Alergi Susu Sapi
Alergi Susu Sapi
Alergi Susu Sapi
Authorship
Alessandro Fiocchi, MD, Pediatric Division, Department of
Child and Maternal Medicine, University of Milan Medical
School at the Melloni Hospital, Milan 20129, Italy.
Holger Schunemann, MD,a Department of Clinical Epidemiology
& Biostatistics, McMaster University Health Sciences Centre,
1200 Main Street West Hamilton, ON L8N 3Z5, Canada.
Sami L. Bahna, MD, Pediatrics & Medicine, Allergy &
Immunology, Louisiana State University Health Sciences
Center, Shreveport, LA 71130.
Andrea Von Berg, MD, Research Institute, Childrens department , Marien-Hospital, Wesel, Germany.
Kirsten Beyer, MD, Charite Klinik fur Padiatrie m.S. Pneumologie und Immunologie, Augustenburger Platz 1,
D-13353 Berlin, Germany.
Martin Bozzola, MD, Department of Pediatrics, British Hospital-Perdriel 74-CABA-Buenos Aires, Argentina.
Julia Bradsher, PhD, Food Allergy & Anaphylaxis Network,
11781 Lee Jackson Highway, Suite 160, Fairfax, VA 22033.
Jan Brozek, MD,a Department of Clinical Epidemiology &
Biostatistics, McMaster University Health Sciences Centre,
1200 Main Street West Hamilton, ON L8N 3Z5, Canada.
Enrico Compalati, MD,a Allergy & Respiratory Diseases
Clinic, Department of Internal Medicine. University of
Genoa, 16132, Genoa, Italy.
Motohiro Ebisawa, MD, Department of Allergy, Clinical
Research Center for Allergy and Rheumatology, Sagamihara National Hospital, Kanagawa 228-8522, Japan.
Maria Antonieta Guzman, MD, Immunology and Allergy
Division, Clinical Hospital University of Chile, Santiago,
Chile. Santos Dumont 999.
Correspondence to: Alessandro Fiocchi, MD, Paediatric Division, Department of Child and Maternal Medicine, University of Milan Medical
School at the Melloni Hospital, Milan 20129 Italy. E-mail: [email protected].
This Review Article is co-published as a Supplement to the May 2010 issue
of Pediatric Allergy and Immunology.
Copyright 2010 by World Allergy Organization
WAO Journal
April 2010
Revision Panel
Amal Assaad, MD, Division of Allergy and Immunology,
Cincinnati Childrens Hospital Medical Center, Cincinnati,
Ohio, USA.
Carlos Baena-Cagnani, MD, LIBRA foundation Argentina,
Division of Immunology and Respiratory Medicine, De-
57
Fiocchi et al
SECTIONS
1: Introduction, p. 58.
2: Methodology, p. 59.
3: Epidemiology of CMA, p. 61.
4: Allergens of Cows Milk, p. 65.
5: Immunological Mechanisms of CMA, p. 71.
6: Clinical History and Symptoms of CMA, p. 76.
7: Diagnosis of CMA According to Preceding Guidelines, p. 85.
8: The Elimination Diet in Work-Up of CMA, p. 88.
9: Guidelines for Diagnosing CMA, p. 89.
10: Oral Food Challenge Procedures in Diagnosis of CMA,
p. 100.
11: Natural History of CMA, p. 108.
12: Treatment of CMA According to Preceding Guidelines, p. 112.
13: When Can Milk Proteins Be Eliminated From Diet Without
Substituting Cows Milk?, p. 117.
14: Guidelines for Choosing a Replacement Formula, p. 119.
15: Milks From Different Animals for Substituting Cows
Milk, p. 124.
16: Nutritional Considerations in CMA Treatment, p. 128.
58
SECTION 1: INTRODUCTION
Definitions
Adverse reactions after the ingestion of cows milk can
occur at any age from birth and even among infants fed
exclusively at the breast, but not all such reactions are of an
allergic nature. A revision of the allergy nomenclature was
issued in Europe in 20019 and was later endorsed by the
WAO10 under the overarching definition of milk hypersensitivity, to cover nonallergic hypersensitivity (traditionally
termed cows milk intolerance) and allergic milk hypersensitivity (or cows milk allergy). The latter definition requires the activation of an underlying immune mechanism to
fit. In DRACMA, the term allergy will abide by the WAO
definition (allergy is a hypersensitivity reaction initiated by
2010 World Allergy Organization
SECTION 2: METHODOLOGY
59
Fiocchi et al
Little information about costs of diagnosis and treatment of IgE-mediated cows milk allergy was available to the
panel and it is very likely that it varies considerably across
geographical areas and jurisdictions. Cost, therefore, plays a
limited role in these recommendations. However, whenever
we considered cost and resource expenditure, we used health
system perspective.11 For individual patients, cost may not be
an issue if the service or treatment strategy is provided at
reduced price or free of charge. Clinicians and patients should
consider their local resource implications when interpreting
these recommendations.
After the GRADE approach we classified recommendations in these guidelines as either strong or conditional
(also known as weak)/weak. The strength of recommendations depends on a balance between all desirable and all
undesirable effects of an intervention (ie, net clinical benefit),
quality of available evidence, values and preferences, and
cost (resource utilization).1 In general, the higher the quality
of the supporting evidence, the more likely it is for the
recommendation to be strong. Strong recommendations based
on low or very low quality evidence are rare, but possible.12
For strong recommendations we used words we recommend and for conditional recommendations, we suggest. We offer the suggested interpretation of strong and
weak recommendations in Table 2-1. Understanding the
Strong
Recommendation
Weak Recommendation
For
patients
For
clinicians
For policy
makers
60
Introduction
61
Fiocchi et al
rently, at least a score of studies have evaluated the selfperception of CMA over the last 20 years in preschoolers,24 33 school-age children (516 years),20,34 38 and young
adults.20,39 45 From these studies, reviewed in the only metaanalysis in the field,35 the prevalence of self-reports varies
between 1 to 17.5% in preschoolers, 1 and 13.5% in 5 to
16-year-olds, and between 1 and 4% in adults.
The children from these studies neither underwent sensitization testing nor oral food challenge. In a population of
6-year-olds, 1 out of 7 cases was based on self-reports whereas
less than one out of 2 children with a positive cows milk
specific skin prick test was confirmed allergic by DBPCFC,
thereby confirming that most parent-reported symptoms of
CMA are unreliable.46 Not only parents, but also health care
professionals, allergists, and nonallergists alike, cite cows milkinduced reactions as the most common food allergy affecting
children.47 Thus, the incidence of self-reports of CMA remains
of interest for public health authorities, health maintenance
organizations and the processed food industry as a metric for
policy planning, planning diagnostic services;48 tabling labeling
legislation and even meeting the demand for milk-free products.
However, as such, this proxy cannot represent the full extent of
the clinical issues at stake.
62
1st
USA
Germany
Spain
Switzerland
Israel
Japan
Egg
Egg
Egg
Egg
Egg
Egg
2nd
Cows
Cows
Cows
Cows
Cows
Cows
milk
milk
milk
milk
milk
milk
3rd
Peanuts
Wheat
Fish
Peanuts
Sesame
Wheat
63
Fiocchi et al
REFERENCES, SECTION 3
1. Eigenmann PA. Future therapeutic options in food allergy. Allergy.
2003;58:12171223.
2. WHO, World Health Statistics 2009. Available at http://www.who.int/
whosis/whostat/2009/en/print.html, accessed June 30, 2009.
3. ISAAC Phase Three Study Group. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema
in childhood: ISAAC Phases One and Three repeat multicountry crosssectional surveys. Lancet. 2006;368:733743.
4. Good Housekeeping Institute, Consumer Research Department. Childcare findings V, Children and Food. New York: A Good Housekeeping
Report. 1989.
5. Good Housekeeping Institute, Consumer Research Department. Womens opinions of food allergens. New York: A Good Housekeeping
Institute Publication. 1984.
6. Sloan AE, Powers ME, Sloan AE, Powers MD. A perspective on popular
perceptions on adverse reaction to food. J Allergy Clin Immunol.
1986;78:128 133.
7. Young E, Stoneham MD, Petruckeirtch A, et al. A population study of
food intolerance. Lancet. 1994;343:112731.
8. Jansen JJ, Kardinnal AF, Huijbers G, Vlieg-Boerstra BJ, Martens BP,
Ockhuizen T. Prevalence of food allergy and intolerance in the adult
Dutch population. J Allergy Clin Immunol. 1994;93:446 456.
9. Bjornsson E Janson C, Plaschke P, Norrman E, Sjoberg O. Prevalence of
sensitization to food allergens in adult Swedes. Ann Allergy, Asthma
Immunol. 1996;77:327332.
10. Osterballe M. The clinical relevance of sensitization to pollen-related
fruits and vegetables in unselected pollen-sensitized adults. Allergy.
2005;60:218 225.
11. Zuberbier T. Prevalence of adverse reactions to food in Germany.
Allergy. 2004;59:338 345.
12. Woods RK, Stoney RM, Raven J, Walters EH, Abramson M, Thien FC.
Reported adverse reactions overestimate true food allergy in the community. Eur J Clin Nutr. 2002;56:3136.
13. Fiocchi A, Bouygue GR, Terracciano L, Sarratud T, Martelli A. The
march of allergic children - excluding allergy in paediatric practice.
Allergy Asthma Proc. 2006;27:306 311.
14. Miyazawa T, Itahashi K, Imai T. Management of neonatal cows milk
allergy in high-risk neonates. Pediatr Int. 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 among school children in The Netherlands. Eur J Clin Nutr. 1998;
52:577581.
16. Eggesbo M, Botten G, Halvorsen R, Magnus P. The prevalence of
allergy to egg: a population-based study in young children. Allergy.
2001;56:403 411.
17. Halmerbauer G, Gartner C, Schierl M, Arshad H, Dean T, et al. Study on
the Prevention of Allergy in Children in Europe (SPACE): Allergic
sensitization in children at 1 year of age in a controlled trial of allergen
avoidance from birth. Pediatr Allergy Immunol. 2002;13(s15):4754.
18. Bock SA. The natural history of food sensitivity. J Allergy Clin Immunol. 1982;69:173177.
19. Bock SA. Prospective appraisal of complaints of adverse reactions to
foods in children during the first three years of life. Pediatrics. 1987;
79:683 688.
20. Steinke M, Fiocchi A, the REDALL group. Perceived Food allergy in
children. A report on a representative telephone survey in 10 European
countries. Int Arch Allergy Asthma Immunol. 2007;143:290 295.
21. Kilgallen I, Gibney MJ. Parental perception of food allergy or intolerance in children under 4 years of age. J Hum Nutr Diet. 1996;9:473 478.
22. Sandin A, Annus T, Bjorksten B, Nilsson L, Riikjarv MA, van HageHamsten M, Brback L. Prevalence of self-reported food allergy and IgE
antibodies to food allergens in Swedish and Estonian schoolchildren.
Eur J Clin Nutr. 2005;59:399 403.
23. Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, et al. The
prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol.
2007;120:638 646.
24. Rance F, Grandmottet X, Grandjean H. Prevalence and main characteristics of schoolchildren diagnosed with food allergies in France. Clin
Exp Allergy. 2005;35:167172.
25. Dalal I, Binson I. Food allergy is a matter of geography after all: sesame
64
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
65
Fiocchi et al
Protein
Caseins
Allergen10
Bos d 8
s1-casein
s2-casein
-casein
1-casein
2-casein
3-casein
-casein
Whey proteins
Alpha-lactalbumin
Beta-lactoglobulin
Immunoglobulin
BSA*
Lactoferrin
Bos
Bos
Bos
Bos
d4
d5
d7
d6
g/L
% Total Protein
30
1215
34
911
80
29
8
27
MW (kDa)
# AA
pI
10
23.6
25.2
24.0
20.6
11.8
11.6
19.0
199
207
209
180
104
102
169
4.95.0
5.25.4
5.15.4
5.5
6.4
5.8
5.45.6
12
34
5.0
11.5
34
0.61.0
0.10.4
0.09
20
5
10
3
1
Traces
14.2
18.3
160.0
67.0
800.0
123
162
583
703
4.8
5.3
4.95.1
8.7
Introduction
Milk can give rise to several food hypersensitivities,
usually classified as milk allergy or milk intolerance.1 The
mechanism of intolerance to cows milk is not IgE antibodymediated and has been blamed on the functionality of a
specific enzyme deficiency, commonly lactose intolerance,
attributable to beta-galactosidase (lactase) deficiency.
DRACMA will not address lactase deficiency or other cows
milk-induced hypersensitivity not mediated by immune
mechanisms, which have been described in detail elsewhere.25 Cows milk allergy is an adverse clinical reaction
associated with the binding of immunoglobulin (IgE) to
antigens capable of eliciting an immune response.6 Where
allergy is not mediated by IgE, other classes of immunoglobulin, immune complexes, or a cell-mediated reaction have
been proposed to be involved. In IgE-mediated allergy, circulating antibodies recognize specific molecular regions on
the antigen surface (epitopes), which are classified according
to their specific amino acid sequence (sequential epitopes) or
the folding and configuration of their protein chains (conformational epitopes). In this section, we describe the chemical
characteristics of cows milk allergens, how they are involved
in cross-reactivity among mammalian species, their resistance to digestion and proteolysis and their response to
technological processing.
66
Alpha-Lactalbumin (Bos d 4)
Alpha-lactalbumin (A-LA) is a whey protein belonging to
the lysozyme superfamily. It is a regulatory subunit of lactose
synthase and is, able to modify the substrate specificity of
galactosyl-transferase in the mammary gland, making glucose a
good acceptor substrate for this enzyme and allowing lactose
synthase to synthesize lactose.11,12 A-LA is produced by the
mammary gland and has been found in all milks analyzed so far.
Table 4-2 shows its main chemical characteristics.
TABLE 4-2. Characteristics of Alpha-Lactalbumin (Bos d 4)
Parameter
Description
Allergen nomenclature
Entry name
Synonyms
Sequence databases
Number of aminoacids
Molecular weight
Isoelectric point
Involvement in allergic sensitization
to cows milk
Bos d 4
LALBA_BOVIN
Lactose Synthase B protein
Genbank: M18780
PIR: A27360, LABO
Swiss-Prot: P00711
123 residues
14.2 kDa
4.8
080% CM allergic subjects
75% CM allergic children by SPT
A-LA contains 8 cysteine groups, all forming internal disulphide bonds, and 4 tryptophan residues. It contains high-affinity calcium binding sites stabilizing its
highly ordered secondary structure. The role of A-LA in
milk allergy is controversial and prevalence data across
studies vary between 0 and 80% of patients reacting to this
protein (reviewed in13). This heterogeneity is probably
linked to whether skin prick test, specific IgE determinations, immunoblotting, or other method of sensitization
assessment was used.
Beta-Lactoglobulin (Bos d 5)
Beta-lactoglobulin (BLG) is the most abundant cows
milk whey protein; it occurs in the milk of many other
mammalian species but is not present in human milk. Bos d
5 belongs to the lipocalin allergen family and is synthesized
by the mammalian gland. Its function is unknown, although it
may be involved in retinol transport, with which it readily
binds.14 Table 4-3 shows its main physical and chemical
characteristics. It contains 2 internal disulphide bonds and
one freeSH group. Under physiological conditions, BLG
exists as an equilibrium mixture of monomer and dimer
forms but, at its isoelectric point, the dimers can further
associate to octamers. There are 2 main isoforms of this
protein in cows milk, the genetic variants A and B, which
differ only by 2 point mutations at amino acids 64 and 118.
Because it is lacking from human milk, BLG has long been
believed to be the most important cows milk allergen. The
literature indicates that the prevalence of allergic subjects
reacting to this protein is between 13 and 76%.15
Number of aminoacids
Molecular weight
Isoelectric point
Involvement in allergic sensitization
to cows milk
Description
Bos d 6
ALBU_BOVIN
BSA
Genbank: M73993
PIR: A38885, ABBOS
Swiss-Prot: P02769
583 residues
67.0 kDa
4.95.1
088% CM allergic subjects
62.5% CM allergic children by
immunoblotting
Immunoglobulins (Bos d 7)
Bovine immunoglobulins are present in blood, tissues,
fluids, and secretions such as milk. Some characteristics of
the bovine IgG are shown in Table 4-5. Bovine IgG seldom
cause clinical symptoms in CMA.18
Caseins (Bos d 8)
Most of the casein aggregates as colloidal particles (the
casein micelle) and its biologic function is to transport calcium phosphate to the mammalian newborn. More than 90%
of the calcium content of skim milk is attached to or included
in casein micelles. Caseins consist of 4 different proteins
(alphas1, alphas2, beta, and kappa casein) with little sequential
homology. Another group, the gamma caseins, are present in
very low quantities in milk and are by-products of beta casein
proteolysis. A distinguishing feature of all caseins is their low
solubility at pH 4.6; another common characteristic is that
caseins are conjugated proteins, most with phosphate
groups esterified to the amino acid serine. Caseins contain
Number of aminoacids
Molecular weight
Isoelectric point
Involvement in allergic sensitization
to cows milk
Description
Bos d 5
LACB_BOVIN
Genbank: X14712
PIR: S10179, LGBO
Swiss-Prot: P02754
162 residues
18.3 kDa
5.135.23 (variants)
1376% CM allergic subjects
73.7% CM allergic children by SPT
Description
Bos d 7
IgG
160.0 kDa
Frequency unknown
67
Fiocchi et al
s1-casein
s2-casein
-casein
-casein
Allergen nomenclature
Entry name
Synonyms
Sequence databases
Bos d 8
CAS1_BOVIN
None
G X00564/M33123
P S22575/KABOSB
S P02662
199
23.6 kDa
4.95.0
65100%
Bos d 8
CAS2_BOVIN
None
G M16644
P JQ2008/KABOS2
S P02663
207
25.2 kDa
5.25.4
65100%
Bos d 8
CASB_BOVIN
None
G M16645/X06359
P I45873/KBBOA2
S P02666
209
24.0 kDa
5.15.4
65100%
Bos d 8
CASK_BOVIN
None
G X14908/M36641
P S02076/KKBOB
S P02668
169
19.0 kDa
5.45.6
65100%
54%
100%
54%
100%
39%
66.7%
NT
91.7%
No. aminoacids
Molecular weight
Isoelectric point
Involvement in allergic sensitization
to cows milk1. whole casein
Involvement in allergic sensitization
to cows milk2. single casein
dae (horse and donkey), and Camelidae (camel and dromedary) families and also with those in human milk. It is
noteworthy that the milks of camels and dromedaries (as well
as human milk) do not contain BLG.
However, phylogeny does not explain everything. In
1996, a clinical trial in France showed that 51/55 children
with cows milk allergy tolerated goats milk for periods
ranging from 8 days to 1 year,22 but subsequent research
showed that other subjects allergic to cows milk did not
tolerate goats and sheeps milks.23 This is consistent with the
pattern of IgE cross-reactivity shown by several independent
studies in vitro, for instance the cross-reactivity between milk
proteins from different mammalian species (including goats
milk).24 Furthermore, selective allergy to goats and sheeps
milk but not to cows milk has also been reported in 28 older
children with severe allergic reactions, including anaphylaxis.
In one study, IgE antibodies recognized caseins from goats
milk but cows milk caseins were not or scarcely recognized.25 This is not an isolated finding,26,27 however, and a
case report of an adult with goats milk allergy without CMA
found specific IgE to caprine ALA.28 Finally, allergy to
sheeps milk can also evolve into allergy to cows milk.29
Mares and donkeys milks have proved sometimes useful to
some patients,30 32 but uncertainties remain about chemical
composition and hygienic control. The same considerations
apply to Camellidae (camel and dromedaries) milks, which
could represent an alternative to cows milk for allergic
subjects because of their low sequence homology with cows
TABLE 4-7. Sequence Homology Between Mammalian Milk Proteins (in Percentage, Relative To Cows Milk Proteins)
Protein
Goat
Ewe
Buffalo
Sow
Mare
Donkey
Dromedary
Human
ALA
BLG
Serum alb.
s1 CAS
s2 CAS
CAS
CAS
95.1
94.4
87.9
88.3
91.1
84.9
97.2
93.9
92.4
88.3
89.2
92.0
84.9
99.3
96.7
97.8
92.6
74.6
63.9
79.9
47.2
62.8
67.0
54.3
72.4
59.4
74.5
60.5
57.4
71.5
56.9
74.1
69.7
Absent
42.9
58.3
69.2
58.4
73.9
Absent
76.6
32.4
56.5
53.2
68
milk and the absence of BLG, if problems related to availability and technological processing to avoid new sensitization.33
Figure 4-1 shows the electrophoretic patterns of milk
from several mammalian species. The pronounced similarity
is evident for milk from cows, goats, and sheep, while the
protein profiles of mares, donkeys, and camels milks
present some specificities. The low cross-immunoreactivity
of horse/donkey milk and the absence of BLG in camels and
human milk is easily visible in immunoblots using antibodies
against bovine BLG.
69
Fiocchi et al
70
37. Norgaard A, Bernard H, Wal JM, Peltre G, Skov PS, Poulsen LK,
Bindslev-Jensen C. Allergenicity of individual cow milk proteins in
DBPCFC-positive milk allergic adults. J Allergy Clin Immunol. 1996;
97(Pt 3):237.
38. Werfel SJ, Cooke SK, Sampson HA. Clinical reactivity to beef in children
allergic to cows milk. J Allergy Clin Immunol. 1997;99:293300.
39. Restani P, Ballabio C, Cattaneo A, Isoardi P, Terracciano L, Fiocchi A.
Characterization of bovine serum albumin epitopes and their role in
allergic reactions. Allergy. 2004;59(Suppl 78):2124.
40. Sampson HA. Update on food allergy. J Allergy Clin Immunol. 2004;
113:805 819.
41. Roth-Walter F, Berin MC, Arnaboldi P, Escalante CR, Dahan S, Rauch
J, Jensen-Jarolim E, Mayer L. Pasteurization of milk proteins promotes
allergic sensitization by enhancing uptake through Peyers patches.
Allergy. 63:882 890.
42. Fenaille F, Parisod V, Tabet J-C, Guy PA. Carbonylation of milk powder
proteins as a consequence of processing conditions. Proteomics. 2005;
5:30973104.
43. Restani P, Velona` T, Plebani A, Ugazio AG, Poiesi C, Muraro A, Galli
CL. Evaluation by SDS-PAGE and immunoblotting of residual antigenicity in hydrolysed protein formulas. Clin Exp Allergy. 1995;25:651
658.
44. Penas E, Restani P, Ballabio C, Prestamo G, Fiocchi A, Gomez R.
Evaluation of the residual antigenicity of dairy whey hydrolysates
obtained by combination of enzymatic hydrolysis and high-pressure
treatment. J Food Prot. 2006;69:17071712.
45. Restani P, Ballabio C, Fiocchi A. Milk allergens: chemical characterization, structure modifications and associated clinical aspects. In: Pizzano R, ed. Immunochemistry in dairy research. Research Signpost,
Kerala. 2006;6176.
Introduction
Acquired immunologic tolerance of environmental agents
is an active mechanism of adaptive immunity that is mediated by
polarized cells of the T helper type I lymphocyte subset but
when, in an atopic individual, the predisposition to secrete IgE
antibody to cows milk antigen goes into overdrive, homeostasis
breaks down and mast cells can become sensitized anywhere in
the body, thereby expressing an often baffling array of symp-
71
Fiocchi et al
GUT BARRIER
The mucosal immune system must adapt and be able to
discriminate between pathogens and harmless antigens and
respond accordingly, that is, to protect the neonate from
enteric pathogens while establishing a state of tolerance to
dietary proteins and commensal bacteria. This important task
is undertaken by cells of the gut-associated lymphoid tissue,
the largest immunologic organ in the body.2 Many studies
have reported increased macromolecular transport across the
gut barrier in children with atopy3,4 which is thought to be
because of mucosal damage induced by local hypersensitivity
reaction to foods.5 Dual sugar intestinal permeability studies
(lactulose/mannitol) showed that in breast-fed infants with
atopy, gut barrier function improved when breast-feeding was
stopped and hypoallergenic formula started.6
ORAL TOLERANCE
The mucosa allows nutrients to be transferred from the
intestinal lumen to the systemic circulation, while protecting
against pathogens by inducing immune responses. Any
down-regulation of immune responses to nonharmful ingested antigens is termed oral tolerance.7 Normally, mature
lymph node lymphocytes become hyporesponsive after oral
administration of these antigens.8
Ingested milk proteins are degraded and their conformational epitopes are destroyed by gastric acid and luminal
digestive enzymes, which often results in the destruction of
immunogenic epitopes. In animal models, disrupting the
process of digestion can inhibit milk tolerance and lead to
hypersensitivity. Untreated bovine serum albumin (BSA) is
immunogenic when administered to mice by means of ileal
injection, but administering a peptic digest of the protein in
the same manner results in immune tolerance.9
Regulatory events after mucosal exposure to antigen
have not been well characterized and remain controversial. In
general, the acquisition of tolerance to milk is seen as a
TH1-skewed response, which on the one hand may prevent
harmful mucosal immune reactions but on the other may
contribute to adverse responses in a susceptible individual.
