users be- lenge. In a population of 6-year-olds, 1 out of 7
tweengeneralandspecialistmedicine(13),and cases was based on self-reports whereas less than
moregenerallyforpublichealthplanning. one out of 2 children with a positive cow(cid:2)s milk
b. Actual food allergy (ie, confirmed by a posi- specific skin prick test was confirmed allergic by
tive oral food challenge) represents the real DBPCFC, thereby confirming that most parent-
extent of this clinical problem. reported symptoms of CMA are unreliable (46).
Not only parents, but also health care profes-
In general, food allergy is more frequent in the sionals, allergists, and nonallergists alike, cite
pediatric, rather than the adult, population. cow(cid:2)s milk-induced reactions as the most com-
According to a recent Japanese multicenter trial, mon food allergy affecting children (47). Thus,
the prevalence of CMA is 0.21% in newborns the incidence of self-reports of CMA remains of
and 0.35% amid extremely premature babies interest for public health authorities, health
(<1000 g) (14). Food allergies are a cause of maintenance organizations and the processed
particular concern for children. Incidence is food industry as a metric for policy planning,
estimated to be greater in toddlers (5-8%) than planningdiagnosticservices;(48)tablinglabeling
it is in adults (1-2%) (15–17). Earlier prospective legislation and even meeting the demand for
challenge-based studies have shown that in a milk-free products. However, as such, this proxy
population of 480 newborns followed up in the cannot represent the full extent of the clinical
setting of a U.S. general pediatric practice issues at stake.
through their third birthday, a parental report
of 28% food allergy translates into a challenge-
Sensitization to Cow(cid:2)s Milk Proteins
confirmedCMArateof8%(18,19),with2.27to
2.5% occurring in the first 2 years of life. The number of studies on CM sensitization in
unselectedpopulationsislimited.Themeta-anal-
ysis carried out by Rona and colleagues (23)
Perceived Cow(cid:2)s Milk Allergy
identified7studiesreportingasensitizationrateof
Similar considerations can be applied to cow(cid:2)s 0.5to2%ofpreschoolers,of0.5%at5to16 years
milkallergyperception.Self-reportiscommon.In ofage,andinlessthan0.5%ofadults(23,25–33).
alargeEuropeansurveyofabove44,000telephone In a later cohort of 543 children from the Isle of
contacts,5millionEuropeanrespondentsclaimed Wight followed-up from birth and tested at 1, 2,
tobemilk-allergic,withadultwomenasthegroup and 3 years of age, a positive milk sensitization
makingmostoftheseclaims.Therewerealsowide testwasfoundin2infantsat12 months(0.37%),
national differences ranging from 13.8% of in 5 at 2 years (0.92%), and in 3 at 3 years
7
WAO DRACMA Guidelines
(0.55%)(49).IntheGerman MulticenterAllergy include IgE sensitization assessments; some stud-
Study, 1314 children initially recruited were fol- ies are based on open oral food challenges, some
lowed from birth for 13 years. The longitudinal performed blinded oral food challenge tests.
data were analyzed for 273 children testing Methods used across studies in this literature of
positive for serum cow(cid:2)s milk specific IgE anti- oral food challenges with (59) cow(cid:2)s milk are not
bodyandwereobtainedatage2,5,7,and10.The standardized(seesectiononDiagnosis).
point prevalence of sensitization to cow(cid:2)s milk Thus, among the unmet needs of epidemiolog-
progressivelydecreasedfromabout4%at2 years ical research in this field are high-quality com-
to less than 1% at 10 years (50). munity studies based on patient data objectively
confirmed by DBPCFC to close the current
knowledge gap on the prevalence of CMA in
Epidemiology of Challenge-Confirmed CMA
the population. To address this, the European
The epidemiology of oral food challenge-con- Commission launched the EuroPrevall Project
firmed CMA of the last 10 years consists of the (http://www.europrevall.org) in 2005 in concert
following 5 studies: with more than 60 partners including patient
organizations, the food industry and research
a. InaDanishstudyof1,749newbornsfollowed institutions from across Europe, Russia, Ghana,
for 12 months, 39 (or 2.22%) were confirmed India, and China. This translational endeavor
allergic (51) involves basic and clinical research components,
b. In a study from Finland 6,209 newborns fol- and large epidemiological studies of both chil-
lowed for 15 months, 118 (1.9%)had positive drenandadults(60).Thefirstresults,willinclude
DBPCFC (52) data on suspicion of CMA, on sensitization to
c. In a Norwegian study of 193 premature and cow(cid:2)s milk and of oral food challenge-confirmed
416full-terminfants,27of555(or4.9%)were diagnosis from 10 birth cohorts (61).
