Diagnosis and Rationale for Action Against Cow's Milk Allergy (DRACMA): a summary report.

Abstract

The 2nd Milan Meeting on Adverse Reactions to Bovine Proteins was the venue for the presentation of the first consensus-based approach to the management of cow's milk allergy. It was also the first time that the Grading of Recommendations, Assessments, Development, and Evaluation approach for formulating guidelines and recommendations was applied to the field of food allergy. In this report we present the contributions in allergen science, epidemiology, natural history, evidence-based diagnosis, and therapy synthesized in the World Allergy Organization Diagnosis and Rationale for Action against Cow's Milk Allergy guidelines and presented during the meeting. A consensus emerged between discussants that cow's milk allergy management should reflect not only basic research but also a newer and better appraisal of the literature in the light of the values and preferences shared by patients and their caregivers in partnership. In the field of diagnosis, atopy patch testing and microarray technology have not yet evolved for use outside the research setting. With foreseeable breakthroughs (eg, immunotherapy and molecular diagnosis) in the offing, the step ahead in leadership can only stem from a worldwide organization implementing consensus-based clinical practice guidelines to diffuse and share clinical knowledge.

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Workshop summary
Diagnosis and Rationale for Action against Cow’s Milk
Allergy (DRACMA): A summary report
Alessandro Fiocchi, MD,aHolger J. Sch€ unemann, MD, PhD,bJan Brozek, MD,bPatrizia Restani, PhD,cKirsten Beyer, MD,d
Riccardo Troncone, MD,eAlberto Martelli, MD,fLuigi Terracciano, MD,fSami L. Bahna, MD,gFabienne Ranc? e, MD,h
Motohiro Ebisawa, MD,iRalf G. Heine, MD, FRACP,jAmal Assa’ad, MD,kHugh Sampson, MD,lElvira Verduci, MD,m
G. R. Bouygue, MSc,fCarlos Baena-Cagnani, MD,nWalter Canonica, MD,oand Richard F. Lockey, MDp
Genoa, Italy, Hamilton, Ontario, Canada, Berlin, Germany, Shreveport, La, Toulouse, France, Kanagawa, Japan, Melbourne, Australia,
Cincinnati, Ohio, New York, NY, Cordoba, Argentina, and Tampa, Fla
Milan, Naples, and
The 2nd Milan Meeting on Adverse Reactions to Bovine
Proteins was the venue for the presentation of the first
consensus-based approach to the management of cow’s milk
allergy. It was also the first time that the Grading of
Recommendations, Assessments, Development, and Evaluation
approach for formulating guidelines and recommendations was
applied to the field of food allergy. In this report we present the
contributions in allergen science, epidemiology, natural history,
evidence-based diagnosis, and therapy synthesized in the World
Allergy Organization Diagnosis and Rationale for Action
against Cow’s Milk Allergy guidelines and presented during the
meeting. A consensus emerged between discussants that cow’s
milk allergy management should reflect not only basic research
but also a newer and better appraisal of the literature in the
light of the values and preferences shared by patients and their
caregivers in partnership. In the field of diagnosis, atopy patch
testing and microarray technology have not yet evolved for use
outside the research setting. With foreseeable breakthroughs
(eg, immunotherapy and molecular diagnosis) in the offing, the
step ahead in leadership can only stem from a worldwide
organization implementing consensus-based clinical practice
guidelines to diffuse and share clinical knowledge. (J Allergy
Clin Immunol 2010;126:1119-28.)
Key words: Cow’s milk allergy, epidemiology, amino acid formula,
hydrolyzed milk formula, soy formula, hydrolyzed rice formula, skin
prick test, specific IgE, oral immunotherapy, Grading of Recommen-
dations, Assessments, Development, and Evaluation approach
The World Allergy Organization’s (WAO) Food Allergy Spe-
cial Committee’s Diagnosis and Rationale for Action against
Cow’s Milk Allergy (DRACMA) guidelines were presented
during the 2nd Meeting on Adverse Reactions to Bovine Proteins
in Milan, Italy, on February 4 and 5, 2010. Because current
recommendations in Europe and the United States are a decade
old,1,2diagnosisandtreatmentofcow’smilkallergy(CMA)prac-
tice guidelines were in need of a reappraisal reflecting recent lit-
erature.3DRACMA encompasses recommendations for the
diagnosis and treatment of IgE-mediated CMA.4The full set is
available in Boxes E1 and E2 (available in this article’s Online
Repository at www.jacionline.org),3and selected conclusions
are included in this report.
The DRACMA guidelines are the fruit of a 2-year WAO
commitment targeted toward an audience of allergists, general
practitioners, pediatricians, gastroenterologists, dermatologists,
andnutritionandfoodchemistryspecialists.Patientadvocacyand
industry focus groups and physicians and their charges, all
stakeholders in DRACMA, are invited to participate in its
implementation through professional bodies, through the soon-
to-be posted dedicated DRACMA pages on the WAO Web site
(>3.6 million hits in 2009), or both.5
Fromathe Department of Child and Maternal Medicine, Melloni Hospital, Milan;bthe
Departments of Clinical Epidemiology and Biostatistics and of Medicine, McMaster
University, Hamilton;cthe Department of Pharmacological Sciences, Universit? a degli
Studi di Milano, Milan;dCharit? e Klinik f€ ur P€ adiatrie m.S. Pneumologie und Immuno-
logie,Berlin,Germany;etheDepartmentofPediatrics,FedericoIIHospital,University
of Naples;fthe Paediatric Division, Department of Child and Maternal Medicine, Uni-
versityofMilanMedicalSchoolattheMelloniHospital;gPediatricsandMedicine,Al-
lergy and Immunology, Louisiana State University Health Sciences Center,
Shreveport;hAllergologie, H^ opital des Enfants, P^ ole M? edicochirurgical de P? ediatrie,
Toulouse, France;ithe Department of Allergy, Clinical Research Center for Allergy
and Rheumatology, Sagamihara National Hospital, Kanagawa;jthe Department of Al-
lergyandImmunology,RoyalChildren’sHospital,UniversityofMelbourne,Murdoch
Childrens Research Institute, Melbourne;kthe Division of Allergy and Immunology,
Cincinnati Children’s Hospital Medical Center;
Mount Sinai School of Medicine, New York;mthe Department of Pediatrics, Univer-
sity of Milan;nthe Division of Immunology and Respiratory Medicine, Department of
Pediatrics, Infantile Hospital Cordoba, Cordoba;othe Allergy and Respiratory Dis-
easesClinic, Department ofInternal Medicine,UniversityofGenoa;andptheDivision
of Allergy and Immunology, University of South Florida College of Medicine,Tampa.