The process starts with the contact of milk allergens with the
intestinal mucosa. Here they interact with mucosal T and B
cells either directly or through antigen-presenting cells
(APCs): macrophages, dendritic cells, or microfold cells (M
cells). T cell recognition of antigen by T cell receptors (TCR)
involves the major histocompatibility complex (MHC) molecules (class I and II) of APCs. Activated T and B cells of
lymphoid follicles migrate first via the lymphatic system and
then via the circulation to any of several target organs
including the gastrointestinal tract, the respiratory system, the
skin, and the central nervous system, a process referred to as
homing. If tolerance is not achieved, T and B cells will
activate at a homing site upon contact with their specific food
antigen and release their cytokines, vasoactive peptides and
72
this context. The probiotic effects of complex oligosaccharides in human milk promote the establishment of a bididogenic microbiota which, in turn, induces a milieu of
tolerogenic immune responses to foods. Several probiotic
bacterial strains have been shown to have similar properties. For example, Lactobacillus paracasei inhibits TH1
and TH2 cytokine production, and induces CD4() T cells
to produce TGF- and IL-10, that is, induces a tolerogenic
response.24 It appears possible that the recent decrease in
exposure to early childhood infections and harmless environmental microorganisms in the westernized environment
has contributed to an increase in T-cell dysregulatory
disorders and autoimmunity.25,26
DYSFUNCTIONAL TOLERANCE
CMA is believed to result from the failure to develop
normal tolerogenic processes or their later breakdown. In the
case of IgE-mediated CMA, a deficiency in regulation and a
polarization of milk-specific effector T cells toward type-2 T
helper cells (TH2) both lead to B-cell signaling to produce
milk protein-specific IgE.27,28 Non-IgE-mediated reactions
may be because of TH1-mediated inflammation.29 Dysfunctional Treg cell activity has been identified as a factor in both
allergy mechanisms.30 Additionally, the induction of tolerance in children who have outgrown their CMA has been
shown to be associated with the development of Treg
cells.31,32 Much research is currently focused on manipulating
the activity of dendritic cells (specialized antigen-presenting
cells important in programming immune responses) to induce
Treg cells and/or to redress TH1/TH2 imbalances to promote
tolerance to allergenic foods.
MILK ALLERGY
An effect of dysfunctional tolerance, milk allergy
designates objectively reproducible symptoms or signs initiated by exposure to cows milk at a dose tolerated by normal
persons.40 The term CMA is appropriate when specific immunologic mechanisms have been demonstrated (see definitions in introductory section). Milk allergy can be either
antibody-mediated or cell-mediated, or occasionally both
may be involved. If IgE is involved in the reaction, the term
atopic food allergy is appropriate. If immunologic mechanisms other than IgE are predominantly involved, the term
non-IgE-mediated food allergy should be used. All other
reactions should be regarded to as nonallergic food hypersensitivity.41
Enhanced immune-mediated reactivity may come
about though any, or a combination of, the 4 basic types of
immunologic reactions outlined by Gell and Coombs:
a. Type I or IgE-mediated hypersensitivity leads to immediate symptoms, such as urticaria, angioedema and/or
other anaphylactic reaction
b. In type II (cytotoxic) reactions, the antigen binds to the
cell surface and the presence of antibodies (IgG, IgM,
or IgA) disrupts the membrane, leading to cell death
c. In type III (Arthus-type) reactions, antigen-antibodycomplement immune complexes (IgG, IgM, IgA, and
IgE antibodies) get trapped in small blood vessels or
renal glomeruli.
d. Type IV (delayed) reactions are mediated by sensitized
T lymphocytes.
Type I reactions are the best understood, and they are often
referred to as the most common and classic allergic reactions.
The 3 other types, collectively described as non-IgE-mediated allergy, are more difficult to investigate and hence less
well understood. In an individual, several types of immune
responses may be activated, although IgE-mediated reactions
are more usually measured.
IGE-MEDIATED CMA
(IMMEDIATE HYPERSENSITIVITY)
IgE-mediated allergy is the best understood allergy
mechanism and, in comparison to non-IgE-mediated reactions, is relatively easily diagnosed. Since the onset of symp-
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Fiocchi et al
NON-IGE-MEDIATED CMA
(DELAYED HYPERSENSITIVITY)
A significant proportion of infants and the majority of
adults with CMA do not have circulating milk proteinspecific IgE and show negative results in skin prick tests and
serum IgE determinations (immune-CAP).53,54 These nonIgE-mediated reactions tend to be delayed, with the onset of
symptoms occurring from 1 hour to several days after ingestion of milk. Hence, they are often referred to as delayed
hypersensitivity. As with IgE-mediated reactions, a range of
symptoms can occur, but are most commonly gastrointestinal
or cutaneous.55 The gastrointestinal symptoms, such as nausea, bloating, intestinal discomfort, and diarrhea, mimic many
symptoms of lactose intolerance and may lead to diagnostic
mislabeling. Anaphylaxis is not a feature of non-IgE mediated mechanisms. IgE- and non-IgE-mediated reactions are
not mutually exclusive and reactions to milk can involve a
mixture of immunologic mechanisms.
The precise immunologic mechanisms of non-IgE-mediated CMA remain unclear. A number of mechanisms have
been suggested, including TH1-mediated reactions (Fig.
5-1),56 63 the formation of immune complexes leading to the
74
activation of complement,64,65 or T-cell/mast cell/neuron interactions inducing functional changes in smooth muscle
action and intestinal motility.1,66,67 A necessarily incomplete
picture of such mechanisms indicates that T cells act through
secretion of cytokines such as IL-3, IL-4, IL-5, IL-13, and
GM-CSF, activating eosinophils, mastocytes, basophils, and
macrophages. Macrophages, activated by CM protein allergens by cytokines, are able to secrete in turn vasoactive
mediators (PAF, leukotriens) and cytokines (IL-1, IL-6, IL-8,
GM-CSF, TNF-) that are able to increase the cellular phlogosis. This involves epithelial cells, which release cytokines
(IL-1, IL-6, IL-8, IL-11, GM-CSF), chemokines (RANTES,
MCP-3, MCP-4, eotaxin) and other mediators (leukotrienes,
PGs, 15-HETE, endothelin-1). This mechanism results in
chronic cellular inflammation (at GI, cutaneous, and respiratory levels) and ultimately in CMA symptoms. When the
inflammatory process is localized at GI level, immune phlogosis can contribute to maintaining epithelial hyper-permeability and potentially to increased exposure to antigenic CM
proteins. This involves TNF- and IFN-, antagonists of
TGF- and IL-10 in mediating oral tolerance.68 It has been
shown that the pattern of TNF- secretion is different in
children with CMA manifested by digestive or cutaneous
symptoms, and the use of TNF- secretion in response to
cows milk antigens has been proposed as a predictive test of
relapse in CMA children undergoing oral provocation.69 In
addition, CMP sensitization of TH1 and TH2 lymphocytes has
been shown at the systemic level in conditions out of the
CMA spectrum as neonatal necrotizing enterocolitis.70
From the discrepancy between reportedly higher rates
of natural recovery during childhood from non-IgE-mediated
CMA than in IgE-mediated CMA7173 and the predominance
of non-IgE-mediated CMA in adult populations49 it has been
postulated that a non-IgE-mediated CMA population emerges
later in life. One study reported an increasing incidence of
non-IgE-mediated food allergies with increasing age.50 However, the emergence of a new CMA population in adults
remains to be conclusively demonstrated. Good epidemiological data for non-IgE-mediated CMA in both adults and
children remain scarce because laborious DBPCFC trials
remain the only conclusive diagnostic tests to confirm this
form of allergy. In many cases, gastrointestinal food allergy
remains undiagnosed or is classified as irritable bowel syndrome.
REFERENCES, SECTION 5
1. Crittenden RG, Bennett LE. Cows milk allergy: a complex disorder.
J Am Coll Nutr. 2005;24(Suppl):582S591S.
2. van Wijk F, Knippels L. Initiating mechanisms of food allergy: Oral
tolerance versus allergic sensitization. Biomed Pharmacother. 2007;61:
8 20.
3. Majamaa H, Isolauri E. Evaluation of gut mucosal barrier: evidence for
increased antigen transfer in children with atopic eczema. J Allergy Clin
Immunol. 1996;97:985990.
4. Pike MG, Heddle RJ, Boulton P. Increased intestinal permeability in
atopic eczema. J Invest Dermatol. 1986;86:101104.
5. Strobel S, Brydon WG, Ferguson A. Cellobiose/mannitol sugar permeability test complements biopsy histopathology in clinical investigation
of the jejunum. Gut. 1984;25:12411246.
6. Arvola T, Moilanen E, Vuento R, Isolauri E. Weaning to hypoallergenic
formula improves gut barrier function in breast-fed infants with atopic
eczema. J Pediatr Gastroenterol Nutr. 2004;38:9296.
7. Shah U, Walker WA. Pathophysiology of intestinal food allergy. Advances in Pediatrics. 2002;49:299 316.
8. Burks AW, Laubach S, Jones SM. Oral tolerance, food allergy, and
immunotherapy: implications for future treatment. J Allergy Clin Immunol. 2008;121:1344 1350.
9. Michael JG. The role of digestive enzymes in orally induced immune
tolerance. Immunol Invest. 1989;18:1049 1054.
10. Sabra A, Bellanti JA, Rais JM, Castro HJ, de Inocencio JM, Sabra S. IgE
and non-IgE food allergy. Ann Allergy Asthma Immunol. 2003;90(Suppl
3):7176.
11. Chehade M, Mayer L. Oral tolerance and its relation to food hypersensitivities. J Allergy Clin Immunol. 2005;115:312.
12. Strobel S. Oral tolerance, systemic immunoregulation, and autoimmunity. Ann N Y Acad Sci. 2002;958:4758.
13. Strobel S, Mowat AM. Oral tolerance and allergic responses to food
proteins. Curr Opin Allergy Clin Immunol. 2006;6:207213.
14. Mestecky J, McGhee JR. Immunoglobulin A (IgA): molecular and
cellular interactions involved in IgA biosynthesis and immune response.
Adv Immunol. 1987;40:153245.
15. Ludviksson BR, Eiriksson TH, Ardal B, Sigfusson A, Valdimarsson H.
Correlation between serum immunoglobulin A concentrations and allergic manifestations in infants. J Pediatr. 1992;121:2327.
16. Walker-Smith J. Cows milk allergy: a new understanding from immunology. Ann Allergy Asthma Immunol. 2003;90(Suppl 3):81 83.
17. Kokkonen J, Haapalahti M, Laurila K, Karttunen TJ, Maki M. Cows
milk protein sensitive enteropathy at school age. J Ped. 2001;139:797
803.
18. Rothberg RM, Farr RS. Anti-bovine serum albumin and antialpha
lactalbumin in the serum of children and adults. Pediatrics. 1965;35:
571578.
19. Schmidt-Weber CB, Blaser K. T-cell tolerance in allergic response.
Allergy. 2002;57:762768.
20. Curotto de Lafaille MA, Lafaille JJ. CD4 regulatory T cells in autoimmunity and allergy. Curr Opinion Immunol. 2002;14:771778.
21. Duez C, Gosset P, Tonnel AB. Dendritic cells and toll-like receptors in
allergy and asthma. Eur J Dermatol. 2006;16:1216.
22. Rautava S, Kalliomaki M, Isolauri E. New therapeutic strategy for
combating the increasing burden of allergic disease: probioticsa Nutrition, Allergy, Mucosal Immunology and Intestinal Microbiota (NAMI)
Research Group report. J Allergy Clin Immunol. 2005;116:3137.
23. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri
R. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T
helper 2 cells. J Exp Med. 2004;199:15671575.
24. von der Weid T, Bulliard C, Schiffrin EJ. Induction by a lactic acid
bacterium of a population of CD4() T cells with low proliferative
capacity that produce transforming growth factor beta and interleukin10. Clin Diagn Lab Immunol. 2001;8:695701.
25. Romagnani S. The increased prevalence of allergy and the hygiene
hypothesis: missing immune deviation, reduced immune suppression, or
both? Immunology. 2004;112:352363.
26. Rook GA, Brunet LR. Microbes, immunoregulation, and the gut. Gut.
2005;54:317320.
27. Beyer K, Castro R, Birnbaum A, Benkov K, Pittman N, Sampson HA.
Human milk-specific mucosal lymphocytes of the gastrointestinal tract
display a Th2 cytokine profile. J Allergy Clin Immunol. 2002;109:707
713.
28. Schade RP, Tiemessen MM, Knol EF, Bruijnzeel-Koomen CA, van
Hoffen E. The cows milk protein-specific T cell response in infancy and
childhood. Clin Exp Allergy. 2003;33:725730.
29. Tiemessen MM, van Hoffen E, Knulst AC, van der Zee JA, Knol EF,
Taams LS. CD4_CD25_ regulatory T cells are not functionally impaired
in adult patients with IgE-mediated cows milk allergy. J Allergy Clin
Immunol. 2002;110:934 936.
30. Perez-Machado MA, Ashwood P, Thomson MA, Latcham F, Sim R,
Walker-Smith JA, Murch SH. Reduced transforming growth factorbeta1-producing T cells in the duodenal mucosa of children with food
allergy. Eur J Immunol. 2003;33:23072315.
31. Karlsson MR, Rugtveit J, Brandtzaeg P. Allergen-responsive
CD4_CD25_ regulatory T cells in children who have outgrown cows
milk allergy. J Exp Med. 2004;199:1679 1688.
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76
IMMDIATE CMA
The most severe form of CMA is cows milkinduced anaphylaxis. Anaphylaxis is a severe systemic or
generalized allergic reaction that is potentially life-threatening. Symptoms typically involve classic allergic symptoms of the skin and one or more other target organs, that
is, the gastrointestinal tract, the respiratory tract, and/or the
cardiovascular system. Milk-induced anaphylaxis may
also be provoked by exercise in patients (food-dependent
exercise-induced anaphylaxis) with previously resolved
CMA or after oral desensitization, and may occur in
biphasic and protracted forms. In various series of anaphylaxis, CMA accounted for 1128% of reactions, including up to 11% of fatal reactions.
Gastrointestinal reactions may elicit symptoms from
the mouth to the lower bowel. After the ingestion of milk,
immediate symptoms similar to the oral allergy syndrome
may occur including lip swelling, oral pruritus, tongue
swelling, and a sensation of tightness in the throat. Immediate symptoms involving the stomach and upper intestinal
tract include nausea, vomiting and colicky abdominal
pain, while symptoms occurring in the lower intestinal
tract include abdominal pain, diarrhea, and occasionally
bloody stools.
Cutaneous reactions are among the most common
because of CMA in children, and most frequently result in
urticaria. However, skin symptoms may also include generalized maculopapular rashes, flushing, and angioedema.
Symptoms may be because of ingestion or contact with
milk proteins on the skin.
Respiratory symptoms because of CMA rarely occur
in isolation, but upper airway symptoms, for example,
nasal pruritus and congestion, rhinorrhea, and sneezing,
occur in about 70% of children undergoing oral milk
challenges. Lower respiratory symptoms, for example,
wheezing, dyspnea, and chest tightness, are less common,
but are more serious and are largely responsible for poor
2010 World Allergy Organization
LATE-ONSET CMA
Symptoms of late-onset CMA are not IgE-mediated
and typically develop one to several hours or after several
days of ingesting cows milk. There are no reliable laboratory tests to diagnose late-onset CMA and tests for IgE
antibodies are negative. The majority of disorders involving late-onset CMA are localized to the gastrointestinal
tract, but disorders involving the skin and respiratory tract
also occur.
Cutaneous symptoms most often present as a form of
eczema because of ingestion or contact with cows milk.
Atopic dermatitis may involve both IgE- and non-IgE
mediated mechanisms in the skin. Up to one third of
children with moderate to severe atopic dermatitis are food
allergic and CMA is the second most common food
allergy in this population. Appropriate diagnosis and elimination of milk products from the diets of affected children
frequently leads to improvement in eczematous symptoms.
Gastrointestinal symptoms of CMA may present as a
variety of different disorders: cryco-pharyngeal spasm,
GERD-like symptoms and allergic eosinophilic esophagitis (EoE), pyloric stenosis, milk protein-induced enterocolitis syndrome, enteropathy or gastroenteritis and proctocolitis, constipation, and irritable bowel syndrome.
Symptoms of gastrointestinal CMA frequently involve
nausea, vomiting, abdominal pain, diarrhea, and in more
chronic disorders, malabsorption and failure to thrive or
weight loss. Some patients presenting with crico-pharyngeal spasm and pyloric stenosis have been found to have
CMA and respond to removal of cows milk from their
diets. Allergic EoE has become more prevalent over the
past decade and is characterized by dysphagia, chest and
abdominal pain, food impaction and food refusal, and in
more severe cases, failure to thrive or weight loss, which
are unresponsive to antireflux medications. Many patients
with EoE have IgE antibodies to some foods and environmental allergens, but the inflammation of the esophagus is
believed to be largely secondary to non-IgE-mediated
mechanisms. CMA is one of the most common causes of
food protein-induced enterocolitis syndrome (FPIES), a
form of non-IgE-mediated allergy that develops 1 to 3
hours after the ingestion of milk protein and results in
repetitive vomiting, hypotonia, pallor, and sometimes hypotension and diarrhea. FPIES frequently occurs with the
first introduction of cows milk into the diet, but has not
been reported in infants while being exclusively breastfed. Remission usually develops within the first few years
of life. Cows milk-induced enteropathy syndrome is a
rare disorder that typically presents as diarrhea, failure to
thrive, and various degrees of vomiting and occasionally
hypoproteinemia and blood streaked stools. While most
children with this disorder respond to extensively hydro 2010 World Allergy Organization
Introduction
As a wide spectrum of adverse reactions may follow the
ingestion of milk, clinical history is essential to reach a
diagnosis in a patient presenting with suspected CMA. Adverse reactions to cows milk can be classified on the basis of
immunologic and nonimmunologic mechanisms, both of
which may induce similar clinical presentations. Immunologic reactions include IgE- and non-IgE-mediated reactions.
There are also conditions, such as irritable bowel syndrome or inflammatory bowel disease, in which some symptoms may induce the suspicion of reactions to milk, while
there may be no consistent connection. It is important to
differentiate these conditions, as history may not always be
relied on to link symptoms with food ingestion. In particular,
patients with psychologic disorders may attribute adverse
reactions to milk ingestion. Physicians must also make their
patients aware that cows milk allergy is not a frequent
occurrence in adults, that cows milk intolerance is widespread and that thus milk allergy may not be the cause of their
complaint.
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Fiocchi et al
I: Anaphylaxis
The most severe manifestation of immediate CMA is
anaphylaxis. Currently defined as a severe systemic or
generalized severe allergic reaction,8 this potentially lifethreatening condition greatly adds to the burden of living with
milk allergy. Diagnostic criteria include sudden onset involving skin, mucosa, or both, with at least one respiratory
symptom such as dyspnoea, bronchospasm, stridor, PEF
reduction, hypoxaemia, fall in blood pressure, organ dysfunction symptoms (hypotonia, syncope, etc), gastrointestinal
symptoms (colic, vomiting), and shock.9 This happens almost
immediately (within minutes and up to 2 hours) after the
ingestion of cows milk or dairy products and is clinically
similar to anaphylaxis from foods other than CM.10 An
anaphylactic reaction may include the after:
a. Cutaneous symptoms, from localized flushing to generalized urticaria, including palmo-plantar, perioral, and
periorbital pruritus.1113
b. Respiratory symptoms, ranging from nasal to asthmatic
symptoms,14 described in up to 79% of cases15 and
associated with mortality.16
c. Gastrointestinal symptoms, including oral allergy syndrome, nausea, abdominal pain, vomiting, or diarrhea. It
has been observed that these symptoms may be predictive of progression to severe anaphylaxis.17
d. Cardiovascular symptoms, reported in 17 to 21% of
food-allergic anaphylactic reactions.9,10,14 Reduced
blood pressure leading to vascular collapse, syncope, or
incontinence have been reported.8
e. Neurologic symptoms reported include tremors, mental
confusion, syncope and seizure.
Anaphylaxis may also present with a biphasic and protracted onset18,19 and a form of food-dependent, exerciseinduced anaphylaxis (FDEIA) is recognized.20,21 FDEIA in
78
milk allergy is of particular severity.44 During food challenges, rhinitis occurs in about 70% of reactions and asthma
in up to 8%.45 48 Children with such symptoms associated
with CMA may subsequently develop respiratory allergy.49
Contact Urticaria
The reaction patterns that can occur upon contact with
milk range from irritant contact dermatitis to allergic contact
dermatitis. The ingestion of milk by sensitized individuals
can provoke a generalized eczematous rash, referred to as
systemic contact dermatitis (see atopic dermatitis). Other
contact reactions to food include contact urticaria, which is
often encountered in patients with atopic dermatitis.58
V: Miscellanea
Some food allergies, and CMA in particular, have been
hypothetically implicated in epilepsy59 and reports of a high
incidence of sensitization to cows milk among epileptic
children60 need to be confirmed with oral food challenges.
Another symptom associated with IgE-mediated CMA is
transient hypogammaglobulinaemia in infancy, which is
characterized by reduced IgG and IgA antibody levels and
preserved functional antibody response.61 Children with primary immunodeficiencies such as hyper-IgE syndromes can
also present with CMA in the context of these conditions.62,63
Late-Onset Reactions
In the section on Mechanisms of CMA we reported that
many infants and most adults with late-onset CMA do not
show circulating milk-specific IgE antibodies and test negative by skin prick testing and assays of serum milk-specific
2010 World Allergy Organization
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Fiocchi et al
to-thrive. In addition to well-recognized immediate-type IgEmediated allergies, a wide variety of more delayed presentations such as gastroesophageal reflux, colic, enteropathy, and
constipation are increasingly considered as part of the clinical
spectrum of milk allergy.76 Most of these syndromes are not
IgE-mediated and derive from other immune aetiologies. In
the gut, the presentation of CMA varies, starting from the
neonatal age.77 The inflammatory response elicited in response to cows milk ingestion may involve the entire gastrointestinal tract. In gastroesophageal reflux studies, half the
confirmed food-allergic patients showed evidence of inflammatory changes in their stomach or duodenum.78
Crico-Pharyngeal Spasm
This disorder of crico-pharyngeal motility, results from
the asynchronous constriction of the pharyngeal muscles
and/or of the upper esophageal sphincter and has been associated with CMA among infants.84
Pyloric Stenosis
While earlier reports suggested an association between
such condition and CMA, a 7-week-old boy presenting with
symptoms suggestive of this was found to have a prepyloric
lobular mass causing near-complete gastric outlet obstruction
and this was associated with CMA.85
80
Laboratory findings
Age at onset
1 day to 1 year
Implicated antigens
Pathology
Inflammatory colitis
Lymphoid nodular hyperplasia
Focal vilus injury
Eosinophilic infiltration of lamina propria
Treatment
Constipation
Chronic constipation is defined as the infrequent passage of hard, lumpy stools for more than 8 weeks, in association with fecal incontinence, withholding behavior or painful defecation.103 Removal of cows milk protein from the diet
may benefit this condition, and CMA has been reported in
2010 World Allergy Organization
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Fiocchi et al
82
IV: Miscellanea
An association between CMA beyond infancy and
recurrent abdominal pain has been reported.136 In addition, it
has been reported that after clinical resolution and in absence
of specific IgE, children with CMA may developed persistent
abdominal pain.137 Neurologic syndromes, such as ADHD,
have been reported with food allergy and in particular with
eczema.138 However, these associations require cautious interpretation and require further validation.
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38. Kalayci O, Akpinarli A, Yigit S, Cetinkaya S. Intrauterine cows milk
sensitization. Allergy. 2000;55:408 409.
39. Hatzidaki EG, Manoura AE, Korakaki EV, Galanakis E, Gourgiotis D,
Giannakopoulou CG. Cows milk allergy presented with bloody stools
from day 1 of life. Eur J Pediatr. 2003;162:214 215.
40. Kumar D, Repucci A, Wyatt-Ashmead J, Chelimsky G. Allergic colitis
presenting in the first day of life: report of three cases. J Pediatr
Gastroenterol Nutr. 2000;31:195197.
41. Mazon A, Solera E, Alentado N, Oliver F, Pamies R, et al. Frequent
IgE sensitization to latex, cows milk, and egg in children with short
bowel syndrome. Pediatr Allergy Immunol. 2008;19:180 183.
42. Spergel JM, Fiedler J. Food Allergy and additives: triggers in asthma.
Immunol Allergy Clin North Am. 2005;25:149 167.
43. James J. Respiratory manifestations of food allergy. Pediatrics. 2003;
111:16251630.
44. Bahna SL. Unusual presentations of food allergy. Ann Allergy Asthma
Immunol. 2001;86:414 420.
45. James JM, Bernhisel-Broadbent J, Sampson HA. Respiratory reactions
provoked by double-blind food challenges in children. Am J Respir Crit
Care Med. 1994;149:59 64.
46. Bock SA. Respiratory reactions induced by food challenges in children
with pulmonary disease. Pediatr Allergy Immunol. 1992;3:188 194.
47. James JM, Eigenmann PA, Eggleston PA, Sampson HA. Airway
reactivity changes in asthmatic patients undergoing blinded food challenges. Am J Respir Crit Care Med. 1996;153:597 603.
48. Sicherer SH. Is food allergy causing your patients asthma symptoms?
J Respir Dis. 2000;21;127136.
49. Huang SW. Follow-up of children with rhinitis and cough associated
with milk allergy. Pediatr Allergy Immunol. 2007;18:81 85.
50. Bonadonna P, Crivellaro M, Dama A, Guarnieri G, Schiappoli M,
Senna G. Occupational asthma induced by casein inhalation. G Ital
Med Lav Ergon. 2003;25(Suppl 3):192193.
51. Bahna SL. Exquisite food allergy without eating. Allergy. 1994;49:
129 130.
52. Ramirez DA Jr, Bahna SL. Food hypersensitivity by inhalation. Clin
Mol Allergy. 2009;7:4 7.
53. Fiocchi A, Restani P, Leo G, Martelli A, Bouygue GR, et al. Clinical
tolerance to lactose in children with cows milk allergy. Pediatrics.
2003;112:359 356.
54. Nowak-Wegrzyn A, Shapiro GG, Beyer K, Bardina L, Sampson HA.
Contamination of dry powder inhalers for asthma with milk proteins
containing lactose. J Allergy Clin Immunol. 2004;113:558 560.
55. Ramirez DA, Bahna SL. Food hypersensitivity by inhalation. Clin Mol
Allergy. 2009;7:4 5.
56. Tan BM, Sher MR, Good RA, Bahna SL. Severe food allergies by skin
contact. Ann Allergy Asthma Immunol. 2001;86:583587.
57. Eda A, Sugai K, Shioya H, Fujitsuka A, Ito S, Iwata T, Funabiki T.
Acute allergic reaction due to milk proteins contaminating lactose
added to corticosteroid for injection. Allergol Int. 2009;58:137139.
58. Killig C, Werfel T. Contact reactions to food. Curr Allergy Asthma
Rep. 2008;8:209 214.