diagnosed with an allergic reaction to cow(cid:2)s
milkonthebasisofanopenchallengebutnot
Different Clinical Presentations of CMA
all children were tested; interestingly, all had
symptoms before 6 months of age (53) In a Danish birth cohort, 60% of children with
d. In an Isle of Wight cohort of 969 newborns CMA presented with gastrointestinal symptoms,
followed for 12 months, 21 (2.16%) reported 50 to 60% with skin issues, and respiratory
CMA but only 2 (0.21%) were actually with symptoms present in 20 to 30% while 9%
IgE-mediated CMA (54) developed anaphylaxis (62, 63). In the Norwe-
e. In a newborn cohort from the Netherlands gian cohort noted above, young infants experi-
1,158 infants prospectively followed through enced pain (48%), gastrointestinal symptoms
12 months of age reporting ‘‘cow(cid:2)s milk pro- (32%), respiratory problems (27%), and atopic
tein intolerance’’ (defined as two positive dermatitis (4.5%) (53). In the Finnish cohort,
cow(cid:2)s milk elimination/challenge tests) re- presentation symptoms included urticaria
ported 26 allergic children (or 2.24%) of 211 (45.76%), atopic dermatitis (89.83%), vomiting
(or 18.2%) suspected cases (33). and/or diarrhea (51.69%), respiratory symptoms
(30.50%), and anaphylaxis (2.54%). The same
In this series of challenge-based studies, the children reacted at oral food challenge with
Danishstudyfurthersuggestedthatreproducible symptoms of urticaria (51.69%), atopic derma-
clinical reactions to CMP in human milk were titis (44.06%), vomiting and/or diarrhea
reported in (cid:2)0.5% of breast-fed infants (55). (20.33%), respiratory symptoms (15.25%), and
Data from cross-sectional studies (analyzed by anaphylaxis (0.84%) (52). In the British study
Rona and coworkers (2)) demonstrated a rate of quoted above, infants reacted to oral food
0.6to2.5%prevalenceinpreschoolers,0.3%at5 challenges with eczema (33%), diarrhea (33%),
to 16 years of age, and of less than 0.5% in vomiting (23.8%), and urticaria in 2 children
adults (23, 56–58). who immediately reacted to the challenge meal
While most of our information on cow(cid:2)s milk (one with wheeze and the other with excessive
allergyprevalencecomesfromnorthernEuropean crying) (54). Dutch infants with CMA from the
andSpanishstudies,therearemethodologicaland study noted above developed gastrointestinal
geographical differences in clinical evaluation, (50%), skin (31%), and respiratory (19%)
which must be considered in assessing the epide- symptoms (33).
miologicalfeatureswediscusshere.Somestudies Several other studies have assessed the inci-
may consider only immediate reactions, while dence of CMA in populations selected for
others include delayed reactions; not all studies referral by other care givers to a tertiary
8
WAO DRACMA Guidelines
institution for specialist assessment of their children 0-15 years per year). Milk caused the
symptoms and therefore requires caution in greatest number of fatal reactions (four of eight)
generalizing the results of such studies. As a (70), in line with reports of both the frequency
case in point, in a long-term study of 97 and severity (71) of reactions to milk.
children with challenge-confirmed CMA, 21%
had atopic dermatitis at the final follow-up
Secular Trends of CMA
evaluation (at 8 years) (62). In another follow-
up study of 42 infants with IgE-mediated CMA, Insuchaleopard-skinepidemiologicalcontext,it
57% of children had developed atopic dermati- is hardly surprising that there is no continuum
tis at the median age of 3.7 years (63). that can be identified across studies regarding
Thus, CMA appears with GI symptoms in 32 time variations in CMA frequency (72). Is CMA
to 60% of cases, cutaneous symptoms in 5 to prevalence on the rise? Utilizing surrogate indi-
90%, anaphylaxis in 0.8 to 9% of cases. Respi- cators, we can only infer changes in CMA
ratory complaints, including asthma, are not prevalence based on studies of general food
rare. Clearly, in most of the populations studied, allergy. Among those, a British study found that
there are overlapping presenting symptoms and the admission rates per million population
multiple symptoms are often confirmed during between 1990 and 2004 rose form 5 to 26 for
challenge. anaphylaxis, from 5 to 26 for food allergy, and
from 16 to 107 specifically for pediatric food
allergy(73).Reinforcingthispicture,eczemarose
CMA in Different Clinical Conditions
from 13% in 1991 to 16% in 2003(3).
