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To the editor,
I have read with interest the paper entitled “Guidelines for the
diagnosis and management of cow’s milk protein allergy in infants”, by
Vandenplas et al., recently published in your journal 1
I think that the paper deals with very important topics, but there
are two points that I want to address:
First, the paper does not define precisely cow’s milk protein allergy
First, the paper does not define precisely cow’s milk protein allergy
(CMPA), assuming indirectly that all cow’s milk related complains of
immunologic or unknown cause are, or can be, “allergic”. The paper states
properly that “CMPA results from an immunological reaction to one or more
milk proteins.2 This immunological basis distinguishes CMP allergy from
other adverse reactions to CMP such as lactose intolerance.5 CMPA may be
immunoglobulin E (IgE) or non-IgE associated.6 In IgE-associated cases,
CMPA may be a manifestation of the atopic diathesis”. But later on the
immunological basis of CMPA seems to be neglected. For example, it
discusses largely a paper 2 in which all double-blind placebo-controlled
food challenges (DBPCFC) positive subjects are considered as allergic. In
fact, DBPCFC is interpreted in the paper as the only diagnostic tool to
diagnose CMPA. It can be assumed that for authors, CMPA means any kind of
reaction related to milk proteins that can be confirmed by PCDBFC.
In that sense, the guidelines can be in some way misleading, because
they don’t seem to be intended for the diagnosis and management of CMPA as
stated by the authors, but to the diagnosis and management of the whole
constellation of cow’s milk protein related complaints of certain (as
immediate IgE cow’s milk allergy) or uncertain ethiology (as failure to
thrive). I think that this is indeed a very important topic, but it is
definitely a different one.
As several diseases or syndromes are included in the same bag, it is
not surprising that no diagnostic method is presented as fully reliable,
because it is difficult to find a test to fit several diseases. So, only
elimination diets and cow’s milk challenge are considered as gold
standards. Unfortunately, a positive challenge (excluding false
positivities), only establishes a link between the food (milk in this
case) and the symptoms, but provides no information about the pathogenesis
3. Not all reproducible conditions are allergic (as lactose intolerance,
stated by the authors) and not all allergic conditions are easily
reproducible (as exercise-induced anaphylaxis in older children and
adults). Furthermore, elimination diets can be misleading if several other
factors besides the milk (but related to symptoms, as concomitant GORD or
coeliac disease) are present, with no or only partial improvement after
milk-free diet implementation.
I think the guidelines are directed to the diagnosis and management
of cow’s milk protein syndromes, one or some of which are clearly
allergic, others probably are and others probably are not, and the paper
and maybe the title should reflect this fact.
Secondly, in my opinion, authors could have divided the patients
depending on the time span elapsed until the reaction occurs, data easily
accessible to primary care physicians and general paediatricians and with
diagnostic and prognostic relevance:
Immediate symptoms occurring after milk intake are highly suggestive
of immediate allergy (IgE-mediated) to milk proteins. In these cases the
possibility of an anaphylactic reaction exists, and even fairly mild or
moderate symptoms can precede severe anaphylactic reactions. Subjects with
immediate reactions should be put on an elimination diet and should be
referred for specialized evaluation. If only mild symptoms (as perioral
erithema) have developed, at least a skin test or a specific IgE
determination to milk should be performed. Also, in these cases, a
positive allergologic study (skin tests, serum determination of specific
IgE…) is very reliable 4. If negative, early reintroduction of milk is
suggested. If positive, further allergologic study should be performed.
In the case of delayed symptoms, the algorithms proposed by the
authors will probably work much better. But even in this case, three
possibilities exist and all are related to the presence or not of atopic
In the case of delayed symptoms associated with atopic diathesis,
such as atopic eczema, the elimination diet should be implemented and
after a period of time the patient should be reassessed, as indicated by
the authors. If no differences in symptoms are observed, a challenge test
prior to milk reintroduction should be performed with care, due to the
possibility of developing an immediate reaction 5.