Disclosure of potential conflict of interest: A. Fiocchi has received support from the
World Allergy Organization (WAO); he is chairman of the American College of
Allergy, Asthma, and Immunology’s (ACAAI) adverse reactions to foods committee
and the WAO’s food allergy special committee. H. J. Schunemann and J. Brozek have
received research support from the WAO. K. Beyer has received research support
from the European Union, Food Allergy and Anaphylaxis Network (FAAN), Phadia,
Paul Ehrlich Institute, and the German Research Foundation. S. L. Bahna has
received research support from Pharming and speaker’s honoraria from Abbott, and
is president of the ACAAI. R. G. Heine is on scientific advisory boards for Nutricia
Australia and Nestle Nutrition Institute Australia, and has received lecture honoraria
from Nutricia Australia. H. A. Sampson has consulted for Allertein Therapeutics,
LLC; has received research support from the Food Allergy Initiative (FAI) and the
National Institutes of Health / National Institute of Allergy and Infectious Diseases;
is a consultant/scientific advisor for FAI; and is part-owner of Herbal Springs, LLC.
The remaining authors declare that they have no relevant conflicts of interest to
disclose.
Received for publication August 5, 2010; revised September 30, 2010; accepted for pub-
lication October 1, 2010.
Reprint requests:Alessandro Fiocchi, MD, Department ofChild and Maternal Medicine,
Melloni Hospital, Via Melloni, 52 Milan–I 20123. E-mail: allerg@tin.it.
0091-6749/$36.00
? 2010 American Academy of Allergy, Asthma & Immunology
doi:10.1016/j.jaci.2010.10.011
lthe Jaffe Food Allergy Institute,
1119

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Abbreviations used
AD: Atopic dermatitis
CMA: Cow’s milk allergy
DRACMA: Diagnosis and Rationale for Action against Cow’s Milk
Allergy
GRADE: Grading of Recommendations, Assessments, Develop-
ment, and Evaluation
OFC: Oral food challenge
OIT: Oral immunotherapy
PICO: Patient Intervention Comparison Outcome
sIgE: Specific IgE
SPT: Skin prick test
WAO: World Allergy Organization
CMA: BASIC SCIENCE
Proteins involved in CMA
Cow’s milk contains approximately 20 potentially sensitizing
proteins(somerecognizedasmajorallergens),whicharefoundin
thewhey and casein fractions, including a-lactalbumin (Bos d 4),
b-lactoglobulin (Bos d 5), BSA (Bos d 6), bovine immunoglob-
ulins (Bos d 7), and casein allergens (Bos d 8)6,7collectively (see
Table E1 in this article’s Online Repository at www.jacionline.
org). The comparative electrophoretic profiles of other genera
and species are shown in Fig E1 (available in this article’s Online
Repository at www.jacionline.org). The effect of industrial pro-
cessing (pasteurization, ultra-high-temperature heating, or dry
blending for cow’s milk formula) on the antigenic/allergenic
properties of cow’s milk proteinsis minimal orabsent.8However,
according to 1 study, up to 70% of children might tolerate milk in
baked products,9potentially improving their quality of life.10
Higher temperatures and longer exposure to heat in baking might
account for this. For choosingan alternativeto cow’s milk, poten-
tial cross-reactivity (caused by protein sequence homology be-
tween related species) should be considered of clinical
relevance. At present, cross-reactivity cannot be ruled in or out
by species phylogeny, although conserved protein sequences are
often cross-reactive (see Table E2 in this article’s Online Repos-
itory at www.jacionline.org).11,12Alternatives from other mam-
mals (eg, mare and camel) should be clinically evaluated for
suitability from a nutritional and allergy point of view.