Reversing the point of view, milk sensitization
and CMA are reportedwith differentfrequencies
Geographical Trends in CMA
in different clinical presentations. In 2184 young
children aged 13-24 months with atopic dermati- Is milk the most important offender in food
tis,thefrequencyofpositiveserumIgEresponses allergy in children? From self-reports, it appears
against cow(cid:2)s milk protein was 3% (64). Among that this may be the case. However, given the
59 breast-fed children with moderate-severe AD, paucity of epidemiological studies, we do not
5 (8,5%) were SPT-positive with milk extracts have sufficient information to argue the relative
(65).Inaconsecutiveserieswithmoderateatopic importance of CMA in different parts of the
eczema referred to a University-affiliated derma- world. The maximum information comes from
tology department, SPT showed 16% of infants Spain, Scandinavian countries, the UK, and
withIgEagainstCMP(66).Inagroupofinfants Germany.Inadequateinformationfromdifferent
and children (mean age 17.6 months) with AD areas in the world are available, including Italy,
and no other allergic manifestations, 20/54 chil- Australia and North America where many
dren(37%)hadadiagnosisofCMA(67).Among cross-sectional and referral studies come from.
90 children with IgE-mediated food allergy, 17% Table 3-1 shows the comparison of the 3 main
wereallergictocow(cid:2)smilk(68).Thus,asreviewed food allergens in the child studies. The pan-
some years ago, nearly one third of AD children European RedAll survey estimated milk as the
have a diagnosis of CMA according to elimina- most frequently reported offender in children
tiondietandchallengetests,andabout40-50%of (38.5% of reports) and the second in adults
children<1 yearofagewithCMAhaveAD(67). (26.2%) (20). In France, 29/182 school-aged
Anexceptiontotheuncertaintyofinformation children with reported food allergy are milk-
aboutepidemiologyof CMAis anaphylaxis. Ina allergic in 11.9% of cases (24). Accordingly, the
prospective survey of hospital admissions for Rona (23) metanalysis indicates milk as the
food-allergic reactions, conducted through the major food offender in challenge-based studies,
British Pediatric Surveillance Unit, covering the followed by egg and fish. However, cow(cid:2)s milk
13 million children in the United Kingdom and accounts for less than one third of any food that
Ireland, 229 cases were reported by 176 physi- canbeblamedforfoodallergyamongthestudies
cians in 133 departments, yielding a rate of 0.89 significantly combined (P < 0.001) (74). Simi-
hospital admissions per 100,000 children per larly a review of studies of various designs
year. With a 10% rate, milk was the third most (surveys,reviews,clinico-epidemiologicalstudies)
frequent allergenic trigger, after peanut (21%) indicated egg as the most frequently found
andtreenuts(16%)(69).IntheUK,thereare13 allergen in children (75). The pattern is repeated
million individuals less than 16 years of age, and in Japan, where CM accounts for 22.6% of
over the past 10 years 8 children died of ana- children with food allergy (76). The same may
phylaxis (incidence of 0.006 deaths per 100 000 notbetrue in other partsof theworld, where the
9
WAO DRACMA Guidelines
prevalencewilllargelyreflectlocalfactorssuchas lected pollen-sensitized adults. Allergy. 2005: 60:
exposure to foods, mode of preparation, and 218–225.
11. Zuberbier T. Prevalence of adverse reactions to food
cultural attitudes. As an example, in Israel
in Germany.Allergy. 2004: 59: 338–345.
sesame is the third most frequently implicated
12. Woods RK, Stoney RM, Raven J, Walters EH,
offending food, probably because of its wide- Abramson M, Thien FC. Reported adverse reactions
spread consumption. Among young Australian overestimatetruefoodallergyinthecommunity.EurJ
adults, the major offender was peanut, followed ClinNutr. 2002:56: 31–36.
by shrimp, wheat, egg, and milk (44). In Iranian 13. FiocchiA,BouygueGR,TerraccianoL,Sarratud
T, Martelli A. The march of allergic children -
children CM is the most common offender
excluding allergy in paediatric practice. Allergy Asth-
identified during diagnostic provocation chal-
ma Proc.2006: 27: 306–311.
lenge (77). Thus, it may be said that the most 14. Miyazawa T, Itahashi K, Imai T. Management of
representative allergen is a hand-maiden to local neonatal cow(cid:2)s milk allergy in high-risk neonates.
customs. PediatrInt. 2009:51: 544–547.
15. Brugman E, Meulmeester JF, Spee-van der WA,
Beuker RJ, Radder JJ, Verloove-Vanhorick SP.
Prevalence of self-reported food hypersensitivity
Table3-1. ComparisonoftheThreeMainFoodAllergensInChildrenStudies
amongschoolchildreninTheNetherlands.EurJClin
75
Nutr.1998: 52: 577–581.
Country 1st 2nd 3rd 16. Eggesbo M, Botten G, Halvorsen R, Magnus P.
The prevalence of allergy to egg: a population-based
USA Egg Cow(cid:2)smilk Peanuts studyin youngchildren. Allergy. 2001: 56: 403–411.