In the case of delayed or chronic symptoms non-related with atopic
diathesis, such as failure to thrive, elimination diet should be
implemented for the shortest span needed to observe differences in
symptoms. If no differences in symptoms are observed, milk should be
In the particular case of non-immediate symptoms in which a specific
IgE response to milk has been detected, but without any immediate symptom
(i.e sensitization to CMP), the diet should be implemented only to
evaluate the evolution of the delayed symptoms but not of the IgE, as
asymptomatic sensitization to allergens has been described 6, 7. In the
case of not observing differences, challenge tests prior to milk
reintroduction should be performed again with care due to the possibility
of developing immediate reactions 5, 7.
In summary, in the algorithms presented, the importance of the time
interval between the milk intake and the suspected reaction to milk is not
sufficiently stressed. This information is easily accessible in the
primary care setting and has important diagnostic relevance. Most infants
with immediate symptoms may have IgE mediated allergy to cow’s milk
proteins and should be referred for allergologic study, as milk challenges
in the primary setting can be risky. On the other hand patients with
delayed symptoms can be managed rather well in the way proposed by authors
but subjects with atopic diathesis should be assessed with care. The
proposed algorithms could be more useful if two additional branches are
included, probably as the first step (before the intensity of symptoms):
immediate symptoms (less than two hours after milk intake, for example)
and non-immediate / delayed symptoms (more than two hours after milk
Finally, in my opinion, a clarification of the meaning of DBPCFC and
a consensus on the nomenclature of cow’s milk related syndromes are
needed. The classification proposed by Sampson of food allergy 8 can be a
step on that direction.
Carlos H Larramendi MD
Allergy Unit. Hospital Marina Baixa
03570 La Vila Joiosa, Alacant. SPAIN
1. Vandenplas Y, Brueton M, Dupont C, Hill D, Isolauri E, Koletzko S
et al. Guidelines for the diagnosis and management of cow's milk protein
allergy in infants. Arch Dis Child 2007;92:902-8.
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 cow's milk allergy: a prospective, randomized
study with a follow-up to the age of 2 years. J Pediatr 2002;140:219-24.
3. Bindslev-Jensen C, Skov PS, Madsen F, Poulsen LK. Food allergy
and food intolerance--what is the difference? Ann Allergy 1994;72:317-20.
4. García-Ara C, Boyano-Martinez T, Díaz-Pena JM, Martín-Muñoz F,
Reche-Frutos M, Martín-Esteban M. Specific IgE levels in the diagnosis of
immediate hypersensitivity to cows' milk protein in the infant. J Allergy
Clin Immunol 2001;107:185-90.
5. Flinterman AE, Knulst AC, Meijer Y, Bruijnzeel-Koomen CAFM,
Pasmans SGMA. Acute allergic reactions in children with AEDS after
prolonged cow's milk elimination diets. Allergy 2006;61:370-4.
6. Bousquet J, Antó JM, Bachert C, Bousquet PJ, Colombo P, Crameri R
et al. Factors responsible for differences between asymptomatic subjects
and patients presenting an IgE sensitization to allergens. A GA2LEN
project. Allergy 2006;61:671-80.
7. Larramendi CH, Martín Esteban M, Pascual Marcos C, Fiandor A,
Díaz Pena JM. Possible consequences of elimination diets in asymptomatic
immediate hypersensitivity to fish. Allergy 1992;47:490-4.
8. Sampson HA. Update on food allergy. J Allergy Clin Immunol
2004;113:805-19; quiz 820.
With interest we have read the review by VandenPlas and coworkers (1)
in which guidelines for the diagnosis and management of cow’s milk protein
allergy (CMPA) in infants are discussed and general recommendations with
respect to these issues are given. The authors present two diagnostic
algorithms, on which we would like to comment.
The authors developed separate diagnostic algorithms for ex...
The authors developed separate diagnostic algorithms for exclusively
breast-fed and formula-fed infants with a suspicion of CMPA. In both
algorithms a clinical assessment divides the flow chart into two branches:
suspicion of mild to moderate CMPA or suspicion of severe CMPA. Symptoms
that put the child at an immediate life-threatening risk or may interfere
with the child’s normal development, differentiate severe from mild to
moderate CMPA. Children with a suspicion of severe CMPA are referred to a
paediatric specialist and a food challenge will be performed in a hospital
Our first comment on the presented diagnostic algorithms concerns the
manner at which the diagnosis CMPA is confirmed. Nowadays the food
challenge, preferable a double blind placebo controlled challenge
(DBPCFC), is the gold standard for the diagnosis of food allergy. The food
challenge is part of a diagnostic procedure that includes three phases:
elimination of the suspected food, challenge with the suspected food, and
re-elimination. For simplicity and socio-economic reasons an open food
challenge instead of a DBPCFC is recommended by the authors. It is well
known that the diagnosis of food allergy based on an open food challenge
will result in large numbers of false positive diagnoses. To limit this
number of false positive diagnoses, the diagnostic procedure should
include the three phases mentioned above. Unfortunately, in both
diagnostic algorithms the re-elimination phase is not mentioned.