59. Pelliccia A, Lucarelli S, Frediani T. Partial cryptogenetic epilepsy and
food allergy/intolerance: a causal or a chance relationship? On three
clinical cases. Min Pediatr. 1999;51:153158.
60. Frediani T, Lucarelli S, Pelliccia A, Vagnucci B, Cerminara C, Barbato
M, Cardi E. Allergy and childhood epilepsy: a close relationship? Acta
Neurol Scand. 2001;104:349 352.
61. Bezrodnik L, Raccio AC, Canil LM, Rey MA, Carabajal PC, Fossati
CA, Docena GH. Hypogammaglobulinaemia secondary to cow-milk
allergy in children under 2 years of age. Immunology. 2007;122:140
146.
62. Hernandez-Trujillo VP, Nguyen WT, Belleau JT, Jeng M, Conley ME,
Lew DB. Cows milk allergy in a patient with hyper-IgE syndrome.
Ann Allergy Asthma Immunol. 2004;92469 92474.
63. Estrada-Reyes E, Hernandez-Roman MP, Gamboa-Marrufo JD, Valencia-Herrera A, Nava-Ocampo AA. Hypereosinophilia, hyper-IgE syndrome, and atopic dermatitis in a toddler with food hypersensitivity.
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64. Pelto L, Laitinen I, Lilius E-M. Current perspectives on milk hypersensitivity. Trends Food Sci Technol. 1999;10:229 233.
65. Pelto L, Impivaara O, Salminen S, Poussa T, Seppanen R, Lilius EM.
Milk hypersensitivity in young adults. Eur J Clin Nutr. 1999;53:620
624.
66. Novembre E, Vierucci A. Milk allergy/intolerance and atopic dermatitis in infancy and childhood. Allergy. 2001;56(Suppl 67):105108.
67. Burks AW, Mallory SB, Williams LW, Shirrell MA. Atopic dermatitis:
clinical relevance of food hypersensitivity reactions. J Pediatr. 1988;
113:447 451.
68. Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA.
Prevalence of IgE-mediated food allergy among children with atopic
dermatitis. Pediatrics. 1998;101:e8.
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138.
colic among breastfed infants: a randomized, controlled trial. Pediatrics. 2005;116:e709 e715.
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intolerance: a long-term prospective study. J Pediatr Gastroenterol
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Savino F, Cresi F, Silvestro L, Oggero R. Use of an amino-acid formula in the
treatment of colicky breastfed infants. Acta Paediatr. 2001;90:359360.
Corvo M, Montalti MG, Startari R, Zoja A, Fiocchi A. The problem of
colics in infants. Pediatr Med Chir. 2005;27:55 61.
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antireflux medication, placebo and infant mental health intervention on
persistent crying: a randomised clinical trial. J Paediatr Child Health.
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admitted to hospital for persistent colic, and comparison with healthy
infants. Acta Paediatr. 2007;96:401 405.
Sicherer SH. Clinical aspects of gastrointestinal food allergy in childhood. Pediatrics. 2003;111(Pt 3):1609 1616.
Lake AM. Food-induced eosinophilic proctocolitis. J Pediatr Gastroenterol Nutr. 2000;30(Suppl):S58 S60.
Faber MR, Rieu P, Semmekrot BA, Van Krieken JH, Tolboom JJ,
Draaisma JM. Allergic colitis presenting within the first hours of
premature life. Acta Paediatr. 2005;94:1514 1515.
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caused by cows milk allergy. Pediatr Surg Int. 2006;22:935938.
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milk allergy presenting Hirschsprungs disease-mimicking symptoms.
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Tikkanen S, Kokkonen J, Juntti H, Niinimaki A. Status of children with
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Schmitt J, Romanos M, Schmitt NM, Meurer M, Kirch W. Atopic
eczema and attention-deficit/hyperactivity disorder in a populationbased sample of children and adolescents. JAMA. 2009;301:724 726.
Introduction
Food allergy in general, and CMA in particular, are
unique examples in which a systematic approach can be
applied. As the disease involves not only the patient, but the
whole family and her social supports, these can be protagonist of the diagnosis itself.1
As in any field of medicine, the diagnosis starts from
suspicion. If patients reports reactions to milk, an accurate
medical history can clarify many aspects of the diagnosis.
The after aspects of the history are particular importance:
Y
Y
Overview
Y
Y
Y
Y
Y
Y
Y
Age at onset
Nature of symptoms
Frequency of their manifestation
Timing between ingestion and onset of symptoms
Quantity of milk necessary to provoke symptoms
Method of milk preparation
Reproducibility of the reaction
Interval of time since last reaction
Influence of external factors on the manifestation (eg,
exercise, hormonal changes, or emotional stress)
85
Fiocchi et al
Y
Y
Y
Y
Y
Food diary
Growth records
Early feeding details (duration of breast-feeding, type of
infant formulas, introduction of weaning solids)
Effect of elimination diets (soy, treatment formulas, diet
of the mother during breast-feeding)
Therapeutic interventions.2
86
of
of
or
its
TABLE 7-1. Diagnosis of Milk Allergy According to the Current Recommendations In Different Countries
ESPACI/ESPGHAN17
How to diagnose
CMA:
elimination
reintroduction
EAACI/GA2LEN
(eczema only; food
allergy)18
Australian Consensus
Panel20
In exclusively breast-fed
infant:
Continue BF - Elimination
diet in mother, no CMP
for 2 weeks or up to 4
weeks in case of AE or
allergic colitis
If improvement: reintroduce
CMP
If no improvement: resume
normal diet in mother
In formula fed infant:
Clinical suspicion 3
elimination diet
If improvement: open
challenge under
supervision
If no improvement: further
elimination period with
AAF or resume CMP
How to diagnose
CMA:
cutaneous
In exclusively breast-fed
infant: No
In formula fed infant:
consider
Appropriate immunological
investigations.
How to diagnose
CMA: sIgE
In exclusively breast-fed
infant: No
In formula fed infant:
consider
Appropriate immunological
investigations.
How to diagnose
CMA:
elimination diet
Diagnostic elimination
diet over a period of
some weeks (eg, 46
weeks)
Diagnosis to be confirmed by
remission of the symptoms
following removal of the
protein.
How to diagnose
CMA:
challenge
In exclusively breast-fed
infant: No
In formula fed infant: not in
diagnostic phase
(elimination/reintroduction
are considered diagnostic)
Perform challenge at 912
months, after at least 6
months elimination
Decision on challenges will
be left to the specialists
decision in case of referral
(severe CMA)
Company-supported guidelines intended for general pediatricians and/or GPs. Recommendations valid for mild to moderate CMA. In case of suspision of severe CMA, refer
to a specialist.
Abbreviations: AAF, amino acid formula; AAP, American Academy of Pediatrics; AE, atopic eczema; APT, atopy patch test; BF, breastfeeding; CM, cows milk; CMA, cows
milk allergy; CMP, cows milk protein; EAACI-GA2LEN, European Academy of Allergy and Clinical Immunology; eHF, extensively hydrolyzed formula; ESPACI, European
Society of Paediatric Allergy and Clinical Immunology; ESPGHAN, European Society of Paediatric Gastroenterology, Hepatology and Nutrition; HA, hypoallergenic formula; OFC,
oral food challenge; pHF, partially hydrolyzed formula; SF, soy formula; SHF, soy hyrdrolyzed formula; SPT, skin prick test.
87
Fiocchi et al
REFERENCES, SECTION 7
1. Arroll B, Pert H, Guyatt G. Milk allergy and bottles over the back fence:
two single patient trials. Cases J. 2008;1:7778.
2. Bahna SL. Diagnosis of food allergy. Ann Allergy Asthma Immunol.
2003;90:S77S80.
3. Sampson HA. Food allergy. Part 2: diagnosis and management. J Allergy
Clin Immunol. 1999;103:981989.
4. Bock SA. Diagnostic evaluation. Pediatrics. 2003;111:1638 1644.
5. Nowak-Wegrzyn A, Assaad AH, Bahna SL, Bock SA, Sicherer SH,
Teuber SS; Adverse Reactions to Food Committee of American Academy of Allergy, Asthma & Immunology. Work Group report: oral food
challenge testing. J Allergy Clin Immunol. 2009;123(Suppl):S365S383.
6. Venter C, Pereira B, Grundy J, Clayton CB, Arshad SH, Dean T.
Prevalence of sensitization reported and objectively assessed food hypersensitivity amongst six-year-old children: a population-based study.
Pediatr Allergy Immunol. 2006;17:356 363.
7. Martelli A, Bouygue GR, Fiocchi A, Restani P, Sarratud T, Terracciano
L. Oral food challenges in children in Italy. Allergy. 2005;60:907911.
8. Keil T, McBride D, Grimshaw K, Niggemann B, Xepapadaki P, et al.
The multinational birth cohort of EuroPrevall: background, aims and
methods. Allergy. 2009 Sep 30. [Epub ahead of print]
9. Sinagra JL, Bordignon V, Ferraro C, Cristaudo A, Di Rocco M, Amorosi
B, Capitanio B. Unnecessary milk elimination diets in children with
atopic dermatitis. Pediatr Dermatol. 2007;24:1 6.
10. Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of
IgE-mediated cows milk allergy. J Allergy Clin Immunol. 2007;120:
11721177.
11. Muraro A. Dietary prevention of allergic diseases in infants and small
children. Part I: immunologic background and criteria for hypoallergenicity. Pediatr Allergy Immunol. 2004;15:10311.
12. Muraro A. Dietary prevention of allergic diseases in infants and small
children. Part II. Evaluation of methods in allergy prevention studies and
sensitization markers. Definitions and diagnostic criteria of allergic
diseases. Pediatr Allergy Immunol. 2004;15:196 205.
13. Muraro A. Dietary prevention of allergic diseases in infants and small
children. Part III: critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr
Allergy Immunol. 2004;15:291307.
14. Prescott SL. The Australasian Society of Clinical Immunology and
Allergy position statement: summary of allergy prevention in children.
Med J Aust. 2005;182:464 467.
15. Chapman JA, Bernstein IL, Lee RE, Oppenheimer J, Nicklas RA, et al.
Food allergy: a practice parameter. Annals Allergy Asthma Immunol.
2006;96(Suppl 2):S1S68.
16. Bruijnzeel-Koomen C, Ortolani C, Aas K, Bindslev-Jensen C, Bjorksten
B, Moneret-Vautrin D, Wuthrich B. Adverse reactions to food. European
Academy of Allergology and Clinical Immunology Subcommittee. Allergy. 1995;50:623 635.
17. Hst A. Dietary products used in infants for treatment and prevention of
food allergy. Joint Statement of the European Society for Paediatric
Allergology and Clinical Immunology (ESPACI) committee on hypoallergenic formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) committee on nutrition.
Arch Dis Child. 1999;81:80 84.
18. Werfel T, Ballmer-Weber B, Eigenmann PA, Niggemann B, Rance F,
Turjanmaa K, Worm M. Eczematous reactions to food in atopic eczema:
position paper of the EAACI and GA2LEN. Allergy. 2007;62:723728.
19. Vandenplas Y, Koletzko S, Isolauri E, Hill D, Oranje AP, Brueton M,
Staiano A, Dupont C. Guidelines for the diagnosis and management of
cows milk protein allergy in infants. Arch Dis Child. 2007;92:902908.
20. Kemp AS, Hill DJ, Allen KJ, Anderson K, Davidson GP, et al. Guidelines for the use of infant formulas to treat cows milk protein allergy: an
Australian consensus panel opinion. Med J Aust. 2008;188:109 112.
21. Niggemann B, Friedrichs F, Koletzko B, et al. Positions papier. Das
Vorgehen bei Sauglingen mit Verdacht auf Kuhmilchproteinallergie.
Padiatrische Allergologie. 2005;4:14 18.
22. Kirchlechner V, Dehlink E, Szepfalusi Z. Cows milk allergy: guidelines
for the diagnostic evaluation. Klin Padiatr. 2007;219:201205.
23. Kneepkens CMF, Van Drongelen KI, Aarsen C. Landelijke standard
voedselallergie bij zuigelingen [National standard for food allergy in
infants]. 5th ed. Den Haag: Voedingscentrum, 2005:80.
88
Introduction
The general treatment for CMA is dietary and consists of
eliminating all dairy products from the diet to avoid exposure to
the implicated allergen(s).1 For this reason, a period of dairy
product avoidance is also part of the work-up to diagnosis in
patients presenting with suspected cows milk allergy.
In patients with a history of life-threatening symptoms,
particularly if respiratory or involving several organ systems,
suspicion of contact with cows milk proteins alone warrants
avoidance. However, because the spectrum of CMA manifestations is so wide, most patients will present with
vague complaints in the primary care setting and a precau 2010 World Allergy Organization
tionary avoidance diet should be prescribed for most patients with suspected CMA until the completion of their
allergy work-up to:
a. Substantiate diagnostic suspicion;
b. Remove the confounding effect of the continued intake
of the suspected allergen;
c. Improve skin prick test (SPT) outcome by reducing
inflammation (especially in atopic dermatitis);
d. Anticipate the oral food challenge phase by minimizing
confounder effect(s).
No study so far has tackled the issue of the optimal duration
of the diagnostic elimination phase but it seems reasonable
that this phase be shorter for immediate CMA and longer for
delayed syndromes. In some cases, such as allergic eosinophilic esophagitis and allergic eosinophilic gastroenteritis,
several weeks of an elemental diet will be necessary to
stabilize patients before conducting food challenge.
On the whole, the rules of application for a diagnostic
elimination diet in the workup of CMA are the same as those
for treatment. In particular, the clinician should take care to
place the patient in a condition to achieve through an elimination diet the after clinical goals:
a. Safety from accidental ingestion of cows milk proteins
b. Safety from inhalation or skin contact with cows milk
c. Avoidance of cross-reactive proteins (milk of buffalo,
goat, or sheep)
d. Nutritional adequacy, especially in children and if prolonged periods of elimination is prescribed
e. Clear patient education to encourage compliance.
In most age groups, including breast-fed and over-2-year-old
children, it may not be necessary to provide a substitute for
cows milk. Nursing mothers should also follow a milk-free
diet, with adequate calcium supplements. A substitute formula will be prescribed to nonbreastfed infants and toddlers.
It is the consensus of this panel that, considering costs, the
least allergenic substitute should be proposed for these children to maximalize the diagnostic power of the elimination
diet. Beef avoidance should also be considered in these
children unless from a technologically processed source,2 as
dairy products and meat contain common antigenic protein3
and up to 20% can be allergic to beef.4
An elimination diet should be continued for at least 2
weeks and up to several weeks in cases of delayed reactions.5,6 If the elimination diet fails to improve the symptoms,
the breast-feeding mother and/or the infant should resume
their normal diet and a referral to a different specialist
(dermatologist, gastroenterologist, etc.) should be considered,
depending on the type and severity of symptoms. If the
clinical picture improves substantially or issues disappear
during the elimination diet, then the child must be referred to
an allergy specialist for further diagnostic steps.
REFERENCES, SECTION 8
1. Nowak-Wegrzyn A. Food allergy to proteins. Nestle Nutr Workshop Ser
Pediatr Program. 2007;59:1731.
Records screened
(n = 3877)
Studies included in
qualitave synthesis
(n = 36)
Records excluded
(n = 3619)
Full text arcles awaing
assessment
( n = 15 )
Full-text arcles excluded,
with reasons
(n = 207)
Studies included in
quantave synthesis
(meta-analysis)
(n = 31 )
89
Fiocchi et al
QUESTION 1
Should skin prick tests be used for the diagnosis of
IgE-mediated CMA in patients suspected of CMA?
Population: patients suspected of CMA
Intervention: skin prick test
Comparison: oral food challenge
Outcomes:
TP: The child will undergo oral food challenge that will turn
out positive with risk of anaphylaxis, albeit in controlled
environment; burden on time and anxiety for family; exclusion of milk and use of special formula. Some children with
high pretest probability of disease and/or at high risk of
anaphylactic shock during the challenge will not undergo
challenge test and be treated with the same consequences of
treatment as those who underwent food challenge.
TN: The child will ingest cows milk at home with no
reaction, no exclusion of milk, no burden on family time
and decreased use of resources (no challenge test, no
formula); anxiety in the child and family may depend on
the family; looking for other explanation of the symptoms.
FP: The patient will undergo an oral food challenge which
will be negative; unnecessary burden on time and anxiety
in a family; unnecessary time and resources spent on oral
challenge. Some children with high pretest probability of
CMA would not undergo challenge test and would be
unnecessarily treated with elimination diet and formula
that may led to nutritional deficits (eg, failure to thrive,
rickets, vitamin D or calcium deficiency); also stress for
the family and unnecessary carrying epinephrine self injector which may be costly and delayed diagnosis of the
real cause of symptoms.
FN: The child will be allowed home and will have an
allergic reaction (possibly anaphylactic) to cows milk at
home; high parental anxiety and reluctance to introduce
future foods; may lead to multiple exclusion diet. The real
cause of symptoms (ie, CMA) will be missed, leading to
unnecessary investigations and treatments.
Inconclusive results: (either negative positive control or
positive negative control): the child would repeat SPT that
may be distressing for the child and parent; time spent by
a nurse and a repeat clinic appointment would have resource implications; alternatively child would have sIgE
measured or undergo food challenge.
Complications of a test: SPT can cause discomfort or
exacerbation of eczema which can cause distress and
parental anxiety; food challenge may cause anaphylaxis
and exacerbation of other symptoms.
Resource utilization (cost): SPT adds extra time to clinic
appointment; however, oral food challenge has much
greater resource implications.
TP true positive (being correctly classified as having
CMA); TN true negative (being correctly classified as not
90
having CMA); FP false positive (being incorrectly classified as having CMA); FN false negative (being incorrectly
classified as not having CMA); these outcomes are always
determined compared with a reference standard (ie, food
challenge test with cows milk).
Outcomes: Question 1
Outcome
TP
TN
FP
FN
Inconclusive results
Complications of a test
Cost
Importance
8
7
7
8
5
3
3
Summary of Findings
We did not find any existing systematic review of
diagnosis of CMA with skin prick testing. However, we
found 25 studies that examined the role of skin prick tests in
comparison to oral food challenge in patients suspected of
CMA.125 All but one study used a cut-off of a mean wheal
diameter of 3 mm; the other study used a cut-off value of
4 mm.7 Four studies included patients with suspected IgEmediated cows milk allergy,1,6,10,16 7 explicitly included only
patients with atopic eczema,4,9,11,19,21,22,24 and the remaining
studies included mixed populations of patients with various
conditions in whom CMA was investigated.
Using the criteria of methodological quality suggested
by the QUADAS questionnaire we found that in many studies
the spectrum of patients was not representative of the patients
who will receive the test in practice. In most studies the
results of a reference standard were very likely interpreted
with the knowledge of the results of the skin prick test or vice
versa. None of the studies reported uninterpretable or intermediate test results. One study reported 8% inconclusive
challenge tests but did not report number of inconclusive skin
prick tests.23
The combined sensitivity in these studies was 0.67
(95% CI: 0.64 0.70) and the specificity was 0.74 (95% CI:
0.72 0.77). Skin prick test accuracy was similar when studies
in patients with atopic eczema were excluded (16 studies;
sensitivity 0.71, 95% CI: 0.68 0.75 and specificity 0.73,
95% CI: 0.70 0.76). In 4 studies that explicitly enrolled
patients suspected of immediate reactions to milk sensitivity
seemed slightly improved (0.77, 95% CI: 0.68 0.84) on the
expense of lower specificity (0.61, 95% CI: 0.52 0.70). We
also investigated the influence of childs age on the accuracy
of skin prick tests in the diagnosis of CMA. In children
suspected of CMA who were on average younger than 12
months sensitivity of skin prick test was lower (0.55, 95% CI:
0.49 0.61 [4 studies]) than in children older than 12 month
of age (0.81, 95% CI: 0.77 0.85 [11 studies]). Age seemed
not to influence the estimate of specificity (0.75, 95% CI:
2010 World Allergy Organization
0.69 0.80 vs. 0.72, 95% CI: 0.68 0.76). The overall quality
of evidence across outcomes was very low.
Other Considerations
In settings where oral food challenges are always performed (because of low testing threshold and high treatment
threshold) the use of skin prick tests is redundant given the
limited sensitivity and specificity of skin prick test compared
with oral food challenge.
Conclusions
In settings where oral food challenge is done routinely
and the clinicians thresholds for testing and treatment are
such that exclusion and confirmation of CMA always has to
be proven by oral food challenge, there is no need to perform
a skin prick test.
2010 World Allergy Organization
Remark
This recommendation applies to clinical practice settings. In research settings there may be compelling reasons to
perform skin prick tests even though a food challenge test
with cows milk is always being done.
Recommendation 1.2
In settings where oral food challenge is not considered
a requirement in all patients suspected of IgE-mediated
CMA, in patients with high pretest probability of CMA we
suggest using a skin prick test with a cut-off value of 3 mm
as a triage test to avoid oral food challenge in those in whom
the result of a skin prick test turns out positive (conditional
recommendation/low quality evidence).
91
Fiocchi et al
reactions during the oral food challenge test (50 70% food
challenges avoided). It places a lower value on unnecessary
treatment of around 1 in 20 patients misclassified as allergic
to cows milk (5 6% false positive results).
Remarks
A high pretest probability of CMA (80%) can be
estimated based on the history and would represent, for
instance, patients who experienced an anaphylactic reaction
in the past.
Recommendation 1.3
In settings where oral food challenge 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 oral food challenge test with cows milk
as the only test without performing a skin prick test with a
cut-off value of 3 mm as a triage or an add-on test to
establish a diagnosis (strong recommendation/very low quality evidence).
Remarks
An average pretest probability of CMA (40%) can be
estimated based on the history and presenting symptoms and
would represent the majority of situations.
Recommendation 1.4
In settings where oral food challenge is not considered
a requirement in all patients suspected of IgE-mediated
CMA, in patients with low pretest probability of CMA we
suggest using a skin prick test with a cut-off value of 3 mm
as a triage test to avoid oral food challenge in those in whom
the result of a skin prick test turns out negative (conditional
recommendation/low quality evidence).
Remarks
A low pretest probability of CMA (10%) can be
estimated based on the history and would represent, for
92
QUESTION 2
Should in vitro specific IgE determination be used
for the diagnosis of IgE-mediated CMA in patients suspected of CMA?
Population: patients suspected of CMA
Intervention: in vitro determination of a cows milk specific IgE
Comparison: oral food challenge
Outcomes:
TP: Children will undergo oral food challenge that will
turn out positive with risk of anaphylaxis, albeit in controlled environment; burden on time and anxiety for family; exclusion of milk and use of special formula. Some
children with high pretest probability of disease and/or at
high risk of anaphylactic shock during the challenge will
not undergo challenge test and be treated with the same
consequences of treatment as those who underwent food
challenge.
TN: Children will receive cows milk at home with no
reaction, no exclusion of milk, no burden on family time
and decreased use of resources (no challenge test, no
formula); anxiety in the child and family may depend on
the family; looking for other explanation of the symptoms.
FP: Children will undergo an oral food challenge which
will be negative; unnecessary burden on time and anxiety
in a family; unnecessary time and resources spent on oral
challenge. Some children with high pretest probability of
CMA would not undergo challenge test and would be
unnecessarily treated with elimination diet and formula
that may led to nutritional deficits (eg, failure to thrive,
rickets, vitamin D or calcium deficiency); also stress for
the family and unnecessary carrying epinephrine self injector which may be costly and delayed diagnosis of the
real cause of symptoms.
FN: Children will be allowed home and will have an
allergic reaction (possibly anaphylactic) to cows milk at
home; high parental anxiety and reluctance to introduce
future foods; may lead to multiple exclusion diet. The real
cause of symptoms (ie, CMA) will be missed leading to
unnecessary investigations & treatments.
Inconclusive results: the child would repeat serum IgE that
may be distressing for the child and parents; increased cost
of testing; alternatively child may undergo food challenge.
Complications of a test: can cause discomfort of blood test
and bleeding that can cause distress and parental anxiety;
food challenge may cause anaphylaxis and exacerbation of
other symptoms.
Resource utilization (cost): sIgE is an expensive test and
requires time for phlebotomy, but does not add time to the
medical consultation.
TP true positive (being correctly classified as having
CMA); TN true negative (being correctly classified as not
having CMA); FP false positive (being incorrectly classi 2010 World Allergy Organization
Importance
8
7
6
8
5
4
4
Summary of Findings
We did not find any systematic review of diagnosis of
CMA with determining the cows milk specific immunoglobulin E (IgE) in serum.
We found 25 studies that examined the role of cows
milk specific IgE in comparison to oral food challenge in
patients suspected of CMA1,2,4,6 8,10,12,1722,26 36. Seventeen
studies used CAP-RAST or FEIA technique of which 13 used
a cut-off threshold of 0.35 IU/L,2,4,6,8,18,19,21,22,28,30,31,32,35 2
used a cut-off of 0.7 IU/L,10,33 and 2 did not report a cut-off
threshold.12,34 Five studies used a Phadebas RAST technique,7,21,26,27,29 one study assessed PRIST RAST,36 one assessed Allercoat EAST,1 and Magic Lite.17
Using the criteria of methodological quality suggested
by the QUADAS questionnaire we found that in many studies
the spectrum of patients was not representative of the patients
who will receive the test in practice (ie, with suspected
IgE-mediated CMA). In most studies the results of a reference standard were very likely interpreted with the knowledge of the results of the cows milk specific IgE or skin prick
test or vice versa. None of the studies reported uninterpretable or intermediate test results. One study reported 8%
inconclusive challenge tests but did not report number of
inconclusive skin prick tests.23
We used studies that used UniCAP or CAP-System
FEIA to inform this recommendation because these techniques are currently commonly used. Other techniques are
either used less frequently because they evolved into the new
ones or the studies included only several patients that made
any estimates of test accuracy unreliable. The combined
sensitivity in the studies of CAP-RAST and FEIA that used a
cut-off of 0.35 IU/L was 0.72 (95% CI: 0.69 0.75) and the
specificity was 0.57 (95% CI: 0.54 0.60). Sensitivity of the
cows milk-specific IgE measurement was lower when studies in patients with atopic eczema were excluded (8 studies;
sensitivity 0.62, 95% CI: 0.58 0.67) with little change in
specificity (0.62, 95% CI: 0.57 0.66). We further examined
the influence of childs age on the accuracy of cows milkspecific IgE measurement in the diagnosis of CMA. In children suspected of CMA who were on average younger than
12 months sensitivity of cows milk-specific IgE was higher
2010 World Allergy Organization
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Fiocchi et al
Other Considerations
The use of milk-specific IgE measurements in settings
where oral food challenges are always performed is redundant given the limited sensitivity and specificity of IgE
measurement compared with oral food challenge.