Germany Egg Cow(cid:2)smilk Wheat 17. Halmerbauer G, Gartner C, Schierl M, Arshad
Spain Egg Cow(cid:2)smilk Fish H,DeanT,etal.StudyonthePreventionofAllergyin
Switzerland Egg Cow(cid:2)smilk Peanuts ChildreninEurope(SPACE):Allergicsensitizationin
Israel Egg Cow(cid:2)smilk Sesame childrenat1yearofageinacontrolledtrialofallergen
Japan Egg Cow(cid:2)smilk Wheat avoidancefrombirth.PediatrAllergyImmunol.2002:
13(s15): 47–54.
18. Bock SA. The natural history of food sensitivity. J
AllergyClin Immunol.1982: 69:173–177.
19. Bock SA. Prospective appraisal of complaints of ad-
References, Section 3
verse reactions to foods in children during the first
1. Eigenmann PA. Future therapeutic options in food three years oflife. Pediatrics. 1987:79: 683–688.
allergy.Allergy. 2003: 58: 1217–1223. 20. Steinke M, Fiocchi A, the REDALL group. Per-
2. WHO, World Health Statistics 2009. Available at ceived Food allergy in children. A report on a repre-
http://www.who.int/whosis/whostat/2009/en/ sentativetelephonesurveyin10Europeancountries.Int
print.html, accessed June30, 2009. ArchAllergyAsthmaImmunol.2007:143:290–295.
3. ISAAC Phase Three Study Group. Worldwide time 21. KilgallenI,GibneyMJ.Parentalperceptionoffood
trends in the prevalence of symptoms of asthma, allergyorintoleranceinchildrenunder4yearsofage.
allergic rhinoconjunctivitis, and eczema in childhood: JHumNutr Diet.1996: 9:473–478.
ISAAC Phases One and Three repeat multicountry 22. Sandin A, Annus T, Bjo¨rkste´n B, Nilsson L, Rii-
cross-sectional surveys. Lancet.2006: 368:733–743. kja¨rv MA, van Hage-Hamsten M, Bra˚ba¨ck L.
4. GoodHousekeepingInstitute,ConsumerResearch Prevalence of self-reported food allergy and IgE anti-
Department. Childcare findings V, Children and bodies to food allergens in Swedish and Estonian
Food.NewYork:AGoodHousekeepingReport.1989. schoolchildren. EurJClin Nutr.2005: 59: 399–403.
5. GoodHousekeepingInstitute,ConsumerResearch 23. Rona RJ, Keil T, Summers C, Gislason D, Zuid-
Department. Women(cid:2)s opinions of food allergens. meerL,etal.Theprevalence offoodallergy:ameta-
New York: A Good Housekeeping Institute Publica- analysis.JAllergy ClinImmunol. 2007:120:638–646.
tion.1984. 24. Rance´ F, Grandmottet X, Grandjean H. Preva-
6. Sloan AE, Powers ME, Sloan AE, Powers MD. A lence and main characteristics of schoolchildren diag-
perspectiveonpopularperceptionsonadversereaction nosedwithfoodallergiesinFrance.ClinExpAllergy.
tofood.JAllergy ClinImmunol. 1986:78: 128–133. 2005: 35:167–172.
7. YoungE,StonehamMD,PetruckeirtchA,etal.A 25. Dalal I, Binson I. Food allergy is a matter of geog-
population study of food intolerance. Lancet. 1994: raphyafterall:sesameasamajorcauseofsevereIgE-
343:1127–31. mediated food allergic reactions among infants and
8. JansenJJ,KardinnalAF,HuijbersG,Vlieg-Boer- youngchildren in Israel.Allergy. 2002:57: 362–365.
stra BJ, Martens BP, Ockhuizen T. Prevalence of 26. Tariq SM, Matthews SM. Egg allergy in infancy
foodallergyandintoleranceintheadultDutchpopu- predicts respiratory allergic disease by 4years of age.
lation.JAllergyClinImmunol.1994:93:446–456. PediatrAllergy Immunol.2000: 11:162–167.
9. Bjornsson E, Janson C, Plaschke P, Norrman E, 27. Garcia Ara MC, Boyano Martinez MT. Incidence
Sjo¨berg O. Prevalence of sensitization to food aller- ofallergytocow(cid:2)smilkproteininthefirstyearoflife
gensinadultSwedes.AnnAllergy,AsthmaImmunol. anditseffectonconsumptionofhydrolyzedformulae.
1996:77: 327–332. AnnPediatr(Barc). 2003: 58:100–105.
10. Osterballe M. The clinical relevance of sensitiza- 28. Kristjansson I, Ardal B, Jonsson JS, Sigurdsson
tion to pollen-related fruits and vegetables in unse- JA, Foldevi M, Bjorksten B. Adverse reactions to
10