Pediatric Allergy and Immunology

REVIEW ARTICLE

How to reintroduce cow′s milk?

Christophe Dupont
^pital Necker-Enfants Malades, Universite
Ho  Paris-Descartes, Paris, France

To cite this article: Dupont C. How to reintroduce cow′s milk?. Pediatr Allergy Immunol 2013: 24: 627–632.

Keywords Abstract
allergy; cows’ milk proteins; children; diet
In a child that is allergic to milk, the natural next step, following the elimination diet,
Correspondence is the reintroduction of cow’s milk. Several questions may arise. When feasible, this
Prof. Christophe Dupont, Service reintroduction has many benefits for the child and his family. However, the disease
d’Explorations Fonctionnelles Digestives needs to be well defined by physicians and explained to parents. They need to
diatriques, Ho
Pe ^pital Necker-Enfants understand that there are different types of allergy to cow’s milk, specifically IgE- and
Malades, 149, rue de Se vres, 75015 Paris, non-IgE-mediated, and each of these may exhibit both a variable duration and
France. frequently an incomplete recovery. Deciding where to first reintroduce cow’s milk to a
l.: +33 1 7119 6083
Te child who has previously followed a milk-free diet, whether it be at home or in a
Fax: +33 1 4438 1660 hospital, also frequently presents an issue. Following this first reintroduction, the
E-mail: christophe.dupont@nck.aphp.fr progressive increase of milk into the diet needs to be managed properly, as not all
children will go back to a normal dairy products intake. Recent studies show that most
Accepted for publication 18 August 2013 children with milk allergy tolerate products containing baked milk and that their
consumption might speed up recovery. Hence, the purpose of the milk challenge in a
DOI:10.1111/pai.12131 child on a milk-free diet is becoming, even in a child still reactive to milk, the first step
of gradual and individually adapted reintroduction of milk or dairy products. When
reintroduction of cow’s milk does not work, immunotherapy becomes an option,
and this is carried out in specialized centers.

Several reviews have handled the specific problem of treating

Reintroducing cow’s milk: what benefit for the child and
cow’s milk allergy in children in the past years (1–7), focusing
his family?
on clinical presentation, diagnosis, milk replacement formulas,
and elimination diets. Cows’ milk proteins (CMP) need to be The elimination diet prevents the deleterious effects of allergic
removed from the child’s diet during CMP allergy (CMPA), inflammation but may impair the adequate intake of essential
but most of the time, even though at least partially related to nutrients: Undernutrition may be the consequence of an
the onset of long-lasting allergic diseases, like asthma (8), uncontrolled elimination diet (11–14). This is all the more
CMPA disappears spontaneously, and milk and dairy prod- important in the case of multiple food allergies when exclusion
ucts are reintroduced. ‘How to reintroduce milk’ in the diet of of foods such as wheat or egg renders the child’s menu very
a milk allergic child is really a practical issue, open to review, difficult to settle and nutritional and growth deficiencies more
as it is not specifically addressed in the only GRADEd likely to occur (14–16). Returning to a normal diet containing
guidelines (5). Classically, the milk challenge is done in the milk and dairy products is desirable for the child’s health, to
hospital to test whether the child is still allergic to cow’s milk improve the quality of life of both children and parents in these
or not. New options now prevail, based on a better knowledge situations (17–19), to favor an appropriate social integration of
of the disease and of its spontaneous evolution (9). Tolerance the child (17) and to avoid unnecessary medical follow-up.
to milk develops with time and the process may be helped by a Briefly, elimination diets may impair proper nutrient intake
progressive reintroduction of milk into the diet of a child who and socialization.
still does not tolerate it well, especially using products
containing small amounts of milk (9) or products containing
What do we already know about the child’s disease?
baked milk (10). Milk challenges are thus transforming into
an analysis of the clinical reactivity to milk meant to be the What clinical pattern of food allergy is this child suffering
first step of a progressive reintroduction of milk or dairy from? All clinical conditions encountered in food allergy have
products. been described, especially for milk (4). There are IgE-mediated