Conclusions
In patients suspected of CMA the net benefit of measuring cows milk-specific IgE instead of oral food challenge
with cows milk is uncertain. The quality of the supporting
evidence is very low.
In settings where the oral food challenge is done routinely and the clinicians thresholds for testing and treatment
are such that exclusion and confirmation of CMA always has
to be proven by oral food challenge, there is no need to
perform cows milk-specific IgE measurements.
In settings where clinicians follow a more prudent approach, determination of the concentration of milk-specific IgE
may help to avoid an oral food challenge in selected patients.
94
Remark
This recommendation applies to clinical practice settings. In research settings there may be compelling reasons to
perform skin prick tests even though a food challenge test
with cows milk is always being done.
Recommendation 2.2
In settings where oral food challenge is not a requirement, in patients with a high pretest probability of IgEmediated CMA we suggest using cows milk-specific IgE
with a threshold of 0.7 IU/L to avoid oral food challenge if a
result of milk-specific IgE turns out positive (conditional
recommendation/low quality evidence).
Remarks
A high pretest probability of CMA (80%) can be
estimated based on the history and would represent, for
instance, patients who experienced an anaphylactic reaction
in the past.
Recommendation 2.3
In settings where oral food challenge 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 oral food challenge test with cows
milk as the only test without measuring milk-specific IgE as
a triage or an add-on test to establish a diagnosis (conditional
recommendation/low quality evidence).
Remarks
An average pretest probability of CMA (40%) can be
estimated based on the history and presenting symptoms and
would represent the majority of clinical situations. Using
higher cut-off 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 2.4
In practice settings where oral food challenge is not a
requirement in all patients suspected of IgE-mediated CMA, in
patients with low pretest probability of IgE-mediated CMA we
suggest using milk-specific IgE measurement with a cut-off
value of 0.35 IU/L as a triage test to avoid oral food challenge
in those in whom the result of milk-specific IgE turns out
negative (conditional recommendation/low quality evidence).
Remarks
A low pretest probability of CMA (10%) can be
estimated based on the history and would represent, for
instance, patients with unexplained gastrointestinal symptoms (eg, gastroesophageal reflux).
2010 World Allergy Organization
QUESTION 3
Should in vitro specific IgE determination be used
for the diagnosis of CMA in patients suspected of CMA
and a positive result of a skin prick test?
Population: patients suspected of CMA with a positive skin
prick test
Intervention: in vitro specific IgE determination
Comparison: oral food challenge
Outcomes:
TP: The child will undergo oral food challenge that will turn
out positive with a risk of anaphylaxis, albeit in controlled
environment; burden on time and anxiety for family; exclusion of milk and use of formula; some children with high
pretest probability (based on history, clinical presentation and
positive result of SPT) may receive treatment without performing food challenge with same consequences as those in
whom challenge test was performed.
TN: The child will undergo oral food challenge that will turn
out negative; burden on time and anxiety for family.
FP: The child will undergo an oral food challenge which will
be negative; unnecessary burden on time and anxiety in a
family; unnecessary time and resources spent on oral challenge.
FN: The child will undergo oral food challenge which will
turn out positive with risk of anaphylaxis, albeit in controlled environment; burden on time and anxiety for family; exclusion of milk and use of special formula.
Inconclusive results: repeated measurement of sIgE that
can cause discomfort of blood test and bleeding which can
cause distress and parental anxiety.
Complications of a test: can cause discomfort of blood test
and bleeding which can cause distress and parental anxiety;
food challenge may cause anaphylaxis and exacerbation of
other symptoms.
Resource utilization (cost): sIgE is an expensive test and
requires time for phlebotomy, but does not add time to the
medical consultation.
TP true positive (being correctly classified as having
CMA); TN true negative (being correctly classified as not
having CMA); FP false positive (being incorrectly classified as having CMA); FN false negative (being incorrectly
classified as not having CMA); these outcomes are always
determined compared with a reference standard (ie, food
challenge test with cows milk).
Outcomes: Question 3
Outcome
TP
TN
FP
FN
Inconclusive results
Complications of a test
Cost
Importance
7
6
6
7
4
4
4
95
Fiocchi et al
Summary of Findings
We did not find any systematic review of diagnosis of
CMA with in vitro specific IgE or SPT.
We found 15 studies that examined the role of milk-specific
IgE measurement and SPT in comparison to oral food challenge
alone in patients suspected of CMA.1,2,4,68,10,12,1722,31 Only 3 of
these studies reported results of using skin prick test and cows milk
specific IgE measurement together8,17,21. All used a threshold for
SPT of 3 mm. All 3 studies used different methods of determination
of milk-specific IgE.
One study reported no negative results, all patients had
either true or false positive results of SPT and milk-specific
IgE combined and 4 results were discordant.8 The pooled
sensitivity and specificity from the remaining 2 studies including 36 patients were 0.71 (95% CI: 0.29 0.96) and 0.93
(95% CI: 0.77 0.99). Discordant results of skin prick test and
milk-specific IgE were observed in 28% of patients.
Using the criteria of methodological quality suggested by
the QUADAS questionnaire we found that one study enrolled
only patients with atopic eczema and the selection criteria were
not described, in all studies the results of the tests were most
likely interpreted with the knowledge of the other tests. The
overall quality of evidence across outcomes was very low.
Conclusions
In patients with low initial probability of CMA, who
have a positive result of a skin prick test, the net benefit of
measuring cows milk specific IgE instead of oral food
challenge with cows milk is unlikely.
In patients with average and high initial probability of
CMA, who have a positive result of a skin prick test, the net
benefit of measuring cows milk specific IgE instead of oral
food challenge with cows milk is uncertain. Positive results
of both skin prick test and milk-specific IgE can help to avoid
an oral food challenge in 22% of patients with average initial
probability of CMA and in 42% of those with high initial
probability of CMA. However, this benefit is counterbalanced
by a risk of falsely classifying a patient as having CMA (3%
in patients with initial average probability of CMA and 1% in
those with high initial probability of CMA).
In patients suspected of CMA, who have a positive
result of a skin prick test, a negative result of milk-specific
IgE is likely to lead to performing food challenge test.
Recommendation 3.1
In patients with a low initial probability of IgE-mediated CMA, who have a positive result of skin prick test (3
mm), we suggest oral food challenge rather than measuring
cows milk-specific IgE level with a cut-off value of 0,35
IU/L (conditional recommendation/low quality evidence).
96
Recommendation 3.2
In patients with a an average or high initial probability
of IgE-mediated CMA, who have a positive result of skin
prick test (3 mm), we suggest measurement of cows
milk-specific IgE with a cut-off value of 0.35 IU/L to avoid
food challenge test in those in whom the result of milkspecific IgE turns out positive (conditional recommendation
low quality evidence).
Remarks
An average pretest probability of CMA (40%) can be
estimated based on the history and presenting symptoms and
would represent the majority of situations.
A high pretest probability of CMA (80%) can be
estimated based on the history and would represent, for
instance, patients who experienced an anaphylactic reaction
in the past.
QUESTION 4
Should in vitro specific IgE determination be used
for the diagnosis of CMA in patients suspected of CMA
and a negative result of a skin prick test?
Population: patients suspected of cows milk allergy (CMA)
with a negative skin prick test
Intervention: in vitro specific IgE
Comparison: oral food challenge
Outcomes:
TP: The child will undergo oral food challenge that will
turn out positive with a risk of anaphylaxis, albeit in
controlled environment; burden on time and anxiety for
family; exclusion of milk and use of formula.
TN: The child will ingest cows milk at home with no
reaction, no exclusion of milk, no burden on family time
and decreased use of resources (no challenge test, no
formula); anxiety in the child and family may depend on
the family; looking for other explanation of the symptoms.
FP: The child will undergo an oral food challenge that will
be negative; unnecessary burden on time and anxiety in a
family; unnecessary time and resources spent on oral
challenge. Some children with high pretest probability of
CMA may not undergo challenge test and would be unnecessarily treated with elimination diet and formula that
may lead to nutritional deficits (eg, failure to thrive, rickets, vitamin D or calcium deficiency); also stress for the
family and unnecessary carrying epinephrine self injector
that may be costly and delayed diagnosis of the real cause
of symptoms.
FN: The child will be allowed home and will have allergic
reactions (possibly anaphylactic) to cows milk at home;
high parental anxiety and reluctance to introduce future
foods; may lead to multiple exclusion diet. The real cause
of symptoms (ie, CMA) will be missed leading to other
unnecessary investigations and treatments.
Inconclusive results: repeated measurement of sIgE that
can cause discomfort of blood test and bleeding that can
cause distress and parental anxiety.
Complications of a test: can cause discomfort of blood test
and bleeding which can cause distress and parental anxiety;
food challenge may cause anaphylaxis and exacerbation of
other symptoms.
Resource utilization (cost): sIgE is an expensive test and
requires time for phlebotomy, but does not add time to the
medical consultation.
2010 World Allergy Organization
Outcomes: Question 4
Outcome
TP
TN
FP
FN
Inconclusive results
Complications of a test
Cost
Importance
7
5
5
7
4
4
4
97
Fiocchi et al
home. False negative result may also lead to unnecessary investigations and possible treatments for other causes of symptoms
while the real cause (ie, CMA) has been missed.
In patients with average and high pretest probability of
CMA (40%) based on the history and presenting symptoms, who have a negative result of a skin prick test (ie,
diameter of 3 mm), measurement of cows milk-specific
IgE in serum with a cut-off value of 0.35 IU/L is unlikely to
be of benefit. In patients with an average initial probability of
CMA one would be able to avoid a food challenge with cows
milk in about 47% of patients with a risk of about 8% false
negative results. In patients with a high initial probability of
CMA one would be able to avoid a food challenge with cows
milk in about 30% of patients, but a risk of incorrectly
classifying a patient as not having CMA would be high (about
17% false negative results). A positive result of milk-specific
IgE in patient with a negative skin prick test is likely to lead
to performing an oral food challenge test regardless.
Conclusions
In patients with low initial probability of CMA, who
have a negative result of a skin prick test, the net benefit of
measuring cows milk specific IgE instead of oral food
challenge with cows milk is uncertain. Negative results of
both skin prick test and milk-specific IgE can help to avoid
an oral food challenge in about 60% of patients. However,
this benefit is counterbalanced by approximately a 2% risk
of falsely classifying a patient as not having CMA.
In patients with average or high initial probability of
CMA, who have a negative result of a skin prick test, the net
benefit of measuring cows milk specific IgE instead of oral
food challenge is unlikely.
In patients suspected of CMA, who have a negative
result of a skin prick test, a positive result of milk-specific
IgE is likely to lead to performing food challenge test.
Remarks
A low pretest probability of CMA (10%) can be
estimated based on the history and would represent, for
instance, patients with unexplained gastrointestinal symptoms (eg, gastroesophageal reflux).
98
Recommendation 4.2
In patients with an average initial probability of IgEmediated CMA, who have a negative result of a skin prick
test, we suggest oral food challenge rather than measuring
cows milk-specific IgE level (conditional recommendation/
low quality evidence).
Remarks
An average pretest probability of CMA (40%) can be
estimated based on the history and presenting symptoms and
would represent the majority of situations.
Recommendation 4.3
In patients with a high initial probability of IgE-mediated CMA, who have a negative result of a skin prick test, we
recommend oral food challenge rather than measuring cows
milk-specific IgE level (strong recommendation/low quality
evidence).
Remarks
A high pretest probability of CMA (80%) can be
estimated based on the history and would represent, for
instance, patients who experienced an anaphylactic reaction
in the past.
QUESTION 5
Should allergen microarrays or component resolved
diagnostics be used for the diagnosis of IgE-mediated
CMA in patients suspected of CMA?
Population: patients suspected of CMA
Intervention: allergen microarrays or component-resolved
diagnostics
Comparison: oral food challenge
Outcomes:
TP: The child will undergo oral food challenge that will
turn out positive with a risk of anaphylaxis, albeit in
controlled environment; burden on time and anxiety for
family; exclusion of milk and use of formula.
2010 World Allergy Organization
Summary of Findings
We did not find any systematic review of the microarrays or
component-resolved diagnostics used for the diagnosis of CMA.
We found 4 studies that examined the role of cows milk
allergen-specific IgE measurement with microarrays.18,3739
Two of these studies did not use a reference standard37,38 and
one did not report any data on test accuracy.39 These 3 studies
used a home-made allergen chip. One study used a commercially available allergen microarray, however, it was custom
modified for the purpose of this study.18 This study also examined the role of component-resolved diagnostics in comparison
to oral food challenge in patients suspected of CMA using an
allergen microarray. We did not identify any study of unmodified commercially available allergen microarray compared with
the oral food challenge test used for the diagnosis of CMA.
In the study that used customized allergen microarray
in children suspected of IgE-mediated cows milk allergy
estimated sensitivity was 0.60 (95% CI: 0.43 0.74) with
specificity of 0.84 (95% CI: 0.69 0.93).
Conclusions, Question 5
Any clinical benefit resulting from using allergen microarrays in the diagnosis of CMA is currently unknown.
Recommendation 5.2
Outcomes: Question 5Should Allergen Microarrays Be
Used for the Diagnosis of IgE-Mediated CMA?
Outcome
Importance
TP
TN
FP
FN
Inconclusive results
Complications of a test
Cost
6
5
5
6
4
3
5
Importance
6
5
5
6
4
4
5
99
Fiocchi et al
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
The food challenge risk index: Predicting positive open food challenges
to milk, egg, and peanuts in children. Pediatric Asthma, Allergy and
Immunol. 2005;18:68 76.
Kekki OM, Turjanmaa K, Isolauri E. Differences in skin-prick and
patch-test reactivity are related to the heterogeneity of atopic eczema in
infants. Allergy. 1997;52:755759.
Keskin O, Tuncer A, Adalioglu G, Sekerel BE, Sackesen C, Kalayci O.
Evaluation of the utility of atopy patch testing, skin prick testing, and
total and specific IgE assays in the diagnosis of cows milk allergy. Ann
Allergy, Asthma, Immunol. 2005;94:553560.
Kim TE, Park SW, Noh G, Lee S. Comparison of skin prick test results
between crude allergen extracts from foods and commercial allergen
extracts in atopic dermatitis by double-blind placebo-controlled food
challenge for milk, egg, and soybean. Yonsei Med J. 2002;43:613 620.
Majamaa H, Moisio P, Holm K, Kautiainen H, Turjanmaa K. Cows
milk allergy: diagnostic accuracy of skin prick and patch tests and
specific IgE. Allergy. 1999;54:346 351.
May CD, Remigio L, Bock SA. Usefulness of measurement of antibodies in serum in diagnosis of sensitivity to cow milk and soy proteins in
early childhood. Allergy. 1980;35:301310.
Mehl A, Rolinck-Werninghaus C, Staden U, Verstege A, Wahn U, Beyer K,
Niggemann B. The atopy patch test in the diagnostic workup of suspected
food-related symptoms in children. J Allergy Clin Immunol. 2006;118:923929.
Nielsen RG, Bindslev-Jensen C, Kruse-Andersen S, Husby S. Severe
gastroesophageal reflux disease and cow milk hypersensitivity in infants
and children: disease association and evaluation of a new challenge
procedure. J Pediatric Gastroenterol Nutr. 2004;39:383391.
Norgaard A, Bindslev-Jensen C. Egg and milk allergy in adults. Diagnosis and characterization. Allergy. 1992;47:503509.
Osterballe M, Andersen KE, Bindslev-Jensen C. The diagnostic accuracy of the atopy patch test in diagnosing hypersensitivity to cows milk
and hens egg in unselected children with and without atopic dermatitis.
J Am Acad Dermatol. 2004;51:556 562.
Ott H, Baron JM, Heise R, Ocklenburg C, Stanzel S, Merk HF,
Niggemann B, Beyer K. Clinical usefulness of microarray-based IgE
detection in children with suspected food allergy [see comment]. Allergy. 2008;63:15211528.
Roehr CC, Reibel S, Ziegert M, Sommerfeld C, Wahn U, Niggemann B.
Atopy patch tests, together with determination of specific IgE levels,
reduce the need for oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2001;107:548 553.
Saarinen KM, Suomalainen H, Savilahti E. Diagnostic value of skin-prick and
patch tests and serum eosinophil cationic protein and cows milk-specific IgE in
infants with cows milk allergy. Clin Exp Allergy. 2001;31:423429.
Sampson HA, Albergo R. Comparison of results of skin tests, RAST,
and double-blind, placebo-controlled food challenges in children with
atopic dermatitis. J Allergy Clin Immunol. 1984;74:26 33.
Sampson HA, Ho DG. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol. 1997;100:444 451.
Sporik R, Hill DJ, Hosking CS. Specificity of allergen skin testing in
predicting positive open food challenges to milk, egg and peanut in
children.[see comment] Clin Exp Allergy. 2000;30:1540 1546.
Stromberg L. Diagnostic accuracy of the atopy patch test and the skin-prick
test for the diagnosis of food allergy in young children with atopic eczema/
dermatitis syndrome. Acta Paediatrica. 2002;91:1044 1049.
Verstege A, Mehl A, Rolinck-Werninghaus C, Staden U, Nocon M,
Beyer K, Niggemann B. The predictive value of the skin prick test weal
size for the outcome of oral food challenges. Clin Exp Allergy. 2005;
35:1220 1226.
Bjorksten B, Ahlstedt S, Bjorksten F, Carlsson B, Fallstrom SP, et al.
Immunoglobulin E and immunoglobulin G4 antibodies to cows milk in
children with cows milk allergy. Allergy. 1983;38:119 124.
Bonifazi E, Garofalo L, Monterisi A, Meneghini CL. Food allergy in
atopic dermatitis: experimental observations. Acta Dermato-Venereologica. 1978;58:349 352.
Breuer K, Heratizadeh A, Wulf A, Baumann U, Constien A, Tetau D,
Kapp A, Werfel T. Late eczematous reactions to food in children with
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Cantani A, Arcese G, Serra A, Lucenti P. Results of skin tests, RAST,
and food challenges in children with atopic dermatitis associated with
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100
he oral food challenge (OFC) is considered the standard reference test for diagnosing CMA. It is warranted in the after situations:
a. Confirmation of suspicion of cows milk allergy
(CMA)
b. periodical follow-up of the condition and monitoring
of the resolution of CMA
c. Assessment of tolerance in SPT-positive breast-fed
infants suspected of CMA who have not yet ingested
cows milk (CM) proteins
d. Assessment of tolerance of cross-reactive foods (beef,
mares milk, donkeys milk, etc)
e. Evaluation of CM reactivity in persons with multiple
dietary restrictions, usually because of subjective complaints
f. Exclusion of possible immediate reactions to milk in
chronic conditions such as atopic dermatitis or allergic
eosinophilic esophagitis
g. Evaluation of the tolerance threshold to CM proteins
A double-blind, placebo-controlled food challenge
(DBPCFC) is the method of choice for research and
2010 World Allergy Organization
Introduction
The diagnosis of CMA can be achieved with certainty
only after direct observation of clinical events after milk
ingestion. In fact, the common tests to identify CM sensitization (at cutaneous level or using specific IgE determination)
have no absolute accuracy.1 They can return often falsely
positive in children who tolerate milk, or conversely can be
negative even in the presence of a delayed, non-IgE mediated,
CMA. The OFC and in particular the DBPCFC is considered
today, according to the literature, the gold standard for
diagnosing food allergies,2,3 able to minimize false positive
diagnoses. Such a specific diagnosis will prevent unnecessary
and potentially deleterious dietary restrictions when a suspected CMA is not present. Unfortunately, in the world not
all children can avail themselves of the OFC in milk allergy
evaluation.4,5 Resources for the practical planning and carrying-out of OFCs are available through many scientific societies6 8 and lay organizations.9
Y
Y
DEFINITIONS
OFC
OFCs with cows milk are in vivo diagnostic tests
performed to definitely confirm a preliminary suspicion of
CMA. OFCs can be performed in 3 different ways:
a. Open, where everyone is aware that milk is brought to
the child that day
b. Single-blinded, where the pediatrician is aware of the
content but child and parents do not
c. DBPCFC when neither the pediatrician nor the child or
parents know the day when milk will be administered.
Positive/Negative OFC
An OFC resulting in a clinical reaction is defined a
positive or failed challenge, whereas an OFC without a
clinical reaction is termed a negative or passed challenge.
For the purpose of this document, the authors chose to use
positive and negative terminology. A positive challenge will
give indication of the tolerated dose, if any, thus allowing the
2010 World Allergy Organization
Open Challenge
This is the simplest procedure, requiring less commitment to the pediatrician, the patients and their families and
thus lowering costs for the health facilities. After a thorough
physical examination, the linchpin for a comparative assessment of pre- and postchallenge, CM is administered openly in
increasing doses up to the dose liable to be responsible for
symptoms. Clinical observation will be carried out for about
2 hours after the last dose of milk for immediate reactions
and, after discharge, an appointment should be scheduled in
101
Fiocchi et al
Open milk
challenge
Single-Blinded Challenge
Single-blind is a procedure in which the pediatrician is
aware of which food is given to the child at that moment. It
is used less than open or DBPCFC, because it entails in
principle the same difficulties found with a DBPCFC, but is
a bit less reliable as it introduces the possible bias of subjective interpretation by observer. Single-blind OFC may be
conducted with or without placebo, depending on the physicians judgment of the potential for subjective symptoms and
the patients anxiety.6 In case of immediate reactions, it will
consist of 2 sessions, one with CM and one with placebo,
completed on one day with at least a 2-hour period separating
the 2 sessions, or on separate days. If 2 foods are tested on the
same day, the sequence of the foods is not revealed to the
child. We must underline that this option is valid only when
delayed symptoms can be excluded in advance. For patients
reporting delayed onset of symptoms, sessions of blinded
OFC should be separated by several days or weeks.16,17 In
patients suspected of having a psychologic response, the
verum might be tested first. In this case, a negative challenge
will spare a second day of procedure. If symptoms develop,
CM should be retested for reproducibility in a DBPCFC.3,7
After a negative blind challenge, CM would be administered openly: this recommendation is based on the possibility of detecting a reaction to an open feeding in children with
delayed CM reactions.18
Double-Blind, Placebo-Controlled
Food Challenge (DBPCFC)
A DBPCFC is the oral administration, usually on different
days, of placebo and increasing amounts of milk. First used in
1973 by May19 in the assessment of allergic reactions to foods in
children with bronchial asthma, the DBPCFC is now the test of
choice in the diagnosis of CMA. In this procedure, only personnel who prepared the test is aware of the food offered at the time:
CM (verum) or placebo. Such personnel, not in contact with
either the child or the family or the doctor, is the only one to
prepare the meals and, in principle, to decide the randomization.
The randomization code is prepared in closed envelopes. A
major problem in the preparation of the placebo is the avoidance
of possibly sensitizing foods. In general, for milk challenges the
use of amino acid mixtures make the test safe from misinterpretations. If another placebo is used, the absence of sensitization
should be tested by SPT. To enhance masking of appearance and
flavor, it is necessary that the amount of placebo in the verum is
approximately half the cows milk. On completion of the challenges, the code is broken, and results are discussed with the
patient or parent. Placebo reactions are infrequent, but possible.20
102
Table 10-2 (indications according to clinical history). Challenges should not be performed in general when a negative
skin test, undetectable serum milk-specific IgE level, and no
history of convincing symptoms of immediate CMA make
the condition very unlikely. In these cases, gradual home
introduction of milk may be attempted. For those patients
who have a history of convincing immediate allergic reactions to milk (within 2 hours) or who present with a history
of anaphylaxis, even in the setting of negative laboratory and
skin tests, a physician-supervised OFC is needed to confirm
or refute allergy to this food.
Clinical Assessment
To undergo challenge procedures, the patient must be
well, without intercurrent fever episodes, vomiting, diarrhea,
nor seasonal rhinitis and/or asthma.30 Atopic dermatitis
should be stabilized in the weeks preceding the OFC, and not
subject to significant fluctuations that would make the test
difficult to interpret. A 10-point increase in postchallenge
SCORAD is considered the minimum threshold for defining
a significant worsening of atopic dermatitis.31 The child
should discontinue antihistamine therapies long enough to get
a normal histamine skin reactivity,32 and at least for 72 hours
before OFC.11
2010 World Allergy Organization
Open
Indicated
Indicated
Indicated
Indicated
Indicated
Generalized, important allergic reaction in a single organ (such as urticaria, angioedema, or vomiting,
or respiratory symptoms) occurred immediately (within 2 hours after ingestion) with positive CM
IgE tests22
Clinical history of Food Protein Enterocolitis from cows milk with at least one previous episode, both
in presence and absence of CMA-specific IgE6
Moderate to severe atopic dermatitis (AD) resistant to properly done topical therapy for a reasonable
period in presence of IgE antibodies to CM. AD of any entity, whether associated with the
occurrence of other possible allergic symptoms (rhinitis, asthma, diarrhoea, vomiting, etc.) both in
the presence and absence of specific IgE to milk23
Clinical situation not suggestive and/or clinical response not immediate (eg. Atopic dermatitis) when
patient or her family are convinced of the existence of CMA and thus inclined to interpret any
clinical signs as related to cows milk ingestion24
Reintroduction of cows milk excluded from the diet for several months on a mere detection of
specific IgE in the absence of a suggestive clinical history25
Clinical subjective symptoms (nausea, abdominal pain, itching, oral, etc.) after CM ingestion7,26
Clinical picture of delayed allergic reaction (chronic diarrhea, colitis, allergic proctocolitis,
gastroesophageal reflux) without CM-specific IgE6
Open
DBPCFC
Open
Open
DBPCFC
DBPCFC
Open
CMA anaphylaxis21
Challenge
Type
Indication
Clinical Situation
Home
Hospital
Hospital
Hospital
Hospital
Hospital
Hospital
Hospital
Hospital
103
Fiocchi et al
OFC Benefits
The benefits of a positive OFC include a conclusive
diagnosis of CMA demonstrating the need for continued
counseling in strict avoidance of cows milk, reduction of the
risk of inadvertent exposures, reduction of anxiety about the
unknown, and validation of the patients and families efforts
to avoid the food. It allows accurate prescription of elimination diet. A positive OFC may induce fear of reactions, thus
leading to closer monitoring of avoidance. The benefits of a
negative OFC include expansion of the diet and improvement
of the patients nutrition and quality of life. This can spare
unnecessary health expenses and reduce the use of special
formula.