Epidemiology of CMA
Food allergy was reported by 40% of 5- to 16-year-olds but
confirmedbychallenge in only 5% of cases.13In a European tele-
phone survey of more than 44,000 contacts, 5 million claimed to
be allergic to milk. Adult women were making most of these
claims. Milk was the food most often reported by or for children
(38.5%) and was the second most often implicated food in adults
(26%).14Challenge-based studies remain the exception rather
than the rule.15More than 20 studies have dealt with self-
perceived or parentally perceived CMA over the last 20 years in
preschoolers,16-25school-aged children (5-16 years),13,26-29and
young adults.30-36Self-report prevalence varies between 1% and
17.5% in preschoolers, 1% and 13.5% in 5- to 16-year-olds, and
1%and4%inadults(seeFigE2inthisarticle’sOnlineRepository
at www.jacionline.org). CMA peaks during the first year of life
andtendstosubsidelaterinatemporalpatternthatappearsunique
among food allergies.37-41Sensitization surveys in the general
population are few (see Fig E3 in this article’s Online Repository
at www.jacionline.org).15,17,19,20,22,34,42The Isle of Wight birth
cohort tested 543 children at 1, 2, and 3 years of age and found
0.37% of infants, 0.92% of 2-year-olds, and 0.55% of 3-year-
olds to be sensitized to cow’s milk.43In the German Multicentre
Allergy Study sensitization decreased from 4% at 2 years to 1%
at 10 years.44In cross-sectional studies a CMA prevalence of
0.6% to 2.5% of preschoolers, 0.3% of older children and teens,
and less than 0.5% of adults is reported (see Fig E2).20,45-47Geo-
graphic differences, blinding (still rare), and method of standard-
ization remain unmet needs of epidemiologic research, as are
high-quality, challenge-controlled, community surveys (see the
section on diagnosis).48On the whole, rates of CMA, in line
with other food allergies, seem to be on the increase.49,50
Pathogenesis of CMA: IgE and non–IgE mediated
CMA presents in 3 clusters of immune mechanisms. The IgE-
mediated forms are characterized by acute onset and involve 1 or
moretargetorgans,suchastheskin(urticariaandangioedema),the
respiratory system (rhinoconjunctivitis and asthma), and the gas-
trointestinal tract (nausea, vomiting, and diarrhea). The cell-
mediated, non-IgE forms are of delayed or chronic onset, with
enterocolitis and proctocolitis as frequent clinical presentations
(TableI).3,51-77A‘‘mixed’’IgEandnon-IgEsetting,alsowithade-
layedorchroniconset,mightpresentasatopicdermatitis(AD)oras
one of the eosinophilic gastroenteropathies (CMA phenotypes).
In common with other food allergies, genetic predisposition,
infections, and intestinal microflora alteration, as well as age at
first exposure, maternal diet, antigen transmission through breast
milk, and the nature, quantity, and frequency of antigen load, are
factors promoting oral tolerance or sensitization to cow’s milk.78
The integrityofthe intestinal epithelial barrier,which controls al-
lergen load to the immunocompetent cells of the mucosa-
associated immune system, plays a key role in the onset of both
IgE- and non–IgE-mediated forms. The delicate balance between
oral tolerance and hypersensitivity is regulated by active immune
mechanisms involving specialized regulatory T cells.79Serum
milk-specific IgG antibodies and T cells have been reported in
the Peyer patches of healthy infants,80as has an antigen-
specificsuppressionofcellularorhumoralresponsesafteroralex-
posure.81Cell-mediated CMA has been far less studied than IgE-
mediated forms.Polarizationof T cells specific for cow’s milk to-
ward the TH2 phenotype has been reported with IgE-mediated
CMA; in contrast, a TH1-skewed type of response mediates
non–IgE-mediated CMA in children. T-cell clones from children
with acute IgE-mediated CMA produce mainly IL-4 and IL-13,
whereas T-cell clones from cow’s milk–tolerant patients are char-
acterized by a marked production of IL-10 and IFN-g, thus sug-
gesting a key role for IL-10 in the induction of tolerance to
cow’s milk. However, cow’s milk–specific T-cell responses per
se do not induce CMA because specific TH1, TH2, and regulatory
T-cell subsets have been described in both healthy and allergic
subjects.80A TH2-skewed cytokine pattern, dominated by IL-
13, IL-5, and IL-4, has also been reported in T-cell clones in a
CMA/AD setting. In contrast, a TH1-skewed response is domi-
nant in T-cell clones from infants without CMA.82Clinically,
most IgE-mediated and non–IgE-mediated forms of CMA are
outgrown during late childhood. T-cell clones with a TR1 pheno-
type (producing IL-10 and IFN-g) have been recovered in chil-
dren who became spontaneously tolerant to cow’s milk
proteins. An association between naturally occurring regulatory
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1120 FIOCCHI ET AL

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T cells (CD251CD271forkhead box protein 3high1cytotoxic T
lymphocyte–associated antigen 41CD127lowcells) and the onset
of tolerance to milk has been found.83
CMA: CLINICAL SCIENCE
CMA phenotypes: Immediate and delayed reactions
From a clinical point of view, patients with CMA can present
with a bewildering variety of symptoms. The classification of
immune-mediated reactions to cow’s milk into immediate (typ-
ically IgE-mediated) or late-onset (non–IgE-mediated or cell-
mediated) reactions still holds true. Currently defined as ‘‘a
severe systemic or generalized severe allergic reaction,’’84cow’s
milk–induced anaphylaxis can be life-threatening and occur at
any time to within minutes and up to 2 hours after ingestion of
dairy products. Like any food-induced anaphylactic reaction,
CMA can present with skin,85-87respiratory tract,88-90and gas-
trointestinal91symptoms (Table I, parts I to VII). Cardiovascular
collapse, syncope, or incontinence are the hallmarks of the most
severe forms. Food-dependent exercise-induced anaphylaxis has
also been reported in children with previous milk allergy, either
after achieving tolerance92or after oral desensitization proto-
cols.93In the United Kingdom milk ingestion was the cause of
fatal anaphylaxis in 4 cases over 10 years and was involved in
10.9% of fatal or near-fatal anaphylactic episodes.94Milk is
one of the leading foods accounting for epinephrine use.95
Cow’s milk has thus far been subject to cautionary labeling
both in Europe and the United States,96but the similar labeling
of milk as an ingredient of pharmaceutical preparations has not
been required, and several cases of anaphylaxis caused by milk
in medicinal fillers, such as lactose, have been reported.97-99
Goat’s and ewe’s milks have also been implicated in anaphylac-
tic reactions.100,101
Unusual clinical presentations of CMA
UnusualclinicalpresentationsareasmuchafeatureofCMAas
one might expect from such a ubiquitous allergen source in food
and the environment as milk (Box 1).102-112
TABLE I. Clinical manifestations of CMA
I. Gastrointestinal reactions
d Oral allergy syndrome (rare in pediatric patients)
d Lip swelling is a commonly observed manifestation during food
challenge procedures.51
Immediate gastrointestinal allergy
d Vomiting (described in children both isolated and as part of
allergic/anaphylactic reactions)
d Diarrhea (usually in, but not limited to, delayed reactions52)
CMA in short bowel syndrome
d Greater than 50% of these patients are also allergic to cow’s milk,
according to 1 case study.53
II. IgE-mediated respiratory reactions
d Rhinitis occurs in 670% of patients during oral cow’s milk challenge,
and asthma occurs in less than 8%.54-56
d Reactions rarely occur in isolation.57
d Reactions correlate with severe CMA.3,58
d Asthma makes for the worst prognosis in children with anaphylaxis.