Pediatric Allergy and Immunology 24 (2013) 627–632 ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 627
How to reintroduce cow′s milk? Dupont

and non-IgE-mediated CMP-induced reactions, including persistent cases of CMPA are characterized by the intensity of
conditions which occur very frequently and which are more the familial atopic disease, a longer period between the
difficult to classify, such as gastro-esophageal reflux, diarrhea, consumption of the CMP and the onset of symptoms, a high
and constipation, that du Toit et al. labeled ‘allergic dysmo- frequency of multiple food allergy and allergic diseases, allergy
tility’ and that are shared by many IgE and non-IgE to casein more than to soluble proteins (33–35), cosensitization
CMP-induced disorders. to inhalant allergens, to ‘less prevalent’ food allergens, and to
IgE-mediated reactions may be dangerous and need recog- beef and reactivity to lower doses of milk (36). In the last
nition before any reintroduction of CMP because of the risk of cohort of infants with IgE-mediated CMPA, one half had
anaphylaxis (1). Milk-specific (s)IgE levels providing 95% resolved over 66 months of follow-up, with baseline milk sIgE
certainty of reactivity to milk have been published (4), above level, SPT wheal size, and atopic dermatitis severity being all
5 kU/l for infants below 2 yr of age and 15 kU/l in all children. important predictors of the likelihood of resolution (37).
For wheal size during skin prick tests (SPT), predictive figures CMPA with early gastrointestinal symptoms has a better
were, respectively, above 6 mm and above 8 mm. Several prognosis (34, 38).
authors also recently described IgE and or SPT threshold The mode of feeding during the elimination diet might affect
values serving as a prognostic marker for IgE-mediated CMPA the natural evolution and prognosis. Because high temperature
resolution (20–22). For Vassilopoulou et al. (20) analyzing 24/ largely destroys conformational epitopes to which IgE anti-
116 positive CMP challenges, a negative outcome is predicted, bodies are primarily directed, the team at Mount Sinai
in order of performance, by sIgE <3.94 kU/l, the combination hypothesized that some children with CMPA would tolerate
of SPT and sIgE or an SPT wheal <4 mm, whereas SPT wheal extensively heated (baked) milk products and showed that the
>7.5 mm or sIgE >25.4 kU/l, or their combination predicts a majority (75%) of these children did indeed tolerate such
positive outcome. Yavuz et al. (21) analyzing 42/94 positive products (39). Interestingly, the addition of baked milk into
CMP challenges, a negative outcome is predicted by sIgE the diet of children tolerating such foods was shown to
<2.8 kU/l for <1 yr, <11.1 for <2 yr, <11.7 for <4 yr, and <13.7 accelerate the development of unheated milk tolerance
for <6 yr. IgG4 and their protective effect have been investi- compared with strict avoidance (10). Also, a study showed
gated more recently (23). that LGG supplementation of an eHF hastened resolution of
It is likely that in the future, different phenotypes of children CMPA (40).
with CMPA will be distinguished by biologic traits, such as Even if it is common for a CMPA to resolve over time, this
described for casein and milk sIgE levels, milk-specific basophil resolution is not always complete and some children considered
reactivity, and milk SPT wheal diameters (24). to be free of CMPA may retain a ‘residual disease’, thus being
For non-IgE-mediated CMPA, biologic tests remain less unable to tolerate a ‘normal’ intake of milk and dairy products
specific (25, 26). The atopy patch test was shown to be later in life (41). ‘Incomplete recovery’ encompasses cases
potentially helpful in predicting the evolution (27), but this where the disappearance of symptoms is accompanied by
remains controversial (28–30). CMP-induced reactions are persistent sensitization, which may explain some intriguing
typically delayed and less dangerous, except for the food issues such as recurrence of symptoms during intercurrent
protein-induced enterocolitis syndrome (FPIES), an acute, illnesses or during pregnancy and lactation (6). It is the
assumed to be a cell-mediated, GI food hypersensitivity author’s experience that these situations may be seen in parents
characterized by severe vomiting and fluid maldistribution of children being treated for CMPA, albeit with no studied
resulting in profuse diarrhea, pallor, and hypotonia. Symptoms frequency at the moment.
usually appear between 1 and 4 h after ingestion and may The required duration of the strict elimination diet and,
progress to a state of dehydration with hypovolemic shock hence, the schedule of the reintroduction of CMP into the diet
requiring parenteral rehydration (31, 32). This situation is cannot be clearly established for a given individual. In
currently largely under-recognized especially in emergency practice, however, early CMPA, non-IgE-mediated, with
departments, where acute reactions to milk are still believed predominantly digestive manifestations, may only last for a
to be associated with high CMP sIgE levels. short period of time, and may warrant considering reintro-
Briefly, (i) milk-specific IgE and wheal size provide some ducing milk from the age of 9 months. In contrast, in cases of
indication as to the potential reactivity in case of IgE-mediated CMPA with later onset, IgE-mediated, with skin manifesta-
reactions; (ii) during IgE-mediated CMPA, anaphylaxis will tions among others, CMPA might be persistent and should
occur during the provocation procedure itself whereas for not require further allergic evaluation before the age of 1 yr.
FPIES, dehydration leading to shock may occur later, when These infants still require surveillance in terms of evaluating
the child is going back home. dietary sufficiency, and their family need assistance with
weaning. Also, severe cases of CMPA, either non-IgE-medi-
ated or with high milk sIgE, can persist in children who will
What can be expected in a condition with a variable
never be able to outgrow it.
duration and frequently incomplete recovery?
Briefly, (i) in infants, non-IgE-mediated milk allergy will last
When treated with an elimination diet, CMPA usually tends less than the IgE-mediated form; (ii) in both conditions, some
toward spontaneous remission, more or less in parallel with the cases seem difficult to outgrow; (iii) recovery may be partial so
evolution of biologic tests, albeit sometimes slowly and that children may tolerate a limited amount of milk and dairy
incompletely as previously reviewed (6). Studies show that products.