OFC Limitations
Challenge procedures are risky, labor- and time-consuming, and costly. Before performing a challenge, procedural details, risks and benefits must be discussed with the
patient and his or her family.3 Immediate systemic reactions
can be severe. They are unpredictable on the basis of sensitization, but an association can be found between clinical
history of severe symptoms and symptoms after OFC.33,34
Similarly, a number of risk factors for more severe reactions
have been suggested: unstable or severe asthma, progressively more severe reactions, reactions to small quantities of
cows milk or treatment with beta-adrenergic antagonists.6 To
minimize these risks, venous access should be maintained
during CM challenges, in particular when a severe systemic
reaction seems possible. In Europe it has been recommended
that for young children intravenous access should be applied
only in selected cases7. These recommendations take into
account the fact that deaths from anaphylaxis are more
frequently described after the age of 5 years. Given these
considerations, it is essential that be conducted under the
observation of a team with specific expertise in pediatric
allergy and supplied with all equipment and drugs for emergency treatment.35
OFCs are more standardized for IgE- than for non-IgEmediated reactions; in the latter case, the observation should
be prolonged for an extended period of time. Thus, a diagnostic elimination diet is generally prescribed and sensitization tests are usually carried-out before DBPCFC. The state
of the art CMA work-up uses the informed prescription of
DBPCFC and various diagnostic tests according to clinical
context. The combination of prechallenge test in DRACMA
is object of GRADE evaluation (see section on GRADE
Assessment of CMA Diagnosis).
104
If the severe reaction occurred immediately after simultaneous introduction of many foods at the same time:
typical example is the introduction of the first solid meal
including CM proteins (and many other putative food
allergens) in a breast-fed
OFC Setting
The challenges are generally labor-intensive and carry
some risk to the patient. Anyone who performs such challenges on children and adults with suspected CM allergies
must have the background and equipment to recognize symptoms of allergy and to treat anaphylactic reactions.36 The first
step is to consider whether the test can be performed at home
or needs to be under direct physician supervision. There are
many specific issues that must be considered in this particular
decision. In general, whenever there is an even remote potential for an acute and/or severe reaction, physician supervision is mandatory. This decision for a supervised challenge
includes, but is not limited to, a history of prior significant
reactions and/or positive tests for IgE to milk.3 The ideal
setting is hospital, both at an in-patient and out-patient level.37 When there is a very high risk for a severe reaction but
OFC is required, challenges preferably should be done in the
intensive care unit. Low-risk challenges in cooperative patients are appropriate for the office setting.
Times and doses can vary according to clinical history.
For a suspected FPIES, the procedure should be administered
with intravenous access with prolonged observation. For
immediate reactions, a limited observation time can ensure
appropriate diagnostic accuracy. In delayed forms, longer
observation periods will be necessary. Challenges requiring
exercise to precipitate symptoms need to be performed where
suitable exercise equipment is available.38
Challenge Procedure
In absence of comparative studies between different
challenge protocols, there is no universal consensus on timing
and doses for milk challenge administration. The consensus
documents published in this field6,7 report some example of
procedures, but the suggestion to individualize doses and
times based on the clinical history remains valid.57,58 Initial
doses has been suggested to be 0.1 mL,7 but can vary
according to the risk of reaction and type of milk allergy (IgE
2010 World Allergy Organization
up to 186 mL
On the first day, rising doses of the placebo
or test formula (1, 5, 10, 50, and 100
mL) challenge period 1 week. Challenge
started in the hospital, continued at home
Up to 143 mL
Successive doses (0.1, 0.3, 1.0, 3.0, 10.0,
30.0, and 100.0 mL) of fresh pasteurized
CM containing 3.5% fat, soy milk, and
wheat powder (Krner; total amount of
10 g of wheat protein) were administered
Not reported
Chapman JA8
Niggemann B11
Sporik R53
Saarinen KM54
Majamaa H55
Roehr CC46
Eigenmann PA56
Klemola T45
Bahna SL14
Dose
50
Bock SA
Sicherer SH3
Sicherer SH51
Ranc F52
Authors
Intervals
Not reported
Not reported
Extensively hydrolyzed
formula
Soy formula
Amino acid formula
Not reported
30 60 minutes
Open
Not specified
Not specified
Placebo
At 30 minutes intervals
Each 20
DBPCFC with CM
DBPCFC or open
challenge with CMF
Method
D: within 5 days
I. within 2 hours
NR
I: 2 hours.
D: 48 hours
Time of Reaction
105
Fiocchi et al
Challenge Interpretation
106
17. Helm RM. Food allergy: in-vivo diagnostics including challenge. Curr
Opin Allergy Clin Immunol. 2001:1;255259.
18. Bahna SL. Food challenge procedure: optimal choices for clinical
practice. Allergy Asthma Proc. 2007;28:640 646.
19. May CD. Objective clinical and laboratory studies of immediate hypersensivity reactions to foods in asthmatic children. J Allergy Clin Immunol. 1976;58:500 515.
20. Vlieg-Boerstra BJ, van der Heide S, Bijleveld CM, Kukler J, Duiverman
EJ, Dubois AE. Placebo reactions in double-blind, placebo-controlled
food challenges in children. Allergy. 2007;62:905912.
21. Joint Task Force on Practice Parameters; American Academy of Allergy,
Asthma and Immunology; American College of Allergy, Asthma and
Immunology; Joint Council of Allergy, Asthma and Immunology. The
diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol. 2005;115:483523.
22. Lieberman P, Decker W, Camargo CA Jr., OConnor R, Oppenheimer J,
Simons FE. SAFE: a multidisciplinary approach to anaphylaxis education in the emergency department. Ann Allergy Asthma Immunol. 2007;
98:519 523.
23. Niggemann B, Sielaff B, Beyer K, Binder C, Wahn U. Outcome of
double-blind, placebo-controlled food challenge tests in 107 children
with atopic dermatitis. Clin Exp Allergy. 1999;29:9196.
24. Venter C. Prevalence of sensitization reported and objectively assessed
food hypersensitivity amongst six-year-old children: a population-based
study. Pediatr Allergy Immunol. 2006;17:356 363.
25. Flinterman AE, Knulst AC, Meijer Y, Bruijnzeel-Koomen CA, Pasmans
SG. Acute allergic reactions in children with AEDS after prolonged
cows milk elimination diets. Allergy. 2006;61:370 374.
26. Niggemann B, Beyer K. Diagnosis of food allergy in children: toward a
standardization of food challenge. J Pediatr Gastroenterol Nutr. 2007;
45:399 404.
27. Eigenmann PA, Sampson HA. Interpreting skin prick tests in the
evaluation of food allergy in children. Pediatr Allergy Immunol. 1998;
9:186 191.
28. Markowitz JE, Spergel JM, Ruchelli E, Liacouras CA. Elemental diet is
an effective treatment for eosinophilic esophagitis in children and
adolescents. Am J Gastroenterol. 2003;98:777782.
29. Werfel T, Ballmer-Weber B, Eigenmann PA, Niggemann B, Rance F,
Turjanmaa K, Worm M. Eczematous reactions to food in atopic eczema:
position paper of the EAACI and GA2LEN. Allergy. 2007;62:723728.
30. Niggemann B, Beyer K. Diagnosis of food allergy in children: toward a
standardization of food challenge. J Pediatr Gastroenterol Nutr. 2007;
45:399 404.
31. Niggemann B, Reibel S, Wahn. The atopy patch test (APT): a useful tool
for the diagnosis of food allergy in children with atopic dermatitis.
Allergy. 2000;55:281285.
32. Bock SA. In vivo diagnosis: Skin testing and oral challenge procedures.
In: Metcalfe DD, Sampson HA, Simon RA, eds. Food allergy: Adverse
Reactions to Foods and Food Additives. 2nd ed. Cambridge MA:
Blackwell Science; 1997.
33. Spergel JM, Beausoleil JL, Fiedler JM, Ginsberg J, Wagner K,
Pawlowski NA. Relation of initial food reactions to observed reactions
on challenges. Ann Allergy Asthma Immunol. 2004;92:217224.
34. Sicherer SH, Morrow EH, Sapmson HA. Dose-response in double-blind,
placebo controlled oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2000;105:582586.
35. Perry TT, Matsui EC, Conover-Walker MK, Wood RA. Risks of oral
food challenges. J Allergy Clin Immunol. 2004;114:1164 1168.
36. Bock SA. Diagnostic evaluation. Pediatrics. 2003;111:1638 1644.
37. Wuthrich B. Ambulatory oral provocation testing. Hautarzt. 1995;46:
352353.
38. Fiocchi A, Mirri GP, Santini I, Ottoboni F, Riva E. Exercise-induced
anaphylaxis following food-contaminant ingestion at Double-Blinded,
Placebo-Controlled, Food-Exercise Challenge. J Allergy Clin Immunol.
1997;100:424 425.
39. Hst A, Samuelsson EG. Allergic reactions to raw, pasteurized, and
homogenized/pasteurized cow milk: a comparison. Allergy. 1988;43:
113118.
40. Taylor SL, Hefle SL, Bindslev-Jensen C. Factors affecting the determination of threshold doses for allergenic foods: how much is too much.
J Allergy Clin Immunol. 2002;109:24 30.
107
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108
64. Williams LW, Bock SA. Skin testing and food challenges in allergy.
Clin Rev Allergy Clin Immunol. 1999;17:323338.
65. Beyer K, Niggemann B, Schulze S, Wahn U. Serum tryptase and urinary
1-methylhistamine as parameters for monitoring oral food challenges in
children. Int Arch Allergy Immunol. 1994;104:348 351.
66. Niggemann B, Beyer K, Wahn U. The role of eosinophils and eosinophil
cationic protein in monitoring oral challenge tests in children with foodsensitive atopic dermatitis. J Allergy Clin Immunol. 1994;94:963971.
67. Beyer K, Lorenz H, Wahn U, Niggemann B. Changes in blood leukocyte
distribution during double-blind, placebo-controlled food challenges in
children with atopic dermatitis and suspected food allergy. Int Arch
Allergy Immunol. 1998;116:110 115.
68. Gabriele C, de Benedictis FM, de Jongste JC. Exhaled nitric oxide
measurements in the first 2 years of life: methodological issues, clinical
and epidemiological applications. Ital J Pediatr. 2009;35:2123.
69. Sutas Y, Kekki M, Isolauri E. Late onset reactions to oral food challenge are
linked to low serum interleukin-10 concentrations in patients with atopic
dermatitis and food allergy. Clin Exp Allergy. 2000;30:11211128.
70. Rautava S, Isolauri E. Cows milk allergy in infants with atopic eczema
is associated with aberrant production of interleukin-4 during oral cows
milk challenge. J Pediatr Gastroenterol Nutr. 2004;39:529 535.
71. Kapel N, Matarazzo P, Haouchine D, Abiola N, Guerin S, et al. Fecal
tumor necrosis factor alpha, eosinophil cationic protein and IgE levels in
infants with cows milk allergy and gastrointestinal manifestations. Clin
Chem Lab Med. 1999;37:29 32.
72. Baehler P, Chad Z, Gurbindo C, Bonin AP, Bouthillier L, Seidman EG.
Distinct patterns of cows milk allergy in infancy defined by prolonged,
two-stage double-blind, placebo-controlled food challenges. Clin Exp
Allergy. 1996;26:254 261.
73. Burks AW, Casteel HB, Fiedorek SC, Willaims LW, Pumphrey CL.
Prospective oral food challenge study of two soybean protein isolates in
patients with possible milk or soy protein enterocolitis. Pediatr Allergy
Immunol. 1994;5:40 45.
74. Eigenmann PA, Caubet JC, Zamora SA. Continuing food-avoidance diets
after negative food challenges. Pediatr Allergy Immunol. 2006;17:601 605.
Introduction
Pediatricians and allergists often have to face parents
who are aware that CMA is not a lifelong condition and
therefore wish to know how long CMA is likely to last.
Adults who have been diagnosed with CMA are few and far
between but the severity of disease is often more worrisome.
Answering these legitimate questions implies practical acquaintance with CMA in both age groups regardless of
prevention and treatment effect. Our actual knowledge of the
natural history of CMA, however, remains hampered by the
fragmentary epidemiology of risk and prognostic factors that
is the flip side of our extensive clinical literature.
109
Fiocchi et al
110
these studies provide information only for generating hypotheses about the natural history of CMA.26,27
Another possibly major influence on CMA outcomes
for which there is a paucity of data are genetics. Children in
whom respiratory symptoms develop at onset, with sensitization to multiple foods and initial sensitization to common
respiratory allergens show a longer duration of disease.22
These results, echoing the findings of earlier epidemiological
studies,7,17 suggest that the influence of allergic phenotypes
beyond immediate environmental factors may play a role in
the onset of CMA. Taken together, these studies are consistent with the suspicion that the allergic march model might be
applicable only in certain phenotypes rather than to all atopic
individuals: in the case of CMA, there may be several
different phenotypes that if identified, could lead to personalized medicine treatment strategies for different populations
of atopic patients.
111
Fiocchi et al
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
112
43.
44.
45.
46.
47.
Table 12-1 summarizes the recommendations made by international scientific societies, as well as several consensus
documents on the treatment of CMA.
As a food allergy, CM is not an exception to the general
rule that the management relies primarily on avoidance of
exposure to the suspected or proven foods.1 Thus, the key
principle in the treatment of CMA, irrespective of the clinical
type, is the dietary elimination of CMP.
In breast-fed infants, and in children after 2 years of
age, a substitute formula may not be necessary. In infants and
children less than 2 years of age, replacement with a substitute formula is mandatory. In this case, the choice of formula
must take into account a series of considerations (see
GRADE evaluation). Basically, in all cases the factors to be
considered are the after:
2010 World Allergy Organization
TABLE 12-1. Treatment of Milk Allergy according to the Current Recommendations in Different Countries
ESPACI/ESPGHAN 199919
Breastfed
In exclusively breastfed
infants, a strict elimination
of the causal protein from
the diet of the lactating
mother should be tried
AAP 200020
Mild-to-moderate CMA:
eHF
When:
The child refuses to
drink eHF, but accepts
AAF
Symptoms do not
improve on eHF after
24 weeks
Costbenefit ratio
favors the AAF
AAF
Severe CMA
Refer to a paediatric
specialist. In the
meantime, an
elimination diet should
be started with AAF
Continue breastfeeding
but avoid CMP in
mothers diet
Australian
Consensus Panel
200822
Breastfeeding may
be continued, and
recommendations
are provided for
eliminating
maternal intake
of CM protein
(plus Ca supplement)
Formula-fed
Allergen elimination is
relatively easy in exclusively
formula fed infants
Partially hydrolyzed
formula (pHF)
Extensively
hydrolyzed formula
(eHF)
Appropriate for
treating CMA
Appropriate for
treating CMA
(Continued)
113
Fiocchi et al
ESPACI/ESPGHAN 199919
AAP 200020
Australian
Consensus Panel
200822
Other milks
Soy hydrolyzed
formula (HSF)
Rice hydrolyzed
formula (HRF)
At the time of
recommendations, not extant
At the time of
recommendations, not
extant
At the time of
recommendations,
not available in
Australia
Are considered to be
nonallergenic. Highly
sensitive patients (ie,
patients reacting to eHF)
may require an amino acid
based dietary product
Tolerated
Appropriate for
treating CMA
Differentiation of
recommendations
by phenotype
114
There is no place
for other
mammalian milks
(such as goats
milk) in treating
CMA
6 months: eHF
for immediate
CMA
(nonanaphylactic),
FPIES, atopic
eczema,
gastrointestinal
symptoms and
food proteininduced
proctocolitis
6 months: SF for
immediate
reactions, GI
symptoms or
atopic dermatitis
in the absence of
failure to thrive
AAF 1st choice in
anaphylaxis and
eosinophilic
oesophagitis
(Continued)
ESPACI/ESPGHAN 199919
AAP 200020
Formula to be given
during the
diagnostic
elimination phase
Australian
Consensus Panel
200822
Mild-to-moderate CMA:
eHF or AAF
Severe CMA: AAF
Anaphylaxis
eHF
AAF
Immediate GI
reactions
eHF
eHF 6 months,
AAF 6 months
IgE-mediated
respiratory reactions
eHF
eHF 6 months,
AAF 6 months
IgE-mediated
cutaneous reactions
eHF
eHF 6 months,
AAF 6 months
Atopic dermatitis
eHF
eHF 6 months,
AAF 6 months
Delayed GI reactions
eHF
eHF 6 months,
AAF 6 months.
AAF in
eosinophilic
oesophagitis
Heiner Syndrome
eHF
eHF? No specific
recommendation
Follow-up
*Company-supported guidelines intended for general pediatricians and/or GPs. Recommendations valid for mild to moderate CMA. In case of suspicion of severe CMA, refer
to a specialist.
115
Fiocchi et al
6.
7.
8.
9.
116
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Introduction
Fully breast-fed infants and toddlers more than 2 years
may not need to substitute cows milk if an adequate supply
of calcium (600 800 mg/day) is provided. From these patients perspective, avoidance means meeting obstacles unshared by their nonallergic peers, thereby curtailing their
quality of life; from the physicians outlook, patient and
parent education, encouraging compliance, and receptiveness
in both patient and caregiver are the major didactic concerns.
The cues for a successful avoidance phase result from a
dialectical assessment of these competing factors in concert
with all parties concerned.
breast-feeding in sensitized infants.2 The mother will also require calcium supplements (1000 mg/day divided into several
doses) while after a milk-free diet.
For the nonbreastfed infants, a substitute formula will be
proposed. Current guidelines define a therapeutic formula as one
that is tolerated by at least 90% (with 95% CI) of CMPA
infants.3 These criteria are met by some extensively hydrolyzed
cows milk whey and/or casein formula, soy and rice hydrolysates, and by amino acid-based formula (AAF). To maximize
the diagnostic significance of the elimination phase, the least
allergenic substitute should be proposed. Children may react to
residual allergens in eHF, with a risk of failure up to 10% of
children with CMA.4 The residual allergens in eHF account for
failure of therapy in this setting,5 and such formula are more
likely to produce gastrointestinal and other non-IgE-associated
manifestations compared with AAF.6,7 However, immediate
reactions have also been reported in connection with eHF treatment.8 In such cases, clinicians should consider either rice
hydrolyzed formula (HRF) or AAF, the safety of which is well
documented9,10 and that provide adequate nutrition,8,11 promote
weight gain, and foster growth.
Planning a dietary regimen avoiding all cows milk
proteins from dairy or processed food products for these
infants and children is a collaborative consensus between
scientific societies, primary care physicians and caregivers
that goes beyond office procedures. For infant foods in
particular, lists of acceptable foods and suitable substitutes
congruent with national context and clinical setting must be
drawn from various sources and adapted to the individual
patients needs and values.12 A dietician can be of help and
specific lists are available to inform the everyday choices of
parents and patients. For children and adolescents, who are
major consumers of prepackaged industrially processed
foods, recognizing the danger signals can be more difficult than
in adult populations. Inadvertent milk contamination is difficult
and costly to consistently eliminate from the food chain and, for
infants and children, good quality alternative protein sources
must be found that are also attractive. To compound the problem, milk allergen inhalant, ingestant, or skin contact forms are
all liable to trigger severe reactions.13,14
117
Fiocchi et al
118
PRESCRIBING A NUTRITIONALLY
ADEQUATE DIET
Formulating the diet of infants and children during the
CMA work-up requires a careful evaluation of all nutritional
aspects and requirements on a strictly individual patient basis.
There has long been a consensus is in the food allergy
literature that extensive [elimination] diets should be used as
a diagnostic tool only for a short period of time31 and that it
is crucial to provide a balanced diet which contains sufficient
proteins, calories, trace elements, and vitamins.32 This is
particularly relevant for infants with CMA, since their nutritional requirements demand a balanced calorie-protein ratio,
amino-acid composition and an adequate calcium source.33
Ignoring these principles can lead to inappropriate diets,
sometimes with dramatic effects.34 As far as cows milk
substitutes are concerned, studies demonstrating their nutritional safety even in the first35 and the second36 semester of
life are part of the body of evidence underlying the consensus
treatment of CMA.
33. Black RE. Children who avoid drinking cow milk have low dietary calcium
intakes and poor bone health. Am J Clin Nutr. 2002;76:675 680.
34. Nguyen J, Cazassus F, Atallah A, Baba N, Sibille G, Coriatt D. Kwashiorkor after an exclusion diet for eczema. Presse Med. 2001;30:1496 1497.
35. Isolauri E, Sutas Y, Makinen-Kiljunen S, Oja SS, Isosomppi R, Turjanmaa
K. Efficacy and safety of hydrolyzed cow milk and amino acid-derived
formulas in infants with cow milk allergy. J Pediatr. 1995;127:550 557.
36. Agostoni C, Fiocchi A, Riva E, Terracciano L, Sarratud T, et al. Growth
of infants with IgE-mediated cows milk allergy fed different formulas
in the complementary feeding period. Pediatr Allergy Immunol. 2007;
18:599 606.
37. Vlieg-Boerstra BJ, van der Heide S, Bijleveld CMA, Kukler J, Duiverman EJ, Wolt-Plompen SAA, Dubois AEJ. Dietary assessment in children adhering to a food allergen avoidance diet for allergy prevention.
Eur J Clin Nutr. 2006;60:1384 1390.
QUESTION 7
Should amino acid formula, extensively hydrolyzed
whey or casein formula, soy formula or rice formula be
used in children with IgE-mediated CMA?
Population: children with CMA
Interventions (management options):
1.
2.
3.
4.
119
Fiocchi et al
Failure to thrive
(Total n = 2206)
Enteropathy, entero/proctocolitis
Weight/height
Duration of CMA
Anthropometric values
Summary of Findings
Systematic Reviews
One systematic review assessed the efficacy of amino
acid-based formulas in relieving the symptoms of cows milk
allergy.1 We could not use this review to directly inform these
recommendations since it did not assess the methodological
quality of included studies, did not combine the results of
individual studies, and included studies done in children
without confirmed CMA.2,3 We assessed all the studies identified in this review and used those that met our prespecified
criteria (see description of individual studies below). We
identified one additional randomized trial of amino acid
versus extensively hydrolyzed formula4 that appeared after
Hill and colleagues review was published.1
We did not identify any systematic review assessing the
relative benefits and downsides of using extensively hydrolyzed formula compared with soy formula or rice formula or
comparing soy to rice formula in children with CMA.
Individual Studies
Altogether we identified 3 randomized trials comparing
amino acid-based formula to an extensively hydrolyzed whey
120
Records screened
(n = 1579)
Records excluded
(n = 1525)
Studies included in
qualitave synthesis
(n = 10)
Studies included in
quantave synthesis
(meta-analysis)
(n = 7)
Records screened
(n = 2954)
Records excluded
(n = 2779 )
Studies included in
qualitave synthesis
(n = 3)
Studies included in
quantave synthesis
(meta-analysis)
(n = 0)
children challenged with extensively hydrolyzed whey formula developed symptoms of allergy: vomiting and diarrhea
(one), urticaria (one), and delayed eczema (one).
No study using amino acid formula reported laryngeal
edema, severe asthma, anaphylaxis, enteropathy, or entero/
proctocolitis. No study measured protein and nutrients deficiency, and quality of life of both children and parents. We
did not identify any study comparing amino acid-based formula to soy formula or rice hydrolysate.
We identified 2 studies that compared extensively hydrolyzed cows milk formula to soy formula9,10. Extensively
hydrolyzed formulas used were Nutramigen regular (Mead
Johnson)9 and Peptidi-Tutteli (Valio)10 and the soy formulas
were Isomil-2 (Ross Abbott)9 and Soija Tutteli (Valio).10 All
studies had methodological limitations, none reported a
method of randomization, concealment of allocation, and
they were not blinded. In one study only results of per
protocol analysis were reported.9 Most outcomes of interest
did not occur in the studies (see evidence profile, Table A3-3
in Appendix 3).
Only one randomized trial compared extensively hydrolyzed formula to rice formula.9 A extensively hydrolyzed
rice formula used in one study was Risolac (Heinz) (see
evidence profile, Table A3-2 in Appendix 3).
We found 2 randomized trials comparing soy formula
to rice formula published by the same group of investigators,
one was the abovementioned study by Agostoni and col 2010 World Allergy Organization
leagues9 and the other was a study by DAuria and colleagues11 (see evidence profile, Table A3-4 in Appendix 3).
Because the information from randomized trials was
sparse, we searched for observational studies with an independent control group that compared different formula in
children with cows milk allergy. We identified 5 observational studies.1216 Two of them reported comparing different
extensively hydrolyzed milk formula only.12,15 One study
described 51 children with immediate allergic reactions to
cows milk protein in whom extensively hydrolyzed milk,
soy or amino acid formula were used.13 The formula were
selected by the clinician and the selection was not described.
Allergic reaction to selected formula was observed in 3 of the
8 children receiving extensively hydrolyzed milk formula,
and none of the children receiving either soy (29 children) or
amino acid formula (6 children). Another study described a
cohort of 25 children sensitized to cows milk proteins
(authors did not report the criteria for diagnosis) that received
either soy formula or extensively hydrolyzed casein formula
for 12 months.14 Authors measured body height, mass and
upper arm circumference and found no difference between the
groups. The third study described 58 children with atopic eczema and CMA, who received a rice hydrolysate formula, soy
formula or an extensively hydrolyzed casein formula.16 The
choice of the formula was reported as being based on allergometric tests, clinical features at the beginning of the diet and
age. Authors measured weight of the children and observed no
difference in the weight-for-age z-score among the groups.
Benefits
In children with atopic eczema extensively hydrolyzed
whey formula had similar impact on the severity of eczema
compared with amino acid-based formula (mean difference in
SCORAD score: 1.39 point higher; 95% CI: 1.08 lower to
3.86 higher). Growth, as measured by relative length and
weight, were similar in both groups, although the results were
imprecise (see evidence profile, Table A3-1 in Appendix 3).
Downsides
Vomiting was noted in fewer children receiving extensively hydrolyzed whey formula compared with amino acid
formula (relative risk: 0.12 [95% CI: 0.02 0.88]; risk difference: 235 fewer per 1000 [from 32 fewer to 261 fewer]),
however, this estimate is based on 9 events only. One study
estimated the cost treatment. The use of extensively hydrolyzed whey formula was associated with direct cost of 149
per child per month and amino acid formula 318 per child
per month (difference: 169 less per child per month). However, this estimate can only serve as a rough guide for
decisions in other settings. Direct cost measured in one
country and jurisdiction at some point in time will likely not
be applicable to different settings. Direct cost may be estimated considering that the children in the study (mean age 8
months) consumed about 600 mL (200) of formula daily.
121
Fiocchi et al
Conclusions
Net clinical benefit of substituting cows milk with
amino acid formula compared with extensively hydrolyzed
whey formula is uncertain. Most outcomes of interest were
not measured in clinical studies and the estimates of outcomes that were measured are very imprecise. The direct cost
of amino acid formula is higher than extensively hydrolyzed
whey formula. There is no information from controlled clinical studies about the relative benefits and downsides of using
amino acid formula compared with soy or rice formula.1
Further research, if done, will have important impact on this
recommendation.
Downsides
Fewer children with CMA experienced allergic reaction
to extensively hydrolyzed formula than to soy formula (relative risk: 0.18; 95% CI: 0.05 0.71) and developed secondary sensitization confirmed by the presence of specific IgE in
serum (relative risk: 0.14; 95% CI: 0.03 0.76). However,
very few events occurred in both groups, thus the results are
imprecise.
Quality of life was not measured in these studies, but
investigators recorded acceptance of a formula.9 All 37
children receiving soy formula accepted it well, but 4 of 35
children receiving extensively hydrolyzed formula accepted it
poorly (relative risk: 0.89; 95% CI: 0.751.02).
Conclusions
Net clinical benefit of substituting cows milk with
extensively hydrolyzed formula compared with soy formula
is uncertain. Most outcomes of interest were not measured in
clinical trials and the estimates of the outcomes that were
measured are very imprecise. Further research, if done, will
have important impact on this recommendation.
Benefits
Growth, as measured by length and weight for age
z-score, was similar in the group receiving extensively hydrolyzed casein formula compared with hydrolyzed rice formula (length for age z-score, mean difference: 0.33 SD
122
higher; 95% CI: 0.13 lower to 0.79 higher, and weight for age
z-score; mean difference: 0.04 SD higher; 95% CI: 0.53
lower to 0.45 higher). The results were imprecise and it is not
certain to what extent these measures of childs growth relate
to outcomes that are important to patients.
Downsides
No allergic reaction to extensively hydrolyzed formula
or to rice formula occurred in this study.9 Acceptance of
extensively hydrolyzed whey formula and extensively hydrolyzed rice formula was similar (relative benefit: RR 1.06;
95% CI: 0.86 1.32), but the results were very imprecise not
excluding appreciable benefit or appreciable harm. Hydrolyzed rice formulas are not available in many countries.
Conclusions
Net clinical benefit of substituting cows milk with
extensively hydrolyzed formula compared with rice formula
is uncertain. Only one relatively small randomized trial is
available that did not report most outcomes of interest and the
estimates of the outcomes that were measured are very
imprecise. Further research, if done, will have important
impact on this recommendation.
Benefits
There was no apparent difference in length and weight
for age z-scores between children receiving soy formula
compared with rice formula (length for age z-score, mean
difference: 0.33 SD higher; 95% CI: 0.13 lower to 0.79
higher, and weight for age z-score, mean difference: 0.04 SD
lower; 95% CI: 0.53 0.45 higher). In a study that enrolled
children with atopic eczema its severity was similar in both
groups both at baseline and at the end of the study, but 11/16
children had SCORAD scores 20 at baseline.9,11
Downsides
Fewer children with CMA experienced allergic reaction
to hydrolyzed rice formula that to soy formula (0/43 versus
5/44; relative risk: 0.08; 95% CI: 0.00 1.52). However, very
few events occurred, thus the results are imprecise.
Conclusions
Net clinical benefit of substituting cows milk with soy
formula compared with extensively hydrolyzed rice formula
is unknown. Most outcomes of interest were not measured
and the estimates of the outcomes that were measured are
very imprecise. The guideline panel felt that any recommendation is not warranted until further research is done comparing the effects of using a soy formula versus a hydrolyzed
rice formula.
Remarks
In controlled settings a trial feeding with an extensively
hydrolyzed milk formula may be appropriate.
Recommendation 7.2
In children with IgE-mediated CMA at low risk of
anaphylactic reactions (no prior history of anaphylaxis or
currently on extensively hydrolyzed milk formula), we suggest extensively hydrolyzed milk formula over amino acid
formula (conditional recommendation/very low quality evidence).
Remarks
Extensively hydrolyzed milk formula should be tested
in clinical studies before being used.19 If a new formula is
introduced, one should carefully monitor if any adverse
reactions develop after first administration.
Recommendation 7.3
In children with IgE-mediated CMA, we suggest extensively hydrolyzed milk formula rather than soy formula
(conditional recommendation/very low quality evidence).
Remarks
Soy should not be used in first 6 months of life, because
of nutritional risks.
2010 World Allergy Organization
Recommendation 7.4
In children with IgE-mediated CMA, we suggest extensively hydrolyzed milk formula rather than extensively
hydrolyzed rice formula (conditional recommendation/very
low quality evidence).
Recommendation 7.5
We suggest that more well designed and executed
randomized trials comparing soy formula to extensively hydrolyzed rice formula are performed in patients suspected of
IgE-mediated CMA.
Remarks
There is very sparse evidence suggesting possible benefit from using extensively hydrolyzed formula compared
with soy formula, but more research is needed to confirm
these observations.
REFERENCES, SECTION 14
1. Hill DJ, Murch SH, Rafferty K, Wallis P, Green CJ. The efficacy of
amino acid-based formulas in relieving the symptoms of cows milk
allergy: a systematic review. Clin Exp Allergy. 2007;37:808 822.
2. Hill DJ, Cameron DJ, Francis DE, Gonzalez-Andaya AM, Hosking CS.
Challenge confirmation of late-onset reactions to extensively hydrolyzed
formulas in infants with multiple food protein intolerance. J Allergy Clin
Immunol. 1995;96:386 394.
3. McLeish CM, MacDonald A, Booth IW. Comparison of an elemental
with a hydrolysed whey formula in intolerance to cows milk. Archives
of Disease in Childhood. 1995;73:211215.
4. Niggemann B, von BA, Bollrath C, Berdel D, Schauer U, et al. Safety
and efficacy of a new extensively hydrolyzed formula for infants with
cows milk protein allergy. Pediatr Allergy Immunol. 2008;19:348 354.
5. Isolauri E, Sutas Y, Makinen-Kiljunen S, Oja SS, Isosomppi R, Turjanmaa K. Efficacy and safety of hydrolyzed cow milk and amino acidderived formulas in infants with cow milk allergy. J Pediatr. 1995;127:
550 557.
6. Niggemann B, Binder C, Dupont C, Hadji S, Arvola T, Isolauri E.
Prospective, controlled, multi-center study on the effect of an aminoacid-based formula in infants with cows milk allergy/intolerance and
atopic dermatitis. Pediatr Allergy Immunol. 2001;12:78 82.
7. Caffarelli C, Plebani A, Poiesi C, Petroccione T, Spattini A, Cavagni G.
Determination of allergenicity to three cows milk hydrolysates and an
amino acid-derived formula in children with cows milk allergy. Clin
Exp Allergy. 2002;32:74 79.
8. Sampson HA, James JM, Bernhisel-Broadbent J. Safety of an amino
acid-derived infant formula in children allergic to cow milk. Pediatrics.
1992;90:463 465.
9. Agostoni C, Fiocchi A, Riva E, Terracciano L, Sarratud T, Martelli A,
Lodi F, DAuria E, Zuccotti G, Giovannini M. Growth of infants with
IgE-mediated cows milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol. 2007;18:599 606.
10. Klemola T, Vanto T, Juntunen-Backman K, Kalimo K, Korpela R,
Varjonen E. Allergy to soy formula and to extensively hydrolyzed whey
formula in infants with cows milk allergy: a prospective, randomized study
with a follow-up to the age of 2 years. J Pediatr. 2002;140:219 224.
11. DAuria E, Sala M, Lodi F, Radaelli G, Riva E, Giovannini M. Nutritional
value of a rice-hydrolysate formula in infants with cows milk protein
allergy: a randomized pilot study. J Intl Med Res. 2003;31:215222.
12. Kaczmarski M, Wasilewska J, Lasota M. Hypersensitivity to hydrolyzed
cows milk protein formula in infants and young children with atopic
123
Fiocchi et al
13.
14.
15.
16.
17.
18.
19.
124
Introduction
Milks from different animals (the goat, ewe, mare,
donkey, or camel) or formulas based on lamb or chicken have
been widely marketed as substitutes for CM in the management of CMA in infants and children. The substitute source
reflects local culture, availability and costs but a comprehensive survey of substitutes for children with CMA is
currently lacking. As described in CM Allergen section,
cross-reactivity between mammalian proteins is in part
explained by bovine taxonomy (Table 15-1), with similarities and differences:
1. Human milk composition differs both in component
ratios and structure from other milks.
2. The protein content of human milk is lower than that
of ruminant dairy animals: cow, buffalo, yak, camel,
goat, sheep, reindeer, but is closer to that of donkeys
and mares milk.1
3. Human milk does not contain beta-lactoglobulin
(BLG), one of the major allergens in cow milk, similarly to camels and dromedarys milks.2
4. BLG is a major whey protein of cows, buffalos,
sheeps, goats, mares, and donkeys milks.
5. The proportion of casein within the total protein fraction is lower in whole human milk, serum proteins are
higher than in cows, buffalos, and ewes milks and
more similar to donkeys and mares milks.
6. The ratio of casein to whey protein is very similar
among Bovidae (between 70:30 and 80:20).
7. Mares and donkeys milks have a lower total protein
content (similar to human milk) and a lower caseinto-whey protein ratio.
8. There is substantial homology between cows, ewes,
or goats milks protein fractions.
9. There is less structural similarity with the milk from
swine, equines and camelids, and human milk.3
10. Human milk, camels and dromedarys milks do not
contain beta-lactoglobulin.
2010 World Allergy Organization
76.6
58.4
62.8
62.4
74.1
74.5
60.0
73.9
Absent
71.5
59.4 (1)
53.2
Absent
56.5
57.4
60.5
58.4
69.2
31.9
58..3
60.0
43.3
44.2
60
42
44
26
1.25
40
2.2
58
2.14
56
3.6
74
79.9
64.2
87.6
71.2
92.4
91.1
100
Average
100
Serum albumin
96.1
63.9
74.6
95.1
94.4
93.9
97.2
100
-Lactoglobulin
96.7
100
-Lactalbumin
99.3
54.3
67.0
91.1
84.9
84.9
92.0
100
-Casein
92.6
100
-Casein
97.8
47.2
62.8
88.3
87.9
88.3
89.2
95.0
100
95.3
100
s2-Casein
42
16
16
18
20
Whey proteis (percent)
Homology
s1-Casein
58
4.8
4.3
84
84
4.9
4.5
82
3.2
80
Casein (percent)
Human
Protein (g percent)
Equus
E. asinus
Donkey
Horse
Equus
E.f. caballus
Dromedary
Camelus
C. dromedarius
Pig
Sus
S. domestico
Capra
C. aegagrus
Goat
Sheep
Ovis
O. aries
Bubalus
B. bubalis
Buffalo
Cow
Bos
B. domesticus
Genus
Species
Homo
H. sapiens
125
Fiocchi et al
Camels Milk
In many parts of the world (North-East Africa,2 the
Middle East,24 the Arabic Peninsula, and China25), camels
and dromedarys milks are used as human milk substitutes for
bottle-fed infants.
Camel milk contains only 2% fat, consisting mainly of
polyunsaturated fatty acids, and is rich in trace elements.26 Its
protein composition makes it a possible alternative to CM for
allergic subjects because of the low sequence homology of its
protein fraction with that of CM and its lack of BLG.27
Tolerance of camel milk has been anecdotally reported
in a limited case series of children suffering from severe, not
challenge-confirmed, CMA with immediate and delayed
symptoms.28
No comparative data are available on the palatability of
camels milk, but it is also reasonable to expect it to taste
TABLE 15-2. Protein Content of Different Milks
(in g/100 mL)
Milk
Total
Albumin
Casein
Human
Donkey
Mare
Cow
Goat
Ewe
1.03
2.0
2.2
3.3
3.7
5.3
0.4
0.7
1.2
2.5
3.1
4.5
0.4
0.6
0.3
0.2
0.6
1.7
126
CONCLUSIONS
In the opinion of the DRACMA Panel, the types and
methods of current studies on the use of other milks for the
2010 World Allergy Organization
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
127
Fiocchi et al
Introduction
The use of diet therapy for the long-term management
of CMA is fraught with nutritional risk. The growth and
biochemical parameters of children with CMA should approach the standards of reference. Unfortunately, very few
studies address these clinical issues. There is also an interest
in the dietary modulation of nutritional factors through the
use of pre, pro-, symbiotic preparations and polyunsaturated
fatty acids (PUFA) representing a new research hypothesis
for both nutritionists and pediatric allergists.
128
Among the causes of growth limitation, the nutritional efficiency of substitute formula has been investigated.5
Formulae designed for infant nutrition when human
milk is not available should achieve both an acceptable
growth rate and blood proteins and amino acid profile that
approach a reference standard, presumably that based on
metabolic data from breast-fed infants.6 Investigations about
the nutritional adequacy of special formula used for CMA
treatment have been known for a long time.7 Earlier studies
indicated lower values of body mass index and higher blood
urea nitrogen by infants fed extensively hydrolyzed formula
(eHF), with differences in plasma amino acidograms showing
higher essential amino acids (AA)/total AA ratio in soy
formula (SF)- and eHF-fed compared with breast-fed infants.
Also, a lower branch-chain AA/essential AA ratio was reported.8 More recently, clinical trials have investigated
growth in infants with CMA fed different formula (eHF or
SF), up to 48 months of age,9 suggesting that in general
nutritional adequacy is guaranteed by these formula. Differences in the increase of standardized growth indices (weightfor-age, length-for-age, and weight-for-length z-scores) in
infants with CMA have been found suggesting that infants
fed hydrolyzed products (eHF, HRF) show a trend toward
higher weight-for-age z-score increments than children fed
SF in the 6 to 12 months period.10 Not only the total amount,
but protein quality seems to be important for both symptomatic treatment and growth. Thus, the use of cows milk or rice
hydrolysates has not been explored during the first months,
when breast- or formula-milk represent the only food
source,11 but their use in the second semester onwards may
have decreased local inflammatory responses, positively affecting the absorption of nutrients from the other solid foods.
This is only an example of the potentially complex effects of
substitute formula in nutrition of children with CMA.
Table 16-1 reports the most relevant nutritional parameters to be assessed in individual formula by the pediatrician
when planning a special diet for CMA treatment. The nutritional parameters of the special formula currently available in
the world are reported in the repository found on the WAO
website.
hydrolysis, heating, . . ..
Carbohydrate source
Lipid source
Formulation
Powder or liquid
Proteins
Amino acids (AA)
g/L
Alanine, Arginine, . . . Tyrosine,
Valine.
Essential AA/total AA
g/L
mg/L
IU/L
mcg/L
mcg/L
mcg/L
mcg/L
mcg/L
mcg/L
mcg/L
mg/L
IU/L
IU/L
mcg/L
mcg/L
mg/L
mcg/L
mg/L
mg/L
mg/L
mg/L
mg/L
mcg/L
mcg/L
mcg/L
mcg/L
mg/L
mg/L
mg/L
mcg/L
mcg/L
mcg/L
Genus,
species
CFU/g
powder
Kcalories/L
%
%
%
%
mOsm/L
mOsm/kg water
mOsm/L
(Continued)
129
Fiocchi et al
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
REFERENCES, SECTION 16
1. Levy Y, Davidovits M. Nutritional rickets in children with cows milk
allergy: calcium deficiency or vitamin D deficiency? Pediatr Allergy
Immunol. 2005;16:553.
2. Fox AT, Du Toit G, Lang A, Lack G. Food allergy as a risk factor for
nutritional rickets. Pediatr Allergy Immunol. 2004;15:566 569.
3. Patel L, Clayton PE, Addison GM, Price DA, David TJ. Linear growth in
prepubertal children with atopic dermatitis. Arch Dis Child. 1998;79:169172.
4. Agostoni C, Fiocchi A, Riva E, Terracciano L, Sarratud T, et al. Growth
of infants with IgE-mediated cows milk allergy fed different formulae
in the complementary feeding period. Pediatr Allergy Immunol. 2007;
18:599 606.
5. Isolauri E, Sutas Y, Salo MK, Isosomppi R, Kaila M. Elimination diet in
cows milk allergy: risk for impaired growth in young children. J Pediatr. 1998;132:1004 1009.
6. Atkinson SA. Feeding the normal term infant: human milk and formula.
130
27.
In: Sinclair JC, Bracken MB, eds. Effective Care of the Newborn Infant.
Oxford: Oxford University Press; 1992:79 92.
Giovannini M, Fiocchi A, Agostoni C, Riva E. Nutrition in infancy and
childhood. In: Wuthrich B, Ortolani C, eds. Highlights in Food Allergy Monogr Allergy 32, Basel:Karger, 1996;2529.
Giovannini M, Agostoni C, Fiocchi A, Bellu` R, Trojan S, Riva E.
Antigen-reduced infant formulae versus human milk: growth and metabolic parameters in the first 6 months of life. J Am Coll Nutr.
1994;13:357363.
Seppo L, Korpela R, Lonnerdal B. A follow-up study of nutrient intake,
nutritional status, and growth in infants with cow milk allergy fed either
a soy formula or an extensively hydrolyzed whey formula. Am J Clin
Nutr. 2005;82:140 145.
Agostoni C, Grandi F, Scaglioni S, Gianni ML, Torcoletti M, et al.
Growth pattern of breastfed and nonbreastfed infants with atopic dermatitis in the first year of life. Pediatrics. 2000;106:73.
Vandenplas Y, Hauser B, Blecker U. The nutritional value of a whey
hydrolysate formula compared with a whey-predominant formula in
healthy infants. J Pediatr Gastroenterol Nutr. 1993;17:9296.
Isolauri E, Arvola T, Sutas Y, Moilanen E, Salminen S. Probiotics in the
management of atopic eczema. Clin Exp Allergy. 2000;30:1604 1610.
Rosenfeldt V. Effect of prebiotic Lactobacillus strains in children with
atopic dermatitis. J Allergy Clin Immunol. 2003;111:389 395.
Passeron T. Prebiotics and synbiotics: two promising approaches for the
treatment of atopic dermatitis in children above 2 years. Allergy. 2006;
61:431 437.
Sistek D. Is the effect of probiotics on atopic dermatitis confined to food
sensitized children? Clin Exp Allergy. 2006;36:629 633.
Brouwer ML. No effects of probiotics on atopic dermatitis syndrome in
infancy: a randomized placebo-controlled trial. Clin Exp Allergy. 2006;
36:899 906.
Betsi GI, Papadavid E, Falagas ME. Probiotics for the treatment or
prevention of atopic dermatitis: a review of the evidence from randomized controlled trials. Am J Clin Dermatol. 2008;9:93103.
Horrobin DF. Fatty acid metabolism in health and disease: the role of
delta-6 desaturase. Am J Clin Nutr. 1993;52:732S735S.
Wright S, Burton JL. Oral evening-primrose-seed oil improves atopic
eczema. Lancet. 1982;2:1120 1122.
Berth-Jones J, Graham-Brown RAC. Placebo-controlled trial of essential fatty
acid supplementation in atopic dermatitis. Lancet. 1993;341:15571560.
Calder PC. Fatty acids and lymphocyte functions. Br J Nutr. 2002;
47(Suppl 2):S60 S61.
Li XM, Brown L. Efficacy and mechanisms of action of traditional
Chinese medicines for treating asthma and allergy. J Allergy Clin
Immunol. 2009;123:297306.
Li XM. Traditional Chinese herbal remedies for asthma and food
allergy. J Allergy Clin Immunol. 2007;120:2531.
Li XM. Food Allergy Herbal Formula-1 (FAHF-1) blocks peanutinduced anaphylaxis in a murine model. J Allergy Clin Immunol.
2001;108:639 646.
Srivastava KD, Kattan JD, Zou ZM, Li JH, Zhang L, et al. The Chinese
herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol.
2005;115:171178.
Qu C. Induction of tolerance after establishment of peanut allergy by the
food allergy herbal formula-2 is associated with up-regulation of interferon-gamma. Clin Exp Allergy. 2007;37:846 855.
Chehade M. IgE and non-IgE-mediated food allergy: treatment in 2007.
Curr Opin Allergy Clin Immunol. 2007;7:264 268.
he DRACMA recommendations about the most appropriate choice of the substitute formula when breastfeeding is
not available (7.17.5) are all conditional, i.e. they should be
interpreted with special attention to patients preferences,
individual clinical circumstances and cost. It is not possible
for any guideline to take into consideration all of the often
2010 World Allergy Organization
1st
choice
2nd
choice
AAF
eHF
eHF
eHF
AAF
eHF
eHF#
AAF/SF
AAF/SF
AAF/SF
eHF
AAF
eHF*
AAF
eHF
AAF
eHF
eHF
AAF
AAF
AAF
eHF
3rd
choice
SF
AAF
Donkey milk
SF
Recommendation 7.1.
Recommendation 7.2.
*If AAF refusal.
Subject to local availability, HRF can be considered instead than eHF (7.4).
#
Subject to a negative SPT with the specific formula (panel recommendation).
AAF if a relatively high value on avoiding sensitization by SF and/or a low value
on resource expenditure are placed.
SF if a relatively low value on avoiding sensitization by SF and/or a high value on
resource expenditure are placed.
Subject to local availability.
**This suggestion attributes a high value on avoiding exposure to even residual
antigenic cows milk proteins.
Given that more than 50% of such children are allergic to soy, a careful clinical
evaluation is necessary (panel recommendation).
compelling individual clinical circumstances or patient characteristics because recommendations in guidelines are for
typical patients. The DRACMA guideline panel made recommendations for use of substitute formulas specifically for
patients with IgE-mediated CMA. However, the choice of the
formula may be different for patients with non IgE-mediated
CMA or in patients with other specific presentations such as
allergic eosinophilic oesophagitis or food protein-induced
enterocolitis syndrome (FPIES). The use of formulas in
patients with these conditions will be addressed in the future
updates of the DRACMA guidelines.
Against this background, table 17 reports a quick reference guide to the recommendations.
Importance
8
7
7
7
7
6
6
6
Summary of Findings
We did not find any systematic review of immunotherapy for CMA. We found 3 randomized trials13 and 3 observational studies4 6 that examined specific tolerance induction
to cows milk in children with cows milk allergy.
Two randomized trials1,3 included children (mean age 9
years; range 517) with CMA confirmed with a blinded placebocontrolled food challenge test. One study used oral immunotherapy with whole milk for 12 months in children with a history of
at least 1 severe allergic reaction and milk-specific IgE levels
greater than 85 kUA/L (assessed with Phadia CAP System
FEIA) who were not able to tolerate more than 0.8 mL of milk
during the challenge test.1 The other study used preparation of
dry nonfat powdered milk for 6 months in children with a history
of IgE-mediated milk allergy (no history of anaphylaxis requiring hospitalization, intubation, or severe asthma), a positive skin
prick test (SPT) result to milk extract or milk-specific IgE level
greater than 0.35 kU/L (assessed with Phadia CAP System
FEIA) who were not able to tolerate more than 75 mL of milk
during the challenge test.3 We used information from these
studies to prepare summaries of evidence for immunotherapy in
patients with CMA.
A third study included children aged 2.2 years (range:
1 6.5) of whom 90% had atopic eczema and were able to
tolerate at least 60 mL of milk; diagnosis was established based
on the results of food challenge test, SPT or serum milk-specific
IgE determination2. We did not combine the results of this study
with the results of the other 2 studies, because the diagnosis of
CMA in included children was uncertain.
Three observational studies reported by the same group
of investigators used oral milk immunotherapy in children
aged 3 to 14 years with CMA confirmed by a blinded
placebo-controlled food challenge test.4 6 No study measured
the quality of life of children or their parents.
Benefits
Two randomized trials showed that the probability of
tolerating at least 150 mL of milk and eat any dairy and
milk-containing products) was 17 times higher (95% CI:
131
Fiocchi et al
95% CI: 3.8 1032.8), and the need for intramuscular epinephrine (rate ratio: 6.4; 95% CI: 1.234.1).
Severe reactions occur rarely, however, once they develop they may pose a serious problem, since they may occur
at home. Immunotherapy for CMA requires long-term compliance and a significant commitment of the childs family,
availability of medical support 24-hour a day, and resources
to treat adverse effects immediately.
Other Considerations
Records screened
(n = 796)
Records excluded
(n = 766)
Conclusions
Studies included in
qualitave synthesis
(n = 2)
Studies included in
quantave synthesis
(meta-analysis)
(n = 2)
Downsides
Local symptoms were the most frequent adverse effects
of immunotherapy occurring during the administration of
16% of doses (rate ratio: 4.5; 95% CI: 3.9 5.2). Lip and/or
mouth pruritus was more than 800 times more frequent in
children receiving immunotherapy than in children not receiving it (rate ratio: 880.1; 95% CI: 54.6 14, 185.8). Other
adverse effects were also more frequent in children receiving
immunotherapy included the after: perioral urticaria (rate
ratio: 9.9; 95% CI: 4.322.9), generalized erythema or urticaria (rate ratio: 16.8; 95% CI: 4.5 63.4), abdominal pain
and/or vomiting (rate ratio: 25.8; 95% CI: 5.9 113.3), rhinoconjunctivitis (rate ratio: 15.5 95% CI: 3.7 64.7), mild laryngospasm (rate ratio: 40.9; 95% CI: 2.5 671.8), mild
bronchospasm (rate ratio: 11.0; 95% CI: 0.97124.0), the
need for oral glucocorticosteroids (rate ratio: 50.9; 95% CI:
7.0 368.7), need for nebulised epinephrine (rate ratio: 62.8;
132
Clinical Recommendation
In patients with IgE-mediated CMA, we recommend that
clinicians do not administer oral immunotherapy with cows
milk, unless this is done in the context of formal clinical research
(strong recommendation/very low quality evidence).
8. Ioannidis JP, Evans SJ, Gotzsche PC, ONeill RT, Altman DG, Schulz
K, Moher D. Better reporting of harms in randomized trials: an extension
of the CONSORT statement. Ann Intern Med. 2004;141:781788.
Epidemiology
Y
Y
Y
Y
Y
Genetics
Y
Y
Y
Y
Y
Y
Family clustering of food and respiratory allergies suggests a genetic basis for the disease
The specific genetic study of CMA remains largely terra
incognita
The disease genotypes are still unknown
The prevalence of susceptibility genes and their distribution across various populations remains unspecified
Even the clinical impact of family history is still unexplored
The genetic basis of the variability in individual responses to CM would be an important breakthrough
Allergens
Y
Y
Y
Mechanisms
Y
Y
Y
Y
Y
Y
Clinical Presentations
Y
Y
Y
Y
Y
Diagnosis
Y
Y
Y
Y
Y
Y
Y
Natural History
Y
Y
Y
Formulae
Y
Y
Y
Y
133
Fiocchi et al
Y
Y
Y
Y
Y
Y
Induction of Tolerance
Y
Y
Y
134
1.
2.
3.
4.
5.
6.
ACKNOWLEDGEMENTS
The WAO Special Committee on Food Allergy is supported through unrestricted educational grants from various
charities and companies that are representative of the food
industry: Danone, Heinz, Ordesa, Nestle Nutrition, Dicofarm, and Invest for Children.
The content of the Guidelines was developed independently, and the GRADE evaluation of the Guidelines was
independently conducted at McMaster University in Hamilton, Ontario, Canada, under Holger Schunemann assisted by
Jan Brozek, Enrico Compalati and Luigi Terracciano.
WHO ICTRP (the World Health Organization International Clinical Trials Registry Platform);
Google Scholar.
Search strategy
Restrictions: Humans, English language, Age [Section 3. Epidemology of CMA for details]. No publication restrictions
were applied.
Panellists were required to apply their clinical experience to compile a draft list of suitable articles for the topic
within their purview.
EPIDEMIOLOGY OF CMA
NCBI PubMed; ISI Web of Science; Google Scholar
Cows milk allergy
Cows milk protein allergy
Cows milk hypersensitivity
Cows milk protein hypersensitivity
Cows milk IgE-mediated reaction*
AND
LIMITATIONS
0-18
childhood
infant*
preschooler*
school age
adolescence
young adults
adults
elderly
135
Fiocchi et al
136
Terms successively
entered in Position 1
-lactalbumin
alpha-lactalbumin
-lactoglobulin
beta-lactoglobulin
c-type lysozyme*
serum albumin*
P02769
P00711 1HFZ
bovine lactalbumin
P04421
bovine lysozyme
lipocalin*
P02754 1BEB
bovine lactoglobulin
P18902 1ERB
Q28133 1BJ7
S1- casein
alpha S1-casein
S2-casein
alpha S2-casein
-casein
beta-casein
-casein
kappa-casein
-casein
gamma-casein
bovine allergen*
Bos d 1
Bos d 2
Bos d 3
Bos d 4
Bos d 5
Bos d 6
Q95182 1EW3
equine allergen
Equ c 1
P02769
threshold*
structural biology
Antibod#
IgE antibod#
IgA antibod#
IgM antibod#
Bioinformatics*
characterisation
cross-reactivity
epitope*
B cell epitope*
T cell epitope*
protein folding
AND
Immune reaction*; immune mechanism; adaptive immunity; Cows milk IgEmediated reaction*; immediate reaction*; delayed reaction*; biphasic reaction*;
inflammation; neutrophilia; specific IgE antibody; specific IgA antibody; tumor
necrosis factor alpha; (cows milk [protein]) sensitisation.
AND
NCBI PubMed;
ISI Web of Science;
Google Scholar
Cows milk allergy
Cows milk protein allergy
Cows milk hypersensitivity
Cows milk protein hypersensitivity
Cows milk IgE-mediated reaction*
AND
1. ANAPHYLAXIS/
1. anaphylactic react$.mp.
2. anaphylactic shock$.mp.
3. anaphylactic syndrome$.mp.
4. anaphylactoid react$.mp.
5. anaphylactoid shock$.mp.
6. anaphylactoid syndrome$.mp.
7. acute systemic allergic react$.mp.
8. idiopathic anaphylaxis.mp.
9. systemic anaphylaxis.mp.
10. or/110
AND
OR
OR
symptom*
presentation
phenotype
137
Fiocchi et al
Anaphylaxis
Oral allergy syndrome
Asthma
Rhinitis
Urticaria and/or angioedema
Atopic dermatitis
Gastro-oesophageal reflux
Pyloric stenosis
Eosinophilic oesophagitis
Enteropathy
Constipation
Colic
Food protein-induced gastroenteritis and/or proctocolitis
Heiners syndrome
AND
AND
OR
OR
History
Clinical presentation
Clinical examination
AND
OR
OR
(Skin/prick)$ test
Elimination
diet
AND
OR
OR
Specific immunoglobulin E
antibody tit$
Elimination diet
Specific immunoglobulin E
antibody level*
Cows milk
hypersensitivity
Cows milk protein
hypersensitivity
Cows milk IgE-mediated
reaction*
138
AND
INDICATION
Diagnosis of cows milk allergy
Double blind placebo-controlled food challenge
SPT endpoint titration
Elimination diet
DOSAGE
Starting dose
Time between steps
Dilution
Threshold dosage
Titration
Concentration
Drops
INTERVENTION
Schedule
Scheme
Protocol
Patient information
Parent information
Ethics Committee Review
((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.
placebos.sh.
placebo$.ti,ab.
random$.ti,ab.
research design.sh.
comparative study.sh.
exp evaluation studies/
follow up studies.sh.
prospective studies.sh.
(control$ or prospectiv$ or volunteer$).ti,ab.
WHEN CAN MILK PROTEINS BE ELIMINATED FROM THE DIET WITHOUT SUBSTITUTING COWS MILK?
1.
2.
3.
4.
5.
6.
7.
8.
9.
ELIMINATION DIET
COWS MILK FORMULA
HYDROLY#ED COWS MILK FORMULA
WHEY HYDROLY#ATE FORMULA
139
Fiocchi et al
BOOLEAN SYNTAX USED IN THE SEARCH FOR SUPPORTING LITERATURE USED IN THE NARRATIVE
SECTIONS
NB: MeSH terms limited to searches of databases supporting this linking format.
Keywords: prevalence, cow's milk allergy, children [N = 120]
Limits: Published between 1st January 1999 and 30th June 2009, Humans, English, 0-18 years.
(("epidemiology"[Subheading] OR "epidemiology"[All Fields] OR "prevalence"[All Fields] OR "prevalence"[MeSH
Terms]) AND cow's[All Fields] AND ("milk hypersensitivity"[MeSH Terms] OR ("milk"[All Fields] AND
"hypersensitivity"[All Fields]) OR "milk hypersensitivity"[All Fields] OR ("milk"[All Fields] AND "allergy"[All Fields])
OR "milk allergy"[All Fields])) AND ("humans"[MeSH Terms] AND English[lang] AND ("infant"[MeSH Terms] OR
"child"[MeSH Terms] OR "adolescent"[MeSH Terms]) AND ("1999/01/01"[PDAT] : "2009/06/30"[PDAT]))
140
141
Fiocchi et al
142
milk"[All Fields] OR "milk"[All Fields] OR "milk"[MeSH Terms]) AND ("allergens"[MeSH Terms] OR "allergens"[All
Fields])) AND ("humans"[MeSH Terms] AND English[lang] AND ("1999/01/01"[PDAT] : "2009/06/30"[PDAT]))
Keywords: cow's milk, epitope [N = 42]
Limits: Published between 1st January 1999 and 30th June 2009, Humans, English
(cow's[All Fields] AND ("milk, human"[MeSH Terms] OR ("milk"[All Fields] AND "human"[All Fields]) OR "human
milk"[All Fields] OR "milk"[All Fields] OR "milk"[MeSH Terms]) AND ("epitope"[MeSH Terms] OR "epitope"[All
Fields])) AND ("humans"[MeSH Terms] AND English[lang] AND ("1999/01/01"[PDAT] : "2009/06/30"[PDAT]))
Keywords: cow's milk, immunology [N = 409]
Limits: Published between 1st January 1999 and 30th June 2009, Humans, English
(cow's[All Fields] AND ("milk hypersensitivity"[MeSH Terms] OR ("milk"[All Fields] AND "hypersensitivity"[All
Fields]) OR "milk hypersensitivity"[All Fields] OR ("milk"[All Fields] AND "allergy"[All Fields]) OR "milk allergy"[All
Fields]) AND ("immunology"[Subheading] OR "immunology"[All Fields] OR "allergy and immunology"[MeSH Terms]
OR ("allergy"[All Fields] AND "immunology"[All Fields]) OR "allergy and immunology"[All Fields])) AND
("humans"[MeSH Terms] AND English[lang] AND ("1999/01/01"[PDAT] : "2009/06/30"[PDAT]))
Keywords: cow's milk, immunopathology [N = 9]
Limits: Published between 1st January 1999 and 30th June 2009, Humans, English
(cow's[All Fields] AND ("milk hypersensitivity"[MeSH Terms] OR ("milk"[All Fields] AND "hypersensitivity"[All
Fields]) OR "milk hypersensitivity"[All Fields] OR ("milk"[All Fields] AND "allergy"[All Fields]) OR "milk allergy"[All
Fields]) AND immunopathology[All Fields]) AND ("humans"[MeSH Terms] AND English[lang] AND
("1999/01/01"[PDAT] : "2009/06/30"[PDAT]))
Keywords: cow's milk, management [N = 65]
Limits: Published between 1st January 1999 and 30th June 2009, Humans, English
(cow's[All Fields] AND ("milk hypersensitivity"[MeSH Terms] OR ("milk"[All Fields] AND "hypersensitivity"[All
Fields]) OR "milk hypersensitivity"[All Fields] OR ("milk"[All Fields] AND "allergy"[All Fields]) OR "milk allergy"[All
Fields]) AND ("organization and administration"[MeSH Terms] OR ("organization"[All Fields] AND
"administration"[All Fields]) OR "organization and administration"[All Fields] OR "management"[All Fields])) AND
("humans"[MeSH Terms] AND English[lang] AND ("1999/01/01"[PDAT] : "2009/06/30"[PDAT]))
Keywords: cow's milk, clinical management [N = 30]
Limits: Published between 1st January 1999 and 30th June 2009, Humans, English
(cow's[All Fields] AND ("milk hypersensitivity"[MeSH Terms] OR ("milk"[All Fields] AND "hypersensitivity"[All
Fields]) OR "milk hypersensitivity"[All Fields] OR ("milk"[All Fields] AND "allergy"[All Fields]) OR "milk allergy"[All
Fields]) AND clinical[All Fields] AND ("organization and administration"[MeSH Terms] OR ("organization"[All Fields]
AND "administration"[All Fields]) OR "organization and administration"[All Fields] OR "management"[All Fields]))
AND ("humans"[MeSH Terms] AND English[lang] AND ("1999/01/01"[PDAT] : "2009/06/30"[PDAT]))
Keywords: cow's milk, therapy OR treatment [N = 242]
Limits: Published between 1st January 1999 and 30th June 2009, Humans, English
(cow's[All Fields] AND ("milk hypersensitivity"[MeSH Terms] OR ("milk"[All Fields] AND "hypersensitivity"[All
Fields]) OR "milk hypersensitivity"[All Fields] OR ("milk"[All Fields] AND "allergy"[All Fields]) OR "milk allergy"[All
Fields]) AND ("therapy"[Subheading] OR "therapy"[All Fields] OR "therapeutics"[MeSH Terms] OR "therapeutics"[All
Fields]) AND ("therapy"[Subheading] OR "therapy"[All Fields] OR "treatment"[All Fields] OR "therapeutics"[MeSH
Terms] OR "therapeutics"[All Fields])) AND ("humans"[MeSH Terms] AND English[lang] AND ("1999/01/01"[PDAT] :
"2009/06/30"[PDAT]))
143
144
23 studies (2302
patients)
23 studies (2302
patients)
23 studies (2302
patients)
1 study (310
patients)
Not reported
Not reported
True negatives
(patients
without
CMA)
False positives
(patients
incorrectly
classified as
having CMA)
False negatives
(patients
incorrectly
classified as
not having
CMA)
Inconclusive
Complications
Cost
Nonconsecutive
series
Consecutive or
nonconsecutive
series
Consecutive or
nonconsecutive
series
Consecutive or
nonconsecutive
series
Consecutive or
nonconsecutive
series
Study Design
Serious
Serious
None
Serious
None
Serious
Serious
None
Indirectness
Limitations
Serious
Serious
Serious
Serious
Inconsistency
None
None
None
None
Imprecision
Undetected
Undetected
Undetected
Undetected
Publication
Bias
QQOO
low
QOOO
very low
QQOO
low
QQOO
low
Final
Quality
Prev 10%: 33
Prev 80%: 92
Effect Per
1000*
Not important
Not important
Important
Critical
Critical
Critical
Critical
Importance
*Based on combined sensitivity of 67% (95% CI: 64 70) and specificity of 74% (95% CI: 7277).
Most studies enrolled highly selected patients with atopic eczema or gastrointestinal symptoms, no study reported if an index test or a reference standard were interpreted without knowledge of the results of the other test,
but it is very likely that those interpreting results of one test knew the results of the other; all except for one study that reported withdrawals did not explain why patients were withdrawn.
Estimates of sensitivity ranged from 10 to 100%, and specificity from 14 to 100%; we could not explain it by quality of the studies, tests used or included population.
There is uncertainty about the consequences for these patients; in some a diagnosis of other potentially serious condition may be delayed.
One study in children 12 months of age reported 8% inconclusive challenge tests but did not report number of inconclusive skin prick tests.
23 studies (2302
patients)
No. of Studies
True positives
(patients with
CMA)
Outcome
Limitations
APPENDIX 2-1. Question 1, Profile 1. Should Skin Prick Tests Be Used for the Diagnosis of IgE-Mediated CMA in Patients Suspected of CMA?
Cut-Off 3 mm/All Populations
Fiocchi et al
WAO Journal April 2010
5 studies (587
patients)
5 studies (587
patients)
5 studies (587
patients)
1 study (310
patients)
Not reported
Not reported
Inconclusive
Complications
Cost
Nonconsecutive series
Consecutive or
nonconsecutive series
Consecutive or
nonconsecutive series
Consecutive or
nonconsecutive series
Consecutive or
nonconsecutive series
Study Design
None
Serious
None
Serious
Serious
Serious
None
Serious
Limitations
Serious
Serious
Serious
Serious
None
None
None
None
Undetected
Undetected
Undetected
Undetected
Publication
Bias
QQOO low
QQOO low
QQOO low
Final Quality
Prev 80%: 50
Prev 40%: 150
Prev 10%: 225
Effect per
1000*
Not important
Not important
Important
Critical
Critical
Critical
Critical
Importance
*Based on combined sensitivity of 55% (95% CI: 49 61) and specificity of 75% (95% CI: 69 80).
Most studies enrolled highly selected patients with atopic eczema or gastrointestinal symptoms, no study reported if an index test or a reference standard were interpreted without knowledge of the results of the other test,
but it is very likely that those interpreting results of one test knew the results of the other; all except for one study that reported withdrawals did not explain why patients were withdrawn.
Estimates of sensitivity ranged from 10 to 100%, and specificity from 14 to 100%; we could not explain it by quality of the studies, tests used or included population.
There is uncertainty about the consequences for these patients; in some a diagnosis of other potentially serious condition may be delayed.
One study reported 8% inconclusive challenge tests but did not report number of inconclusive skin prick tests.
5 studies (587
patients)
No. of
Studies
Outcome
APPENDIX 2-1. Question 1, Profile 2. Should Skin Prick Tests Be Used for the Diagnosis of IgE-Mediated CMA in Children Younger Than 12 Months
Suspected of CMA?
Cut-Off 3 mm/Children Younger Than 12 Months Suspected of IgE-Mediated CMA
145
146
11 studies (1088
patients)
11 studies (1088
patients)
11 studies (1088
patients)
Not reported
Not reported
Not reported
Inconclusive
Complications
Cost
Consecutive or
nonconsecutive series
Consecutive or
nonconsecutive series
Consecutive or
nonconsecutive series
Consecutive or
nonconsecutive series
Study Design
None
Serious
Serious
Serious
None
Serious
Serious
Serious
Serious
None
None
None
Undetected
Undetected
Undetected
Undetected
None
None
Serious
Serious
Publication
Bias
Limitations
QQOO low
QQOO low
QQOO low
Final Quality
Prev 80%: 56
Prev 40%: 168
Prev 10%: 252
Effect per
1000*
Importance
Not important
Not important
Important
Critical
Critical
Critical
Critical
*Based on combined sensitivity of 81% (95% CI: 77 85) and specificity of 72% (95% CI: 68 76).
Most studies enrolled highly selected patients with atopic eczema or gastrointestinal symptoms, no study reported if an index test or a reference standard were interpreted without knowledge of the results of the other test,
but it is very likely that those interpreting results of one test knew the results of the other; all except for one study that reported withdrawals did not explain why patients were withdrawn.
Estimates of sensitivity ranged from 10 to 100%, and specificity from 14 to 100%; we could not explain it by quality of the studies, tests used or included population.
There is uncertainty about the consequences for these patients; in some a diagnosis of other potentially serious condition may be delayed.
One study in a different population (children younger than 12 months) reported 8% inconclusive challenge tests but did not report number of inconclusive skin prick tests.
11 studies (1088
patients)
No. of Studies
Outcome
APPENDIX 2-1. Question 1, Profile 3. Should Skin Prick Tests Be Used for the Diagnosis of IgE-Mediated CMA in Children Older Than 12 Months Suspected
of CMA?
Cut-Off 3 mm/Children Older Than 12 Months Suspected of IgE-Mediated CMA
Fiocchi et al
WAO Journal April 2010
14 studies (1646
patients)
14 studies (1646
patients)
14 studies (1646
patients)
1 study (310
patients)
Not reported
Not reported
Inconclusive
Complications
Cost
Nonconsecutive
series
Consecutive or
nonconsecutive
series of patients
Consecutive or
nonconsecutive
series of patients
Consecutive or
nonconsecutive
series of patients
Consecutive or
nonconsecutive
series of patients
Study Design
Serious
None
Serious
Serious
None
Serious
Serious
None
Indirectness
Limitations
Serious
Serious
Serious
Serious
Inconsistency
None
None
None
None
Imprecision
Undetected
Undetected
Undetected
Undetected
Publication
Bias
QQOO
low
QOOO
very low
QQOO
low
QQOO
low
Final
Quality
Prev 80%: 86
Prev 40%: 258
Prev 10%: 387
Effect per
1000*
Important
Important
Important
Critical
Important
Critical
Critical
Importance
*Based on combined sensitivity of 0.72 (95% CI: 0.690.75) and the specificity of 0.57 (95% CI: 0.54 0.60).
Half of the studies enrolled highly selected patients with atopic eczema or gastrointestinal symptoms, no study reported if an index test or a reference standard were interpreted without knowledge of the results of the other
test, but it is very likely that those interpreting results of one test knew the results of the other; all except for one study that reported withdrawals did not explain why patients were withdrawn.
Estimates of sensitivity ranged from 12 to 100%, and specificity from 30 to 100%; we could not explain it by quality of the studies, tests used or included population.
There is uncertainty about the consequences for these patients; in some a diagnosis of other potentially serious condition may be delayed.
One study in children 12 months of age reported 8% inconclusive challenge tests but did not report number of inconclusive IgE tests.
14 studies (1646
patients)
No. of Studies
Outcome
APPENDIX 2-2. Question 2. Profile 1. Should In Vitro Cows Milk-Specific IgE Determination Be Used for the Diagnosis of IgE-Mediated CMA?
Threshold: 0.35 IU/L/All Populations
147
148
2 studies (403
patients)
2 studies (403
patients)
2 studies (403
patients)
2 studies (403
patients)
1 study (310
patients)
Not reported
Not reported
Inconclusive
Complications
Cost
Nonconsecutive series
Consecutive or nonconsecutive
series of patients
Consecutive or nonconsecutive
series of patients
Consecutive or nonconsecutive
series of patients
Consecutive or nonconsecutive
series of patients
Study Design
None
Serious
None
Serious
Serious
Serious
None
Serious
Limitations
Serious
Serious
Serious
Serious
None
None
None
None
Undetected
Undetected
Undetected
Undetected
Publication
Bias
QQOO low
QQOO low
QQOO low
Final Quality
Prev 80%: 96
Prev 40%: 288
Prev 10%: 432
Effect per
1000*
Important
Important
Important
Critical
Important
Critical
Critical
Importance
*Based on combined sensitivity of 0.77 (95% CI: 0.71 0.83) and the specificity of 0.52 (95% CI: 0.45 0.59).
Half of the studies enrolled highly selected patients with atopic eczema or gastrointestinal symptoms, no study reported if an index test or a reference standard were interpreted without knowledge of the results of the other
test, but it is very likely that those interpreting results of one test knew the results of the other; all except for one study that reported withdrawals did not explain why patients were withdrawn.
Estimates of sensitivity ranged from 12 to 100%, and specificity from 30 to 100%; we could not explain it by quality of the studies, tests used or included population.
There is uncertainty about the consequences for these patients; in some a diagnosis of other potentially serious condition may be delayed.
One study in children 12 months of age reported 8% inconclusive challenge tests but did not report number of inconclusive IgE tests.
No. of Studies
Outcome
APPENDIX 2-2. Question 2. Profile 2. Should In Vitro Cows Milk-Specific IgE Determination Be Used for the Diagnosis of IgE-Mediated CMA in Children
12 Months of Age?
Threshold: 0.35 IU/L/Children Younger Than 12 Months Suspected of IgE-Mediated CMA
Fiocchi et al
WAO Journal April 2010
6 studies (500
patients)
1 study (310
patients)
Not reported
Not reported
False negatives
(patients incorrectly
classified as not
having CMA)
Inconclusive
Complications
Cost
Serious
None
Serious
Serious
None
Serious
None
Indirectness
Serious
Limitations
Serious
Serious
Serious
Serious
Inconsistency
None
None
None
None
Imprecision
Undetected
Undetected
Undetected
Undetected
Publication
Bias
QQOO low
QQOO low
QQOO low
Final Quality
Prev 10%: 48
Prev 80%: 58
Prev 40%: 174
Prev 10%: 261
Effect per
1000*
Importance
Important
Important
Important
Critical
Important
Critical
Critical
*Based on combined sensitivity of 0.52 (95% CI: 0.45 0.58) and the specificity of 0.71 (95% CI: 0.64 0.77).
Half of the studies enrolled highly selected patients with atopic eczema or gastrointestinal symptoms, no study reported if an index test or a reference standard were interpreted without knowledge of the results of the other
test, but it is very likely that those interpreting results of one test knew the results of the other; all except for one study that reported withdrawals did not explain why patients were withdrawn.
Estimates of sensitivity ranged from 12 to 100%, and specificity from 30 to 100%; we could not explain it by quality of the studies, tests used or included population.
There is uncertainty about the consequences for these patients; in some a diagnosis of other potentially serious condition may be delayed.
One study in children 12 months of age reported 8% inconclusive challenge tests but did not report number of inconclusive IgE tests.
Nonconsecutive
series
Consecutive or
nonconsecutive
series of patients
6 studies (500
patients)
Study Design
No. of Studies
Outcome
APPENDIX 2-2. Question 2. Profile 3. Should In Vitro Cows Milk-Specific IgE Determination be Used for the Diagnosis of IgE-Mediated CMA in Children
12 Months of Age?
Threshold: 0.35 IU/L/Children Older Than 12 Months Suspected of IgE-Mediated CMA
149
150
2 studies (81
patients)
2 studies (81
patients)
2 studies (81
patients)
test.
Cost
Nonconsecutive
series
Consecutive or
nonconsecutive
series of patients
Consecutive or
nonconsecutive
series of patients
Consecutive or
nonconsecutive
series of patients
Consecutive or
nonconsecutive
series of patients
Study Design
Serious
None
Serious
Serious
None
Serious
Serious
None
Indirectness
Limitations
None
Serious
Serious
None
Inconsistency
Serious
Serious
Serious
Serious
Imprecision
Undetected
Undetected
Undetected
Undetected
Publication
Bias
QQOO low
QQOO low
Final Quality
Prev 80%: 48
Prev 40%: 144
Prev 10%: 216
Effect per
1000*
Important
Important
Important
Critical
Important
Critical
Critical
Importance
Only 80 patients.
There was serious inconsistency in the estimation of specificity.
There is uncertainty about the consequences for these patients; in some a diagnosis of other potentially serious condition may be delayed.
One study in children 12 months of age reported 8% inconclusive challenge tests but did not report number of inconclusive IgE tests.
*Based on combined sensitivity of 0.58 (95% CI: 0.52 0.65) and the specificity of 0.76 (95% CI: 0.70 0.81).