d Asthma in patients with CMA is of particular severity.3,59
d Respiratory symptoms in patients with CMA can progress to
respiratory allergy.60
d Inhalation of milk vapor has been associated with severe respiratory
tract reactions.61,62
III. IgE-mediated skin reactions
Acute urticaria or angioedema
d Urticaria is a feature of most anaphylactic reactions to cow’s milk.
d Urticaria with inhalation63or accidental skin contact64is often severe.
Contact urticaria
d Pattern varies from irritant to allergic contact dermatitis.
d Generalized eczematous rash (systemic contact dermatitis) is present.
d Contact reactions are frequent in patients with AD.65
IV. Late-onset reactions
d Symptoms not IgE mediated
d Mostly localized in the gastrointestinal tract
d Typically develop 1 to several hours or even days after ingestion
d No reliable laboratory tests to diagnose late-onset CMA: IgE test
results are negative
Skin
Gastrointestinal tract
d AD
d Gastroesophageal reflux disease
d Allergic eosinophilic esophagitis
d Food protein–induced enterocolitis syndrome
d Cow’s milk protein–induced enteropathy
d Constipation
d Severe irritability (colic)
d Food protein–induced gastroenteritis and
proctocolitis
Respiratory system
d Milk-induced chronic pulmonary disease
d Heiner syndrome
V. AD
d AD is most often present as an eczematous lesion (after ingestion or
contact).
d AD can involve both IgE-mediated and non–IgE-mediated skin
responses.
d Less than 30% of children with moderate-to-severe AD have food
allergy, and CMA is the second most common food allergy in this
population.66
d The earlier the age of onset, the greater the severity and frequency of
high of cow’s milk sIgE levels.67
d Appropriate diagnosis and elimination diets frequently lead to
symptom improvement.68
VI. Gastrointestinal syndromes
Symptoms frequently include nausea, vomiting, abdominal pain, diarrhea,
and, with chronic disease, malabsorption and failure to thrive or weight
loss.
(Continued)
TABLE I. (Continued)
d Food protein–induced enterocolitis syndrome, the primary cause of
which is CMA69,70
d Cow’s milk–induced enteropathy syndrome and secondary lactose
malabsorption71
d Cow’s milk–induced proctocolitis syndrome (relatively benign
disorder)72
d Gastroesophageal reflux disease–like symptoms73,74
d Eosinophilic esophagitis75
d Constipation
d Irritable bowel syndrome76
VII. Milk-induced chronic pulmonary disease77
d Heiner syndrome is a very rare form of pulmonary hemosiderosis
caused by CMA.
d Young children typically present with recurrent pulmonary infiltrates
associated with chronic cough, tachypnea, wheezing, rales, recurrent
fevers, and failure to thrive.
d Milk-precipitating antibodies are found in the serum.
d Symptoms generally resolve after an elimination diet.
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The natural history of CMA
CMA is primarily of pediatric onset,113-115is generally out-
grown, and is often the first stage of the ‘‘allergic march.’’ The
take-home message about the latest developments regarding the
natural history of CMA is reviewed in Table II.1,38,116-135
CMA GUIDELINES: METHODS
The Grading of Recommendations, Assessments,
Development, and Evaluation (GRADE) approach
for developing management guidelines in patients
with CMA
The Grading of Recommendations Assessment, Development,
and Evaluation (GRADE) working group defines quality of
evidence as the extent of confidence that estimates of effect for
anoutcome(includingdiagnosticaccuracyestimates)arecorrect.
An estimate of such an effect therefore underpins a recommen-
dation in guidance/guideline formulation.136-141GRADE is used
by more than 50 international organizations, including the World
Health Organization,the CentersforDisease Controland Preven-
tion, the Allergic Rhinitis in Asthma Guidelines, and the Ameri-
can Thoracic Society. Considerations of health benefits and
harms, burden of disease, patient preferences, and resource use
lead to specific and explicit recommendations for patients and
caregivers.
Using and searching for evidence to guide clinical practice
requires formulating research questions before turning to the
literature.142Key considerations (ie, patient [P]; intervention, in-
cluding diagnostic tests or strategies [I] or exposure [C; and out-
comes[O]) combineto form
Comparison Outcome (PICO) format for this purpose. Evidence
was collected by an independent panel of researchers who con-
ducted systematic reviews of the published evidence for all PICO
questions.3Randomized controlled trials and observational evi-
dence were considered when available or relevant. GRADE is a
thePatient Intervention
system for evaluating the quality of evidence, as well as a system-
atic and transparent approach to develop recommendations (and
their relative strength) for clinical practice use, also specifying
the strength of these recommendations. Four grades of evidence
areused:high,moderate,low,andverylowquality.Fivefactorsde-
crease the confidence in an estimate of an effect and consequently
decreaseitsgrade,and 3factorsincreaseit(see TableE3inthisar-
ticle’s Online Repository at www.jacionline.org). The strength
(strong/weak or ‘‘conditional’’) of a for-or-against recommenda-
tionexpressesthedegreeofconfidencewithwhichthedesirableef-
fects outweigh the undesirable effects of the intervention.
A recommendation for action requires the consideration of the
magnitude of the expected benefit/downside tradeoff in view of
all patient outcomes, associated values/preferences, and resource
use (see Table E4 in this article’s Online Repository at www.
jacionline.org). Panel deliberation and consensus after consider-
ation of the factors listed in Table E4 allow the recommendations
to be formulated reflecting the quality of evidence, the strength
of the recommendations themselves, and the inclusion of patients’
valuesandpreferences.ThustheGRADEsteppedapproach,which
requires and reflects judgmental and stakeholder inputs, compre-
hensively and explicitly facilitates the scrutiny and transparency
of these judgments throughout the guideline development process.
GRADE assessment of the diagnostic tests in
patients with CMA, their diagnostic properties, and
consequences for use in daily practice
An oral food challenge (OFC) with cow’s milk is the reference
standard for the diagnosis of CMA. However, it is resource
intensive and not easily performed or interpreted and might carry
a significant risk of anaphylaxis. In many parts of the world, it is
not realized in clinical practice precisely because of the above
reasons.ThustheDRACMApanelresearchquestionwaswhether
reducing OFCs was possible though better deployment of skin
prick tests (SPTs) or cow’s milk–specific IgE (IgE) in vitro
BOX 1: Unusual clinical manifestations and routes of exposure
Manifestation
Constipation
Heiner syndrome
Unusual routes of exposure
Skin contact
See Table I
See Table I
Iacono et al102
Moissidis et al103
Direct or indirect contact in bathtub into which a few
drops of milk were spilled by a younger brother
Kiss
Vaginal contact
Milk vapor or casein powder
Liccardi et al104
Mucous membrane contact
Hallett et al105
Liccardi et al106
Bonadonna et al,107Vargiu
et al108
Inhalation
Environmental exposure
Poor food labeling
Labeling of commercially prepared foods might not be
accurate
Contamination in restaurants or factories
Ignorance of catering personnel
In lactose
Joshi et al109
Hidden or contamination in other
foods
Mu~ noz-Furlong et al110
Hidden or contamination in
medications
Nowak-Wegrzyn et al111
In dermatologic preparations or injectable corticosteroidsEda et al112
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determinations. Following the GRADE Working Groupapproach
for making recommendations, the panel formulated several spe-
cific clinical questions and specified outcomes of interest,3such
aspatient-orientedconsequencesoftakingintoaccountbeingcor-
rectly or incorrectly classified as allergic to cow’s milk, the con-
sequences of indeterminate results, the complications of tests,
and resource use. The panelists carried out a systematic review
of all available evidence that addressed these questions. Thirty-
six studies were included in the final qualitative analyses.3The
combined accuracy of the SPTs and sIgE measurements were es-
timated, the risk of bias in the studies included was assessed by
using the Quality Assessment of Studies of Diagnostic Accuracy
tool, andthe panelists’ratings (from 1to 10) ofthequalityofsup-
porting evidence for each outcome of interest were reported.143
The cutoff values for positivity of SPT results and sIgE determi-
nations reported in most studies in the literature are a greater
than 3-mm wheal diameter and a greater than 0.35 kU/L sIgE
level, respectively. The guideline panel concluded that there
was insufficient evidence to support recommendations of other
cutoff values. The overall quality of the evidence was either low
or very low because of the risk of bias and unexplained heteroge-
neity in the results of individual studies. Based on estimated
combined accuracy, we calculated the numbers of patients who
experience particular consequences of being correctly or incor-
rectly classified as having CMA. The DRACMA guideline panel
considered the balance of desirable and undesirable conse-
quences, the quality of available evidence, patients’ values and
preferences, and the resource implications of each diagnostic op-
tion. The panel made several recommendations for the use of
SPTs and sIgE measurements as a single test or in combination
in patients with high, average, or low initial probability of
IgE-mediated CMA. The panel also made 2 recommendations
for further research on allergen microarrays and component-
resolved diagnostics before they can be used in clinical practice.
The 6 clinical research questions identified by the panelists
(who screened 3877 articles3) deal with issues regarding the set-
tings of high, medium, and low suspicion of CMA. Below is the
summary of the recommendations presented by the panelists.
CMA: DIAGNOSIS
The recommendations on diagnosis using SPTs and sIgE
determinations are reported in Box E1.3,144According to these
recommendations,achildwitharecentcutaneousreactionimme-
diatelyaftertheingestionofamealincludingmilk(highprobabil-
ityofIgE-mediatedCMA)musthavehisorherdiagnosisbasedon
a challenge. If not easily feasible, a positive SPTresult or IgE de-
termination will surrogate the reference test with an acceptable
accuracy:witha5%to6%false-positiverate,only1in20patients
will be misclassifiedas having CMA and will receivean unneces-
sary exclusion diet. If these sensitization test results are negative,
a challenge must be done to diagnose or exclude CMA.
Vice versa, a negative sensitization test result in a child with
mildeczema(lowprobabilityofCMA)willexcludethecondition
in most cases. In this case, given the 2% to 4% of false-negative
results, an allergic reaction (possibly mild) will be possible in
1 in 25 to 50 patients misclassified as not having CMA although
actually being allergic to cow’s milk. Regarding the use of the at-
opy patch test for CMA diagnosis, the low correlation with skin
tests for single allergens and the unsatisfactory reproducibility
TABLE II. Natural history of CMA at a glance
Temporal pattern:
In the 1990s, a Danish birth cohort study found that more than 50% of children outgrow their CMA at 1 year of age.116,117Subsequent studies have reported
a longer duration of CMA, with tolerance developing in 51% of patients within 2 years after diagnosis.
Tolerance:
Referral studies indicate that 80% of patients achieve tolerance within 3 to 4 years. In several studies children with delayed reactions became tolerant faster
than those with immediate reactions.118-121
Duration:
In retrospective studies the duration of CMA differs in different settings.1In a population of breast-fed infants with cow’s milk–induced allergic
proctocolitis, tolerance developed between 6 and 23 months.
Onset:
The onset of CMA is related to antigen exposure. A cow’s milk avoidance diet, once thought of as the only treatment for CMA, has recently been challenged
by opposite theories on the basis of human and animal studies.
Risk factors:
A family history of progression to atopic asthma, rhinitis, eczema, early respiratory symptoms with skin and/or gastrointestinal symptoms, or severe
symptoms are considered risk factors for persistent CMA.
A larger wheal diameter on SPTs with fresh milk significantly correlates with CMA persistence. A smaller eliciting dose on OFCs also correlates with
longer duration of CMA.120
Severe symptoms reported at diagnosis are consistent with the worse prognosis for duration.120,123-125Children with earlier or more severe AD have a higher
prevalence of early-onset bronchospasm compared with those with AD or mild AD.38
Phenotypes:
There might be different CMA phenotypes that, once identified, could lead to personalized treatment strategies for different populations of atopic patients.
Tolerance factors:
Low milk-specific IgE levels correlate with earlier onset of tolerance, and a 99% reduction in sIgE concentrations over 12 months translates into a 94%
likelihood of achieving tolerance to cow’s milk protein within that period.
Tolerance of cow’s milk protein might correlate with reduced concentrations of IgE- and IgG-binding casein epitopes, and an involvement of tertiary or
linear casein epitope structures has been hypothesized.126-129However, the maintenance of tolerance in atopic patients is associated with persistently
increased milk-specific IgG4 antibody concentrations.130Tolerance of cow’s milk protein might correlate with a shift toward IgA131,132and reduced
concentrations of T-cell epitopes of casein in either IgE-mediated or non–IgE-mediated allergy.133,134Tolerance maintenance is associated with persistently
increased milk-specific IgG4 antibody concentrations.135
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of food atopy patch tests in children argue against their wide-
spread clinical use in diagnosing CMA.145,146
CMA: TREATMENT
Dietary treatment
Thus far, the only treatment of CMA is strict avoidance of
cow’s milk proteins, which nevertheless carries a number of
drawbacks, as outlined in Box 2. Planning a dietary regimen
avoiding all cow’s milk proteins from dairy or processed food
products for these infants and children should be backed by a col-
laborative effort between scientific societies, clinical specialists,
primary care physicians, and caregivers. For infant foods in par-
ticular, lists of acceptable foods and suitable substitutes in line
with national recommendations and clinical settings must be
drafted from various sources and adapted to suit the individual
subject’s needs and values.147It is DRACMA’s contention
that all dietary interventions and avoidance strategies be re-
evaluated with patients and their families on a yearly basis, ide-
ally after OFCs carried out under medical supervision (see the
section on diagnosis). The panelists’ consensus was that to fulfill
the nutritional requirements of young children, a substitute for-
mula should be prescribed until at least 2 years of age. This
applies to most countries in the world. As a rule, extensively
hydrolyzed formulae are the first choice, except in patients
with anaphylaxis and eosinophilic esophagitis.3Soy formulae
should never be prescribed during the first 6 months of life.3
Where available, rice-based hydrolysates can adequately substi-
tute extensively hydrolyzed cow’s milk proteins.3
Prescribing a nutritionally adequate diet
Formulating the diet of infants and children during the CMA
workup requires careful evaluation of nutritional aspects on a
strictly individual basis.148The aim is to achieve a balanced cal-
orie/protein ratio and amino acid composition and an adequate
calcium source.149,150Noncompliance with recommendations
can lead to inappropriate diets, sometimes with dramatic
effects.151The literature supports the nutritional safety of cow’s
milk substitutes both during the first152and second153semesters
of life.
Experimenting with immunotherapy for CMA
Animal studies have shown that, under certain circumstances,
tolerance can develop through apoptosis on exposure to high
BOX 2: What DRACMA brings to the treatment of CMA3
General treatment principles
d Apply strict avoidance of all cow’s milk protein in food.
d Consider a maternal elimination diet in breast-fed infants.
d Use a replacement formula in formula-fed children <2 years of age.
d It is often possible to switch to a milk-free diet in children >2 years of age.
d Continue elimination diet until tolerance has developed.
d Provide intramuscular adrenaline autoinjector to children at risk of anaphylaxis.
Clinical goals
d Remission of cow’s milk–induced symptoms
d Prevention of accidental ingestion of cow’s milk proteins
d Prevention of inhalation or skin contact with cow’s milk
d Avoidance of cross-reactive milk proteins (buffalo’s, goat’s, or ewe’s milk)
d Monitoring of nutritional adequacy of elimination diets, especially if maintained for prolonged periods
d Patient education to improve adherence
Problems
d Inadvertent intake (labeling and level of dietary education)
d Misconceptions about safety of partially hydrolyzed formula, heated milk products, or homologous nonbovine milk formula (eg, goat’s milk
formula)
d Taste aversion for treatment formula
d Poor intake and feeding difficulties or refusal to feed
d Risk of decreased growth velocity
d Other confounding food allergies (eg, egg, soy, or wheat)
How long should an elimination diet be maintained?
d Prolonged elimination diets might adversely affect nutritional outcomes, particularly if poorly supervised.
d The aim is to normalize elimination diets as soon as feasible.
d Patients on elimination diets require regular reassessment of tolerance (SPTs, sIgE antibody measurements, and diagnostic OFCs).
d Dairy products are often tolerated by 2-3 years of age.
d In case of unremitting CMA beyond 2 years of age, consider shifting from replacement formula to a milk-free diet.
Maternal elimination diet
d Encourage continued breast-feeding.
dAmaternaleliminationdietmightbeusefulifthereisclearevidenceofongoingclinicalallergicreactionsaftermaternalcow’smilkingestionwhile
the infant is exclusively breast-fed.
d A maternal elimination diet is not required if the infant tolerates breast milk while the mother is on an unrestricted diet (eg, previous reaction
occurred to supplemental cow’s milk formula or dairy products).
d Monitor maternal protein and calcium intake (1.2 g of calcium daily in divided doses), as supervised by a dietician.
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antigen loads.154Different studies have shown that the tendency
of T cells to become tolerant can be triggered by the ingestion
of minimal quantities of the incriminated allergen.155,156The
wide array of allergens that can be introduced in the diet is an
obvious risk factor for allergy very early on, when the immune
system is still functionally immature, and the jury is still out on
whether early contact with a potential antigen can modulate the
response of the organism either toward hyperresponsiveness or
tolerance.157-160In this context oral immunotherapy (OIT) has
been attempted for at least a decade, with mixed success. In
some cases OIT has been supplemented with IFN-g161or
mAbs. From these studies, it is shown that standard OIT can in-
crease the threshold of reactivity in about 80% of patients with
CMA.However,mildadversereactionsareverycommon,andoc-
casionally more severe reactions occur (approximately 1 in 100
doses resulted in multisystem reactions).162-169Taken together,
these studies leave an important question unanswered: Are we
dealing with desensitization or induced tolerance? Only prospec-
tive studies will tell.
FUTURE DEVELOPMENTS
Microarray technology is progressing apace toward a future in
which allergen testing can be carried out on a microchip.
However, several paradigmatic shifts are necessary before this
can occur, and this is reflected in the GRADE recommendations
in the absence of more studies with larger samples and wider
allergy applications. DRACMA recommends allergen micro-
arrays and component-resolved diagnostics to be used only in the
context of well-designed studies investigating their accuracy
against OFCs for diagnostic purposes.
Another promising approach is represented by insights
afforded by molecular studies of the underlying immune mech-
anisms mediated through specific IgA, IgG, IgE, and regulatory
T-cell expression in patients with CMA.83These developments
might lead to clinical breakthroughs in the near future, hopefully
leading to tests assisting clinicians in characterizing phenotypical
expression of CMA and thus defining patients’ prognostic
profiles.170
In conclusion, DRACMA should contribute to research by
focusingaworldwideawarenesstodealwiththeunmetneedsthat
current CMA research has identified. Toward these goals, the
WAO provides an instrument and a forum to generate solutions to
clinical aspects of the problem and to coordinate energies from
the multidisciplinary approaches needed to tackle the problem of
CMA.
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FIG E1. SDS-PAGE of cow’s milk. ALA, Bovine a-lactalbumin; a-cas, bovine a-casein; b-cas, bovine
b-casein; BLG, bovine b-lactoglobulin; Hcas, Human casein; HLA, human lactalbumin; Lfe, human
lactoferrin.
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FIG E2. Self/parental report of CMA stratified by age. P values connote the level of heterogeneity by age
group and in total.
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FIG E3. Prevalence of symptoms and sensitization (tested by means of
SPTs or IgE antibody assays) and stratification by age. P values connote the
level of heterogeneity by age group and in total. N/A, Not applicable.
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BOX E1: Recommendations for the diagnosis of CMA
Should SPTs be carried out for the diagnosis of IgE-mediated CMA in patients with suspected CMA?
Recommendation 1
In settings in which an OFC is considered a requirement for making a diagnosis of IgE-mediated CMA, we recommend using
an OFC with cow’s milk as the only test without performing an SPT as a triage or an add-on test to establish a diagnosis
(strong recommendation/very low-quality evidence).
Underlying values and preferences
This recommendation places a relatively high value on avoiding resource consumption and the risk of anaphylactic reactions
at home in patients who would be misclassified by an SPT alone. It places a lower value on anaphylactic reactions in a
controlled setting that can be managed by experienced personnel when an OFC is performed. This recommendation also
places a high value on avoiding any unnecessary treatment in patients who would be incorrectly classified by an SPT as
allergic to cow’s milk.
Remark
This recommendation applies to clinical practice settings. In research settings there might be compelling reasons to perform
an SPT even though a food challenge with cow’s milk is being done.
Recommendation 2
In settings in which an OFC is not considered a requirement in all patients suspected of IgE-mediated CMA, in patients with
high pretest probability of CMA, we suggest using an SPT with a cutoff value of 3 mm or greater as a triage test to avoid an
OFC in those in whom the result of an SPT turns out positive (conditional recommendation/low quality evidence).
Underlying values and preferences
This recommendation places a relatively high value on avoiding burden, resource use, and very likely anaphylactic reactions
during the OFC (approximately 50% to 70% of food challenges avoided). It places a lower value on unnecessary treatment of
around 1 in 20 patients misclassified as allergic to cow’s milk (5% to 6% false-positive results).
Remarks
A high pretest probability of CMA (approximately 80%) can be estimated based on the history and would represent, for
instance, patients who experienced an anaphylactic reaction in the past.
Recommendation 3
In settings in which an OFC is not considered a requirement in all patients suspected of IgE-mediated CMA, in patients with
an average pretest probability of CMA, we suggest using an OFC with cow’s milk as the only test without performing an SPT
with a cutoff value of 3 mm or greater as a triage or an add-on test to establish a diagnosis (strong recommendation/very low-
quality evidence).
Underlying values and preferences
This recommendation places a high value on avoiding resource consumption and the risk of anaphylactic reactions at home in
a large proportion of patients who would be incorrectly classified by an SPT alone. It places a lower value on anaphylactic
reactions in a controlled setting that can be managed by experienced personnel when an OFC is performed. This
recommendation also places a high value on avoiding any unnecessary treatment in patients who would be incorrectly
classified by an SPT as allergic to cow’s milk.
Remarks
An average pretest probability of CMA (approximately 40%) can be estimated based on the history and presenting symptoms
and would represent the majority of situations.
Recommendation 4
In settings in which OFCs are not considered a requirement in all patients suspected of IgE-mediated CMA, in patients with a
low pretest probability of CMA, we suggest using an SPT with a cutoff value of 3 mm or greater as a triage test to avoid an
OFC in those in whom the result of an SPT turns out negative (conditional recommendation/low-quality evidence).
Underlying values and preferences
This recommendation places a relatively high value on avoiding burden and resource use with an OFC (approximately 70% of
challenges avoided). It places a lower value on avoiding an allergic reaction (possibly a mild one) in around 1 in 25 to 50
patients misclassified as not having CMA although actually allergic to cow’s milk (2% to 4% false-negative results).
Remarks
A low pretest probability of CMA (approximately 10%) can be estimated based on the history and would represent, for
instance, patients with unexplained gastrointestinal symptoms (eg, gastroesophageal reflux).
Should in vitro sIgE determination be carried out for the diagnosis of IgE-mediated CMA in patients suspected of CMA?
(Continued)
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Recommendation 1.
In practice settings in which an OFC is a requirement in all patients suspected of IgE-mediated CMA, we recommend using
an OFC with cow’s milk as the only test without measuring a cow’s milk–specific IgE level as a triage or add-on test to
establish a diagnosis (strong recommendation/low-quality evidence).
Underlying values and preferences
This recommendation places a relatively high value on avoiding resource consumption and the risk of anaphylactic reactions
at home in patients who would be misclassified by a milk-specific IgE test alone. It places a lower value on anaphylactic
reactions in a controlled setting that can be managed by experienced personnel when an OFC is performed. This
recommendation also places a high value on avoiding any unnecessary treatment in patients who would be incorrectly
classified based on milk-specific IgE measurement as allergic to cow’s milk.
Remark
This recommendation applies to clinical practice settings. In research settings there might be compelling reasons to perform
SPTs even though a food challenge with cow’s milk is being done.
Recommendation 2.
In settings in which an OFC is not a requirement, in patients with a high pretest probability of IgE-mediated CMA, we
suggest using cow’s milk–specific IgE with a threshold of 0.7 IU/L to avoid an OFC if a result of milk-specific IgE
measurement turns out positive (conditional recommendation/low-quality evidence).
Underlying values and preferences
This recommendation places a relatively high value on avoiding burden, resource use, and very likely anaphylactic reactions
during an OFC (food challenges would be avoided in 50% of patients with milk-specific IgE results > _0.7 IU/L). It places a
lower value on unnecessary treatment of around 1 in 20 patients misclassified as allergic to cow’s milk (5% false-positive
results).
Remarks
A high pretest probability of CMA (approximately 80%) can be estimated based on the history and would represent, for
instance, patients who experienced an anaphylactic reaction in the past
Recommendation 3.
In settings in which an OFC is not a requirement in all patients suspected of IgE-mediated CMA, in patients with an average
pretest probability of IgE-mediated CMA, we suggest using an OFC with cow’s milk as the only test without measuring milk-
specific IgE levels as a triage or add-on test to establish a diagnosis (conditional recommendation/low-quality evidence).
Underlying values and preferences
This recommendation places a high value on avoiding resource consumption and the risk of anaphylactic reactions at home in
a large proportion of patients who would be incorrectly classified by a milk-specific IgE test alone. It places a lower value on
anaphylactic reactions in a controlled setting that can be managed by experienced personnel when an OFC is performed. This
recommendation also places a high value on avoiding any unnecessary treatment in patients who would be incorrectly
classified by a milk-specific IgE test as allergic to cow’s milk.
Remarks
An average pretest probability of CMA (approximately 40%) can be estimated based on the history and presenting symptoms
and would represent the majority of clinical situations. Using higher cutoff values (eg, 2.5 IU/L) might be of benefit; however,
we believe the available evidence does not allow us to make a recommendation to support any recommendation.
Recommendation 4.
In practice settings in which an OFC is not a requirement in all patients suspected of IgE-mediated CMA, in patients with a
low pretest probability of IgE-mediated CMA, we suggest using milk-specific IgE measurement with a cutoff value of 0.35
IU/L as a triage test to avoid an OFC in those in whom the result of milk-specific IgE measurement turns out negative
(conditional recommendation/low-quality evidence).
Underlying values and preferences
This recommendation places a relatively high value on avoiding burden and resource use with an OFC (approximately 50% to
70% of food challenges avoided). It places a lower value on avoiding an allergic reaction (possibly a mild one) in around 1 in
20 to 50 patients misclassified as not having CMA (2% to 5% false-negative results).
Remarks
A low pretest probability of CMA (approximately 10%) can be estimated based on the history and would represent, for
instance, patients with unexplained gastrointestinal symptoms (eg, gastroesophageal reflux).
Should in vitro sIgE antibody determination be used for diagnosis in patients with suspected CMA and a positive SPT result?
BOX E1. (Continued)
(Continued)
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