628 Pediatric Allergy and Immunology 24 (2013) 627–632 ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Dupont How to reintroduce cow′s milk?

among those who tolerate it (24). Also, combined with clinical

Customizing of the milk challenge: small amounts,
history and the expertise of the physician, the use of cutoff
cooked, fermented milk?
decision points for sIgE levels to casein could identify the
When the physician considers discontinuing the elimination optimal candidates for baked milk oral challenges and improve
diet, he usually begins with an oral milk challenge or the management of children with suspected CMA (44).
provocation test, typically performed in the hospital day care Following this introduction of baked milk, it might prove
unit, and followed by the gradual reintroduction of milk and interesting to try using less baked milk products and to try
dairy products at home (9). more raw ones, as several factors in bovine milk have been
A complete milk challenge usually goes up to approximately described that might explain how raw cow’s milk consumption
200 ml, that is one bottle, and when this amount is tolerated, a can decrease the risk of allergies early in life (45).
tolerance can be said to have been achieved, at least in most Briefly, (i) consider reintroducing small amounts, even in the
cases. hospital ward, to test the potential reintroduction of limited
A negative milk challenge in patients previously diagnosed amounts at home; (ii) consider a provocation test with baked
with CMPA is logically followed by a normal diet, stopping an forms of milk; (iii) milk allergic children might now be
elimination that has become unnecessary (17–19). However, classified as baked milk-tolerant vs. baked milk-intolerant.
tolerance is not always achieved despite a normal milk
challenge (19), indicating a late reaction and some families
Where to challenge children with milk, at hospital or at
continue milk avoidance (17).
home?
If the child is not able to tolerate a large amount of milk, the
physician may be willing to reintroduce small amounts, in an Several working parties have set up rules for oral food challenges
attempt not only to facilitate the family cooking, but also in an (46–48), which are very useful from a practical and legal point of
attempt to ‘force’ tolerance, in what may actually be labeled an view, indicating, among other recommendations, that the milk
‘oral immunotherapy’, previously referred to as an ‘induction challenge must be carried out in an area equipped for severe
of tolerance’. Milk challenges with low doses have been reactions, close to an intensive care unit, by a medical personnel
suggested and seem efficacious (42). This is all the more and paramedics in the habit of performing these tests and present
important as food allergy is no longer a matter of ‘yes’ or ‘no’ on site to detect adverse reactions, with informed consent from
but a matter of ‘how much is tolerated’. A child reacting with patients and their families. These recommendations also include
30 ml of milk is still considered allergic to milk but nowadays the schedule of the test and the doses of the food to be used.
also as being able to tolerate lower amounts of milk: He can be Duration of monitoring depends on the clinical circumstances:
fed daily with minute amounts of CMP, progressively increas- Children with IgE-mediated CMA usually react within 1–2 h
ing thereafter. Some authors now suggest a progressive (48), whereas in children with FPIES, a delayed reaction takes
reintroduction of milk into the diet based on this first place, usually appearing within 4 h (49).
evaluation of the tolerated level (9). From a practical point of view, however, this admission to
Actually, the recent evidence that the majority of children the hospital, even for only one day, is a limiting factor, at least
with CMPA tolerate baked milk (39) changes the purpose of in Europe where healthcare systems are reluctant to spend
milk challenges and the way they are conducted: The physician money. Alternative pathways need to be sought, taking into
now wants to know whether the child tolerates baked milk and account the ethical and legal issue of food challenges in allergic
in what quantities, so that he may introduce products children outside the hospital. If a child had inadvertent milk
containing baked milk into the diet of the child, both challenge (e.g., a glass of milk at a friend’s house) and it is clear
alleviating the family burden of the elimination diet and, from the history that no reaction occurred, admitting him to
hopefully, speeding up the recovery process. Recently, a fully hospital for a similar challenge is not worthwhile. Most
maturated cheese (Parmigiano-Reggiano) was tolerated by children with non-IgE-mediated CMPA do not need day care
58% of CMPA children, in correlation with the absence of IgE admission, as they are not at risk of anaphylactic shock, except
toward beta-lactoglobulin (43), opening new prospects for the those recognized as having FPIES, which puts them at risk of
role of transformed milk in the reintroduction process. dehydration following the end of the milk challenge.
Milk oral challenges are thus changing, evolving from a Briefly, (i) milk challenges are mostly done in the hospital in
reintroduction of a bottle of milk in the hospital to more case of IgE-mediated CMPA and at home in case of non-IgE-
personalized procedures where according to age, clinical mediated milk allergy; (ii) FPIES, a non-IgE-mediated disease,
presentation and past tests on the child, milk may be offered nonetheless merits a hospital challenge, with a follow-up
in higher or lower amounts, in more or less baked and/or several hours thereafter.
fermented products or not, sometimes first baked and then
raw, consecutively during the same day. However, it is not
At home, managing the progressive increase of milk into
possible at the moment to really predict who is able and who is
the diet
unable to pass a complete milk challenge and which form seems
the most adapted. Biologic tests may help. It was shown that Following the initial oral milk challenge, the progressive
casein and milk sIgE level, milk-specific basophil reactivity, reintroduction of CMP continues at home. The clinical
and milk SPT wheal diameter are all significantly greater response of a durable exposure to CMP in a child who was
among patients with CMPA who react to baked milk than on elimination diet is also difficult to predict. Reactions may