One study enrolled highly selected patients with atopic eczema, in another study not all patients received verification using a reference standard and a different reference standard was used based on the results of the index
Not reported
Not reported
Complications
1 study (310
patients)
4 studies (481
patients)
Inconclusive
No. of Studies
Outcome
APPENDIX 2-2. Question 2. Profile 4. Should In Vitro Cows Milk-Specific IgE Determination Be Used for the Diagnosis of IgE-Mediated CMA?
Threshold: 0.7 IU/L/Patients Suspected of IgE-Mediated CMA
Fiocchi et al
WAO Journal April 2010
1 study (161
patients)
1 study (161
patients)
1 study (161
patients)
1 study (161
patients)
1 study (310
patients)
Not reported
Not reported
Inconclusive
Complications
Cost
Nonconsecutive
series
Consecutive series
of patients
Consecutive series
of patients
Consecutive series
of patients
Consecutive series
of patients
Study Design
None
Serious
None
Serious
Serious
Serious
None
Serious
Limitations
None
None
None
None
Serious
Serious
Serious
Serious
Undetected
Undetected
Undetected
Undetected
Publication
Bias
QQOO low
QQOO low
QQOO low
Final Quality
*Based on combined sensitivity of 0.48 (95% CI: 0.35 0.60) and the specificity of 0.94 (95% CI: 0.88 0.98).
Not all patients received verification using a reference standard and a reference standard used is likely to overestimate the prevalence of CMA (open food challenge).
There is uncertainty about the consequences for these patients; in some a diagnosis of other potentially serious condition may be delayed.
One study in children 12 months of age reported 8% inconclusive challenge tests but did not report number of inconclusive IgE tests.
No. of Studies
Outcome
Prev 80%: 10
Prev 40%: 30
Prev 10%: 45
Effect per
1000*
APPENDIX 2-2. Question 2. Profile 5. Should In Vitro Cows Milk-Specific IgE Determination Be Used for the Diagnosis of IgE-Mediated CMA?
Threshold: 2.5 IU/L/Patients Suspected of IgE-Mediated CMA
Important
Important
Important
Critical
Important
Critical
Critical
Importance
151
152
1 study (239
patients)
1 study (239
patients)
1 study (239
patients)
1 study (239
patients)
1 study (310
patients)
Not reported
Not reported
Inconclusive
Complications
Cost
Nonconsecutive
series
Nonconsecutive
series of patients
Nonconsecutive
series of patients
Nonconsecutive
series of patients
Nonconsecutive
series of patients
Study Design
None
None
Serious
None
None
None
None
None
None
None
None
None
Undetected
Undetected
Undetected
Undetected
None
None
None
None
Publication
Bias
Limitations
*Based on combined sensitivity of 0.25 (95% CI: 0.17 0.33) and the specificity of 0.98 (95% CI: 0.94 1.00).
Withdrawals from the study were not explained and the independent interpretation of the tests was not reported.
There is uncertainty about the consequences for these patients; in some a diagnosis of other potentially serious condition may be delayed.
One study in children 12 months of age reported 8% inconclusive challenge tests but did not report number of inconclusive IgE tests.
No. of Studies
Outcome
QQQQ high
QQQO moderate
QQQQ high
QQQQ high
Final Quality
Prev 80%: 4
Prev 40%: 12
Prev 10%: 18
Effect per
1000*
APPENDIX 2-2. Question 2. Profile 6. Should In Vitro Cows Milk-Specific IgE Determination Be Used for the Diagnosis of IgE-Mediated CMA?
Threshold: 3.5 IU/L/Patients Suspected of IgE-Mediated CMA
Important
Important
Important
Critical
Important
Critical
Critical
Importance
Fiocchi et al
WAO Journal April 2010
2 studies (36
patients)
2 studies (36
patients)
2 studies (36
patients)
3 studies (57
patients)
Not reported
Not reported
Inconclusive
Complications
Cost
Consecutive or
nonconsecutive
series of patients
Consecutive or
nonconsecutive
series of patients
Consecutive or
nonconsecutive
series of patients
Consecutive or
nonconsecutive
series of patients
Consecutive or
nonconsecutive
series of patients
Study Design
None
None
Serious
Serious
Serious
Serious
None
None
Indirectness
None
None
None
None
None
Inconsistency
Undetected
Serious
Undetected
Undetected
Undetected
Undetected
Publication Bias
Serious
Serious
Serious
Serious
Imprecision
Serious
Serious
Limitations
*Based on combined sensitivity of 0.71 (95% CI: 0.29 0.96) and specificity of 0.93 (95% CI: 0.77 0.99).
Positive results are defined as both skin prick test and cows milk-specific IgE tests being positive.
One study enrolled only patients with atopic eczema and in all studies the results of the tests were most likely interpreted with the knowledge of other tests.
Negative results are defined as both skin prick test and cows milk-specific IgE tests being negative.
Only 16 events.
2 studies (36
patients)
No. of
Studies
Outcome
QQOO low
QQOO low
QOOO very
low
QQOO low
QQOO low
Final
Quality
28%
Prev 80%: 14
Prev 40%: 42
Prev 10%: 63
Effect per
1000*
Important
Important
Important
Critical
Important
Important
Critical
Importance
APPENDIX 2-3. Question 3. Should In Vitro Specific IgE Determination Be Used for the Diagnosis of CMA In Patients Suspected of CMA and a Positive Result
of a Skin Prick Test? Question 4. Should In Vitro Specific IgE Determination Be Used for the Diagnosis of CMA In Patients Suspected of CMA and a Negative
Result of a Skin Prick Test?
Threshold: skin prick test (3 mm, milk-specific IgE) 0.35 IU/L
153
154
Design
Limitations
Inconsistency
Indirectness
Extensively
Other
Hydrolyzed
Imprecision Considerations Milk Formula
Amino
Acid
Formula
No. of Patients
Mild symptoms of CMA (erythema, urticaria, angioedema, pruritus, diarrhea, rhinitis, conjunctivitis), not reported
0
23
Critical
Important
(Continued)
Important
Important
Important
Important
Q
Critical
Very low
Q
Critical
Very low
Important
**
Critical
Critical
Critical
Importance
QQQ
Critical
Moderate
Quality
42
MD 1.39 higher
(1.08 lower to
3.86 higher)*
Absolute
Effect
Summary of Findings
Severe symptoms of CMA (severe laryngeal edema, severe asthma, anaphylaxis), not reported
0
Moderate symptoms of CMA (mild laryngeal edema, mild asthma), not reported
0
Atopic eczema severity (follow-up 6 to 9 months; measured with: SCORAD; range of scores: 0103; better indicated by lower values)
3
Randomized Serious
No serious
No serious
No serious
None
85
95
trials*
inconsistency
indirectness
imprecision
No. of
Studies
Quality Assessment
1. Isolauri E, Sutas Y, Makinen-Kiljunen S, Oja SS, Isosomppi R, Turjanmaa K. Efficacy and safety of hydrolyzed cow milk and amino acid-derived formulas in infants with cow milk allergy. J Pediatr.
1995;127:550 557.
2. Niggemann B, Binder C, Dupont C, Hadji S, Arvola T, Isolauri E. Prospective, controlled, multi-center study on the effect of an amino-acid-based formula in infants with cows milk allergy/intolerance and
atopic dermatitis. Pediatr Allergy Immunol. 2001;12:78 82.
3. Niggemann B, von BA, Bollrath C, Berdel D, Schauer U, Rieger C, Haschke-Becher E, Wahn U. Safety and efficacy of a new extensively hydrolyzed formula for infants with cows milk protein allergy. Pediatr
Allergy Immunol. 2008;19:348 354.
Date: 2010-02-06
Question: Should Extensively Hydrolyzed Milk Formula Versus Amino Acid Formula be Used in Children With Cows Milk Allergy?
References:
APPENDIX 3-1.
Fiocchi et al
WAO Journal April 2010
Design
Limitations
Inconsistency
Indirectness
30
Absolute
169 Lower
Effect
Summary of Findings
QQ
Low
Quality
Important
Importance
*All studies included predominantly children with atopic eczema. They made up to 100% in one study, 90% in the second, and 76% in the third. It is possible that the effected might have been underestimated because of
the inclusion of the SCORAD results in children without atopic eczema.
Studies did not report the method of randomization, concealment of allocation, and blinding. One study was clearly not blinded and only results of per protocol analysis were reported.
Only 180 patients. It is not defined what SCORAD score represents a minimal important difference. However, the upper limit of the 95% CI was 3.86 points which is unlikely to be close to MID on a 103-point SCORAD
scale.
The study did not report method of randomization, concealment of allocation, blinding, and method of analysis.
There is uncertainty to what extent a length for age z-score reflects a change in growth that would have an important consequence for a patient.
Only 73 patients.
**The median value in children receiving amino acid-based formula was 0 SD (range: -2.11 to 2.6) and the median value in children receiving extensively hydrolyzed whey formula was -0.96 (range: -2.54 to 0.61).
The study did not report method of randomization, concealment of allocation, blinding, and method of analysis.
There is uncertainty to what extent a change in weight reflects a change in growth that would have an important consequence for a patient.
Only 45 patients.
Two randomized food challenges compared amino acid-based formula to extensively hydrolyzed casein formula (Caffarelli 2002, Sampson 1992). Sampson and colleagues enrolled 28 children and there were no reactions
with amino acid formula and one with extensively hydrolyzed formula (vomiting, erythema, rhinitis, laryngeal edema, and wheezing). Caffarelli and colleagues enrolled 20 children and 2 children challenged with amino acid formula
developed a delayed eczema, 4 children receiving extensively hydrolyzed milk formula had immediate diarrhea, vomiting, urticaria, and delayed eczema.
The study did not report method of randomization and concealment of allocation, was not blinded, and reported the results of per protocol analysis only.
***Only 9 events.
There is uncertainty to what extent cost measured in one country and jurisdiction will apply to different settings.
32
Amino
Acid
Formula
No. of Patients
Extensively
Other
Hydrolyzed
Imprecision Considerations Milk Formula
Resource utilization (cost) (follow-up 9 months; measured with: Euro; better indicated by lower values)
None
1
Randomized No serious
No serious
Very serious No. serious
imprecision
trials
limitations
inconsistency
No. of
Studies
Quality Assessment
155
156
Design
Limitations
Inconsistency
Indirectness
No. of Patients
0/36 (0%)
30
0/35 (0%)
31
30
0/35 (0%)
0/35 (0%)
31
0/36 (0%)
0/35 (0%)
Not estimable
Not estimable
MD 0.04 lower
(0.53 lower to
0.45 higher)
MD 0.33 higher
(0.13 lower to
0.79 higher)
Not estimable
Not estimable
Absolute
Q Critical
Very
low
Q Critical
Very
low
QQ Critical
Low
QQ Critical
Low
QQ Critical
Low
QQ Critical
Low
Quality Importance
*Study did not report allocation concealment, was not blinded, and reported the results of per protocol analysis only.
Only 63 children.
No. events.
There is uncertainty to what extent a length for age z-score or a weight for age z-score reflect a change in growth that would have an important consequence for a patient.
Critical
Mild symptoms of CMA (any of the following: erythema, urticaria, angioedema, pruritus, diarrhea, rhinitis, conjunctivitis) (follow-up 12 months)
None
0/35 (0%)
0/36 (0%) Not estimable
QQ Important
1
Randomized Serious*
No. serious
No. serious
Serious
Low
trials
inconsistency
indirectness
Development of secondary sensitization, not reported
0
Important
Quality of life of a patient (follow-up 12 months; as measured by a good acceptance no/some difficulties in getting the meal finished and/or minimal amount generally left out)
1
Randomized Serious*
No serious
No serious
Very serious
None
31/35 (88.6%)
30/36
RR 1.06 (0.86 to 1.32) 50 more per 1000 Q Important
trials
inconsistency
indirectness
(83.3%)
(from 117 fewer
very
to 267 more)
low
Quality of life of caregivers, not measured
0
Important
Resource utilization (cost), not measured
0
Important
Failure to thrive (measured as: weight for age z-score) (follow-up 12 months; better indicated by higher values)
Serious
None
1
Randomized Serious*
No serious
Serious
trials
inconsistency
0/36 (0%)
0/35 (0%)
Effect
Summary of Findings
Extensively
Extensively
Other
Hydrolyzed
Hydrolyzed
Imprecision Considerations Milk Formula Rice Formula
Severe symptoms of CMA (severe laryngeal edema, severe asthma, anaphylaxis) (follow-up 12 months)
None
1
Randomized Serious*
No serious
No serious
Serious
trials
inconsistency
indirectness
Allergic reaction to formula (follow-up mean 12 months)
1
Randomized Serious*
No serious
No serious
Serious
None
trials
inconsistency
indirectness
Moderate symptoms of CMA (mild laryngeal edema or mild asthma)
1
Randomized Serious*
No. serious
No. serious
Serious
None
trials
inconsistency
indirectness
Enteropathy or enteroproctocolitis (follow-up 12 months)
1
Randomized Serious*
No serious
No serious
Serious
None
trials
inconsistency
indirectness
Failure to thrive (measured as: length for age z-score) (follow-up 12 months; better indicated by higher values)
1
Randomized Serious*
No. serious
Serious
Serious
None
trials
inconsistency
No. of
Studies
Quality Assessment
Date: 2009-12-01
Question: Should Extensively Hydrolyzed Milk Formula Versus Extensively Hydrolyzed Rice Formula be Used in Children With Cows Milk Allergy?
Reference:
1. Agostoni C, Fiocchi A, Riva E, Terracciano L, Sarratud T, et al. Growth of infants with IgE-mediated cows milk allergy fed different formulas in the complementary feeding period. Pediatr
Allergy Immunol. 2007;18:599 606.
APPENDIX 3-2.
Fiocchi et al
WAO Journal April 2010
Design
Limitations
Inconsistency
Indirectness
Soy
Formula
No. of Patients
Extensively
Other
Hydrolyzed
Imprecision Considerations Milk Formula
Relative (95% CI)
Effect
Absolute
Severe symptoms of CMA (severe laryngeal edema, severe asthma, anaphylaxis) (follow-up 12 and 24 months)
None
0/125 (0%)
0/117 (0%) Not estimable
2
Randomized Serious*
No serious
No serious
No serious
trials
inconsistency
indirectness
imprecision
Allergic reaction to formula (follow-up 12 and 24 months)
2
Randomized Serious*
No serious
No serious
Serious
None
2/125 (1.6%) 13/117 (11.1%)RR 0.18 (0.05 to 0.71) 91 fewer per 1000
trials
inconsistency
indirectness
(from 32 fewer to
106 fewer)
Moderate symptoms of CMA (mild laryngeal edema or mild asthma)
None
0/125 (0%)
0/117 (0%) Not estimable
2
Randomized Serious*
No serious
No serious
No serious
trials
inconsistency
indirectness
imprecision
Enteropathy or enteroproctocolitis (follow-up 12 and 24 months)
2
Randomized Serious*
No serious
No serious
No serious
None
0/125 (0%)
0/117 (0%) Not estimable
trials
inconsistency
indirectness
imprecision
Failure to thrive (measured as: length for age z-score) (follow-up 12 months; better indicated by higher values)
1
Randomized Serious*
No serious
Serious
Serious
None
31
32
MD 0.27 higher
trials
inconsistency
(0.19 lower to
0.73 higher)
Failure to thrive (measured as: weight for age z-score) (follow-up 12 months; better indicated by higher values)
Serious
None
31
32
MD 0.23 higher
1
Randomized Serious*
No serious
Serious
(0.01 to 0.45
trials
inconsistency
higher)
Protein or nutrient deficiency, not reported
0
Mild symptoms of CMA (any of the following: erythema, urticaria, angioedema, pruritus, diarrhea, rhinitis, conjunctivitis) (follow-up 12 and 24 months)
None
2/125 (1.6%) 13/117 (11.1%)RR 0.18 (0.05 to 0.71) 91 fewer per 1000
2
Randomized Serious*
No serious
No serious
Serious
(from 32 fewer to
trials
inconsistency
indirectness
106 fewer)
Development of secondary sensitization (follow-up 12 and 24 months; specific IgE)
Serious
Serious
None
1/125 (0.8%) 10/117 (8.5%) RR 0.14 (0.03 to 0.76) 74 fewer per 1000
2
Randomized Serious**
No serious
(from 21 fewer to
trials
inconsistency
83 fewer)
Quality of life of a patient (follow-up 12 months; as measured by a good acceptance no/some difficulties in getting the meal finished and/or minimal amount generally left out)
None
31/35 (88.6%) 37/37 (100%) RR 0.89 (0.75 to 1.02) 110 fewer per 1000
1
Randomized Serious*
No serious
No serious
Serious
(from 250 fewer
trials
inconsistency
indirectness
to 20 more)
No. of
Studies
Quality Assessment
Summary of Findings
Critical
(Continued)
Important
Critical
Q
Very low
QQ
Low
Critical
Q
Very low
Important
Critical
QQQ
Moderate
Q
Very low
Critical
QQQ
Moderate
Important
Critical
QQ
Low
QQ
Low
Critical
Importance
QQQ
Moderate
Quality
1. Agostoni C, Fiocchi A, Riva E, Terracciano L, Sarratud T, et al. Growth of infants with IgE-mediated cows milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol.
2007;18:599 606.
2. Klemola T, Vanto T, Juntunen-Backman K, Kalimo K, Korpela R, Varjonen E. Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cows milk allergy: a prospective, randomized
study with a follow-up to the age of 2 years. J Pediatr. 2002;140:219 224.
Date: 2009-12-01
Question: Should Extensively Hydrolyzed Milk Formula Versus Soy Formula be Used in Children With Cows Milk allergy?
References:
APPENDIX 3-3.
157
158
Design
Limitations
Extensively
Other
Hydrolyzed
Imprecision Considerations Milk Formula
Soy
Formula
No. of Patients
Effect
Summary of Findings
Absolute
Quality
Important
Important
Importance
*Allocation concealment was not reported and studies were not blinded. One study reported the results of per protocol analysis only.
Only 15 events.
There is uncertainty to what extent a length for age z-score reflects a change in growth that would have an important consequence for a patient.
Only 62 children.
There is uncertainty to what extent a weight for age z-score reflects a change in growth that would have an important consequence for a patient.
**Allocation concealment was not reported and studies were not blinded. In one study outcome was measured only in patients who developed symptoms.
One additional study (Salpietro 2005) included children with cows milk allergy (23%) or intolerance and reported a relative risk of secondary sensitization to extensively hydrolyzed casein formula compared to soy formula
of 1.33 (95% CI: 0.37 4.82).
Only 11 events.
Only 4 events.
Indirectness
Inconsistency
No. of
Studies
Quality Assessment
Fiocchi et al
WAO Journal April 2010
Design
Limitations
Inconsistency
Indirectness
Other
Imprecision Considerations
Soy Formula
QQ
Low
Critical
Critical
Q
Very low
QQQ
Moderate
Important
Important
Important
Important
Critical
Critical
Q
Very low
QQ
Low
Critical
Critical
Critical
Critical
Importance
QQ
Low
**
*Studies did not report allocation concealment, one was not blinded, and one reported the results of per protocol analysis only.
No. events.
Only 87 children.
There is uncertainty to what extent a length for age z-score or a weight for age z-score reflect a change in growth that would have an important consequence for a patient.
Only 16 patients.
**There was no difference between the groups: total protein concentration was 65 (2) g/l in each group.
Study did not report allocation concealment, was not blinded, and measured IgE only in children who developed symptoms.
RR 6.82 (0.36 to
127.44)
0/36 (0%)
6 and 12 months)
0/43 (0%)
Not estimable
43
Not estimable
0/43 (0%)
RR 10.71 (0.61
to 186.92)
0/43 (0%)
43
Not estimable
0/43 (0%)
QQ
Low
Quality
Absolute
Not estimable
Relative (95%
CI)
Effect
Summary of Findings
0/43 (0%)
Extensively
Hydrolyzed
Rice Formula
No. of Patients
Severe symptoms of CMA (severe laryngeal edema, severe asthma, anaphylaxis) (follow-up 6 and 12 months)
2
Randomized Serious*
No serious
No serious
Serious,
None
0/44 (0%)
trials
inconsistency
indirectness
Moderate symptoms of CMA (mild laryngeal edema or mild asthma) (follow-up 6 and 12 months)
2
Randomized Serious*
No serious
No serious
Serious,
None
0/44 (0%)
trials
inconsistency
indirectness
Allergic reaction to formula (follow-up 6 and 12 months)
2
Randomized Serious*
No serious
No serious
Very serious
None
5/44 (11.4%)
trials
inconsistency
indirectness
Enteropathy or enteroproctocolitis (follow-up 6 and 12 months)
2
Randomized Serious*
No serious
No serious
Serious,
None
0/44 (0%)
trials
inconsistency
indirectness
Failure to thrive (measured as: length for age z-score) (follow-up 6 and 12 months; better indicated by higher values)
2
Randomized Serious*
No serious
Serious
Serious
None
44
trials
inconsistency
Failure to thrive (measured as: weight for age z-score) (follow-up 6 to 12 months; better indicated by higher values)
Serious
None
44
2
Randomized Serious
No serious
Serious
trials
inconsistency
Protein or nutrient deficiency (measured as: total protein concentration) (follow-up 6 months; better indicated by higher values)
1
Randomized No serious
No serious
No serious
Serious
None
8
trials
limitations
inconsistency
indirectness
Mild symptoms of CMA (any of the following: erythema, urticaria, angioedema, pruritus, diarrhea, rhinitis, conjunctivitis) (follow-up
2
Randomized Serious*
No serious
No serious
Serious,
None
0/44 (0%)
trials
inconsistency
indirectness
Development of secondary sensitization (follow-up 12 months; specific IgE)
No serious
Serious
Very serious
None
3/37 (8.1%)
1
Randomized Serious
inconsistency
trials
Quality of life of a patient, not measured
0
No. of
Studies
Quality Assessment
Date: 2010-02-06
Question: Should Soy Formula Versus Extensively Hydrolyzed Rice Formula be Used in Children With Cows Milk Allergy?
References:
1. Agostoni C, Fiocchi A, Riva E, Terracciano L, Sarratud T, et al. Growth of infants with IgE-mediated cows milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol. 2007;18:599 606.
2. DAuria E, Sala M, Lodi F, Radaelli G, Riva E, Giovannini M. Nutritional value of a rice-hydrolysate formula in infants with cows milk protein allergy: a randomized pilot study. J Intl Med Res. 2003;31:215222.
APPENDIX 3-4.
159
160
Serious
None
Serious***
Serious
None
None
Very serious
None
No serious
indirectness
Reporting
bias
Indirectness
Partial tolerance (able to ingest 5 to 150 mL of cows milk) (follow-up 6 and 12 months)
No serious
No serious
2
Randomized No serious
Serious**
trials
limitations*
inconsistency
indirectness
Inconsistency
Reporting
bias
Limitations
198/13
67/30
51/30
40/42
1/13 (7.7%)
22/42 (52.4%)
17/42 (40.5%)
Control
28/7
1/30
1/30
0/37
1/7 (14.3%)
0/42 (0%)
0/37 (0%)
No. of Patients
Other
Imprecision Considerations Oral Immunotherapy
Full tolerance (able to ingest 150 mL of cows milk) (follow-up 6 and 12 months)
No serious
No serious
2
Randomized No serious
Serious
trials
limitations*
inconsistency
indirectness
Design
Quality Assessment
No. of
Studies
Effect
Absolute
Rate ratio
15.90 (1.14
to 221.7)
RR 0.54 (0.06
to 4.82)
66 fewer per
1000 (from
134 fewer to
546 more)
Relative (95%
CI)
Summary of Findings
Importance
Critical
Important
Critical
Critical
(Continued)
QQQO
Important
Moderate
QQQO
Important
Moderate
QQOO
Low
QQQO
Critical
Moderate
QOOO
Very
low
QQQO
Critical
Moderate
QQQO
Critical
Moderate
Quality
Author(s): JB&EC
Date: 2009-11-26
Question: Should Oral Immunotherapy be Used in Children With Cows Milk Allergy?
Settings: tertiary care university hospitals
References:
1. Longo G, Barbi E, Berti I, Meneghetti R, Pittalis A, Ronfani L, Ventura A. Specific oral tolerance induction in children with very severe cows milk-induced reactions. J Allergy Clin Immunol. 2008;121:343347.
2. Skripak JM, Nash SD, Rowley H, Brereton NH, Oh S, Hamilton RG, et al. A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cows milk allergy. J Allergy Clin Immunol.
2008;122:1154 1160.
APPENDIX 4.
Fiocchi et al
WAO Journal April 2010
Design
Limitations
Inconsistency
Indirectness
None
None
Serious
None
Serious
Serious
None
Serious
1369/43
31/30
537/43
52/43
Other
Imprecision Considerations Oral Immunotherapy
No. of Patients
110/37
2/30
17/37
1/37
Control
Not pooled
Absolute
Not pooled
Effect
Relative (95%
CI)
Summary of Findings
Importance
QQOO
Low
QQOO
Low
Important
Important
QQQO
Important
Moderate
QQQO
Important
Moderate
Quality
*One of the studies was not blinded. There is some uncertainty to what extent this might have influenced the results, especially reporting of adverse effects. However, we did not downgrade for risk of bias because we already
downgraded the quality of evidence for imprecision and likelihood of publication bias.
There is some uncertainty if the single challenge with milk reflects long term tolerance.
There were only 17 events and the confidence interval was very wide.
Only 2 small studies showing very large effect on beneficial outcomes and very little information about adverse effects.
Only one study reported exacerbations of eczema. No study reported any other measure of the severity of eczema.
Study was not blinded. There is some uncertainty to what extent this might have influenced the results, especially reporting of adverse effects.
Only 60 patients.
***No explanation was provided
Only 20 patients.
Only 80 patients.
In one unblinded study that used whole milk local reactions were 83 times more frequent (95% CI: 37.2185.6) in immunotherapy group compared to control group. In the other, blinded study that used preparation of
dry nonfat powdered milk the rate of local reactions in children given immunotherapy was 4.5 times higher (95% CI: 3.955.19).
No. of
Studies
Quality Assessment
APPENDIX 4. Continued
161