Second, in the algorithm for formula-fed infants angio-edema and
urticaria are described as mild to moderate symptoms. This implies that
children with these symptoms are not referred to a paediatric specialist
and a food challenge will be performed in a non-hospital setting, with
which we strongly disagree. Urticaria and angio-edema are both
manifestations of a systemic reaction and are the most common
manifestations of anaphylaxis (2;3). No clear data are available that
describe the risk of a severe life threatening allergic reaction in
children suspected of CMPA with initial symptoms such as urticaria and
angio-edema. For other food allergies such as nut allergy, it is known
that severity of subsequent reactions can not be predicted by history
alone (4). Furthermore, in children with initial mild symptoms such as
atopic eczema dermatitis syndrome, acute allergic reactions to cow’s milk
after a prolonged cow’s milk protein diet are described (5). In our
opinion children with initial symptoms of angio-edema and generalized
urticaria are at risk of a similar or even severe allergic reactions when
they are challenged with the suspected food. Therefore, a challenge test
should be performed in a hospital setting supervised by a medical staff
experienced in recognizing and managing severe allergic reactions.
Third, the instructions how to perform a food challenge in formula-
fed infants are incomplete. The authors propose a challenge protocol with
a stepwise increased dose scheme expressed in milliliters formula. No
instructions are given about the amount of cow’s milk protein needed in
each dose step. The amount of cow’s milk protein is different in each
infant formula. Therefore the guideline should provide information about
the amount of cow’s milk protein in milligrams needed in each challenge
Furthermore, no instructions are given by the authors how to perform a
food challenge in breast-fed infants. According to the national guideline
of the baby health clinics in the Netherlands (6), we propose that a food
challenge in breast-fed infants is performed by instructing the mother to
drink a stepwise increasing amount of milk on three consecutive days (up
to 500ml daily). If symptoms of CMPA re-appear, the challenge is followed
up by a re-elimination phase of one week. If no reaction occurs, the
mother is instructed to drink 500ml milk each day for the next two weeks
and the parents are told to observe the child for late reactions.
In summary, children suspected of CMPA need to complete a diagnostic
procedure including a re-eliminiation phase to confirm the diagnosis CMPA.
Furthermore, children suspected of CMPA with initial symptoms such as
urticaria and angio-edema should be referred to a paediatric specialist
and a food challenge needs to be performed in a hospital setting.
Finally, instructions on how to perform a food challenge should include
the amount of cow’s milk protein needed in each challenge step.
(1) Vandenplas Y, Brueton M, Dupont C et al. Guidelines for the
diagnosis and management of cow's milk protein allergy in infants. Arch
Dis Child 2007; 92(10):902-908.
(2) Lieberman P, Kemp SF, Oppenheimer J et al. The diagnosis and
management of anaphylaxis: An updated practice parameter. Journal of
Allergy and Clinical Immunology 2005; 115(3, Supplement 2):S483-S523.
(3) Bindslev-Jensen C, Ballmer-Weber BK, Bengtsson U et al.
Standardization of food challenges in patients with immediate reactions to
foods--position paper from the European Academy of Allergology and
Clinical Immunology. Allergy 2004; 59(7):690-697.
(4) Wang J, Sampson HA. Food anaphylaxis. Clin Exp Allergy 2007;
(5) Flinterman AE, Knulst AC, Meijer Y, Bruijnzeel-Koomen CA,
Pasmans SG. Acute allergic reactions in children with AEDS after prolonged
cow's milk elimination diets. Allergy 2006; 61(3):370-374.
(6) Kneepkens CM, van Drongelen KI, Aarsen C. Landelijke standaard
voedselallergie bij zuigelingen. 5e druk. Den Haag; voedingscentrum, 2005.