Pediatric Allergy and Immunology 24 (2013) 627–632 ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 629
How to reintroduce cow′s milk? Dupont

occur, especially in the case of non-IgE-mediated CMA, days goat, sheep, donkey, horses, and camel makes them nutritionally
or weeks after starting the reintroduction process. A gradual absolutely unsuitable for infants, whether they are allergic or not.
increase of the milk and dairy product intake at home is thus After infancy, if a tolerance to cows’ milk has not been acquired,
desirable. This progressive reintroduction at home allows goat’s and ewe’s milk, fermented or not, and cheeses might
determining the CMP dose that the child is able to tolerate. provide a real benefit, including for Ca intake (6). However,
This dose may correspond to the usual intake of milk and dairy goat’s and ewe’s milk proteins may cross-react with CMP in
foods in a Western diet or be more limited in children who patients with CMPA: Their potential use depends on individual
continue to suffer from the ‘residual disease’ mentioned above susceptibility (55–57), being probably lower than 25% for goat’s
(41). The current state of research does not allow us to say milk (58), but seemingly improving in children treated with oral
what percentage of children who are able to tolerate one bottle immunotherapy (59). Their tolerance has to be demonstrated, at
will actually exhibit a limited long-term tolerance to dairy in-hospital challenges, at least for IgE-mediated CMA.
products. The persistence of clinical symptoms suggestive of Children allergic to milk are allergic to bovine meat in
the recurrence of a CMPA during the gradual increase of CMP 13–20% of cases (60), which means that most of the time, they
intake at home does not ipso facto warrant a return to the strict may be fed beef and veal, if clinically tolerated.
exclusion of CMP. Indeed, several recent studies indicate that Briefly, (i) vegetable juices can occasionally be used if ready-
the continued presence of CMP in the diet at a tolerated dose fortified with Ca, and under a trained dietician surveillance; (ii)
facilitates the acquisition of a long-term tolerance (50, 51). The ewe and goat milks and dairy products can be part of complemen-
increase in food diversity allowed into the diet also makes tary feeding after 1 yr of age, but tolerance has to be tested first.
social life easier. Such a management requires a full education
and the active participation of parents and is not always
Forcing tolerance in case of ‘resistance’
feasible. It is facilitated by the knowledge of the protein
concentrations in the dairy products available (6). Cases where the acquisition of a tolerance is lagging behind are
Briefly, (i) back home, the clinical reaction to milk may be responsible for attempts at ‘forcing’ it using ‘immunotherapy’,
delayed: wait at least another day before giving milk back that is, various amounts of milk given orally, either in increasing
home (never give milk during dinner the day of the challenge); amounts to be swallowed or limited amounts to be placed
(ii) tolerance of milk in a one day oral challenge does not sublingually (61). These techniques are intended to produce either
always mean that daily iterative ingestions will be tolerated. a ‘tolerance’, a final state of non-reactivity to the allergen
independent of its regular use, or only ‘desensitization’ with a
mere increase in the threshold in reactivity to milk. For milk oral
When reintroduction of cow’s milk does not work
immunotherapy, the quality of trials has increased with time, but a
Feeding older children still allergic to milk may be problematic, Cochrane review (62) showed that studies to date have involved
for different reasons. First, milk is so prevalent in children’s small numbers of patients, with the quality of evidence generally
food and in food processing that milk avoidance leads to low. Milk oral immunotherapy can lead to desensitization in the
constraints which could potentially limit the socialization of majority of individuals with IgE-mediated CMPA, but the
children. Second, in the regular children’s diet, there is a development of long-term tolerance has not been established
potential risk of inappropriate calcium intake, in the absence of (63). To that end, different diets are being studied (64). A major
approximately two sufficient amounts of milk or dairy prod- drawback is the frequency of adverse effects, even thoughmost are
ucts every day. Third, in the general view of most parents, mild and self-limited and the use of parenteral epinephrine not
prohibiting the intake of dairy products prevents the child from infrequent (65). There are no standardized protocols, and authors
having a ‘normal’ breakfast, with some liquid to drink. suggest generating guidelines prior to incorporating desensitiza-
The child may be kept on regular feeding with adapted tion into clinical practice (62). Sublingual immunotherapy has
formulas (protein hydrolysates or amino-acids), if the child still also been attempted (66) alone or combined with milk oral
accepts, but this represents a non-negligible cost, often immunotherapy (67), showing that the oral route was more
unbearable in the absence of reimbursement. efficacious for desensitization than the sublingual one alone but
Replacement foods may be needed. After 6 months of age, accompanied by more systemic side effects, with clinical desen-
and also subject to prior verification of clinical tolerance, soy sitization being lost in some cases within 1 wk off therapy.
protein follow-on formulas may be used. Vegetable juices made Briefly, (i) milk immunotherapy is still in a research phase; (ii)
of soy, rice, almond, coconut, or chestnut, often labeled obtaining tolerance might be a long process, requiring years.
‘milks’, mostly sold in organic outlets, do not meet the
nutritional needs of an infant (52–54). In older children, they
Accompanying parents in the reintroduction process
can occasionally be used provided that they are ready-fortified
with Ca, and as long as there is a trained dietician involved. If Reintroducing milk in a child always told about the potential
parents are in need of liquid food, for breakfast for instance, lethal effect of this food may be very troublesome for the child.
vegetable juices can thus be part of complementary feeding, A personal study showed that the prevalence of food neopho-
provided that the diets of such children are correctly balanced. bia, that is, the refusal by children to eat new food, known to
There tends to be some confusion regarding the appropriate- be a normal phenomenon between 2 and 10 yr of age, seems to
ness of milk from mammals other than cow. The composition be more common or pronounced when an elimination diet has
(i.e., the protein, fat, folic acid, and mineral content) of milk from been imposed by a food allergy (68).

630 Pediatric Allergy and Immunology 24 (2013) 627–632 ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Dupont How to reintroduce cow′s milk?

Conclusion baked, in an attempt to speed up the acquisition of a tolerance.

Creating a tolerance to milk in children for whom such an
Allergy to milk is evolving. Elimination diet and clinical obser-
evolution could not be expected before has also become a goal.
vation were the mainstays of treatment. Children are now being
Some caution should still be taken, as this approach is new and
taken care of more actively, using milk and dairy products both in
largely in the research phase.
increasing amounts and with transformed proteins, especially

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632 Pediatric Allergy and Immunology 24 (2013) 627–632 ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd