nutrients

Review
Prevention and Management of Cow’s Milk Allergy
in Non-Exclusively Breastfed Infants
Yvan Vandenplas
Kidz Health Castle, UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium;
[Link]@[Link]; Tel.: +32-2-477-5780; Fax: +32-2-477-5784

Received: 11 April 2017; Accepted: 30 June 2017; Published: 10 July 2017

Abstract: Introduction: The prevention and management of cow milk allergy (CMA) is still
debated. Since CMA is much less frequent in breastfed infants, breastfeeding should be stimulated.
Method: Literature was searched using databases to find original papers and reviews on this topic.
Results: Hydrolysates with a clinical proof of efficacy are recommended in the prevention and
treatment of CMA. However, not all meta-analyses conclude that hydrolysates do prevent CMA or
other atopic manifestations such as atopic dermatitis. There are pros and cons to consider partially
hydrolysed protein as an option for starter infant formula for each non-exclusively breastfed infant.
A challenge test is still recommended as the most specific and sensitive diagnostic test, although a
positive challenge test does not proof that the immune system is involved. The Cow Milk Symptom
Score (CoMiSS™) is an awareness tool that enables healthcare professionals to better recognize
symptoms related to the ingestion of cow milk, but it still needs validation as diagnostic tool.
The current recommended elimination diet is a cow milk based extensive hydrolysate, although rice
hydrolysates or soy infant formula can be considered in some cases. About 10 to 15% of infants
allergic to cow milk will also react to soy. Mainly because of the higher cost, amino acid based
formula is reserved for severe cases. There is no place for infant formula with intact protein from
other animals as cross-over allergenicity is high. During recent years, attention focused also on the
bifidogenic effect of prebiotics and more recently also on human milk oligosaccharides. A bifidogenic
gastrointestinal microbiome may decrease the risk to develop allergic disease. The addition of
probiotics and prebiotics to the elimination diet in treatment may enhance the development of
tolerance development. Conclusion: Breastfeeding is the best way to feed infants. Cow milk
based extensive hydrolysates remain the first option for the treatment of CMA for the majority of
patients, while amino acid formulas are reserved for the most severe cases. Rice hydrolysates and
soy infant formula are second choice options. Partial hydrolysates with clinical proof of efficacy are
recommended in some guidelines in the prevention of CMA and allergic disease in at risk infants,
and may be considered as an option as protein source in starter infant formula.

Keywords: cow milk allergy; hydrolysate; infant formula; functional gastrointestinal disorder;
prevention; treatment

1. Introduction
This manuscript discusses the prevention and management of cow’s milk allergy (CMA) in
non-exclusively breastfed infants. CMA is an adverse health effect arising from a specific immune
response that occurs reproducibly on exposure to a protein present in cow milk. Breastfeeding is the
first choice feeding for infants, and allergic and functional gastrointestinal disorders occur more often
in non-exclusively breastfed than in breastfed infants. The prevalence of allergic diseases involving
the gastrointestinal (GI) tract, respiratory tract and the skin is likely to be rising worldwide [1]. Food
allergy is a growing health concern in the westernized world with approximately 6% of children

Nutrients 2017, 9, 731; doi:10.3390/nu9070731 [Link]/journal/nutrients

Nutrients 2017, 9, 731 2 of 15

suffering from it [2]. CMA is one of the most frequent causes of food allergies in young children with
an estimated prevalence between 1.9% and 4.9% in the first year of life [3,4]. Whether there has also
been an increase in CMA has not been thoroughly studied [5]. According to a report from Denmark,
CMA is up to half of the allergic children immunoglobulin E (IgE) mediated [6]. The risk to develop
allergic disease is multifactorial. Recent evidence suggests that low blood vitamin D level is a risk
factor for food allergy; vitamin D deficiency predisposes to GI infections, which may promote the
development of food allergy. Several data suggest that serum 25-hydroxyvitamin D levels are often
insufficient in children with asthma, atopic dermatitis, and food allergy [7]. There is no evidence
that supplementation of poly-unsaturated fatty acids in infancy has an effect on infant or childhood
allergy, asthma, dermatitis/eczema or food allergy [8]. Many infants present with symptoms related
to milk ingestion. The most frequent symptoms and signs related to CMA are listed in Table 1. Both
IgE and non-IgE mediated CMA exist. Allergic symptoms must be reproducible. The involvement
of the immune system in non-IgE mediated allergy is difficult to demonstrate. Non-IgE mediated
allergy is the cause of symptoms in a subset of patients with “hypersensitivity”. Sometimes the
symptoms caused by ingestion of milk are very likely to be immune mediated, as in the case of atopic
dermatitis improving during a cow milk elimination diet. However, in the case of GI symptoms, such
as regurgitation, constipation or general symptoms such as crying or distress, the involvement of
the immune system cannot (easily) be demonstrated. . It is likely that there is overlap between the
latter and functional GI symptoms. Experts agreed that the likely prevalence for colic, regurgitation,
and functional constipation is 20%, 30% and 15%, respectively [9]. The perception of parents that an
infant may have cow milk related symptoms is much greater than the reported incidence of CMA
since parents report an incidence of up to 17% [10]. The relationship between some of these common
symptoms of infancy and CMA is not clear. The best example may be upper respiratory tract symptoms
which can seldom be related to CMA, but most frequently are caused by viral infections. It is only in
a minority of infants that functional GI symptoms such as regurgitation, constipation and colic are
of allergic origin. Intolerance is the consequence of lactase deficiency, the brush border enzyme that
digests lactose, the predominant sugar in milk, and is almost always secondary to another condition
in young infants. The meaning and definition of a “hypo-allergenic formula” varies in different
parts of the world. While in Europe a “hypo-allergenic formula” means a formula that contains
hydrolyzed protein and thus a reduced allergenicity, the American Academy of Pediatrics defined it
as a formula that is effective in the treatment of at least 90% of the children with CMA, with a 95%
confidence interval. It has to be recognized that an extensive hydrolysate is “tolerated” by the vast
majority of CMA-patients but that such an elimination diet is not really “treatment” as the elimination
diet does not change the immune response. Oral immunotherapy or anti-IgE actually modify the
individual propensity to react to cow’s milk and are therefore therapeutic. However, since most
literature, including guidelines, recommend the use of extensive hydrolysates as first choice in the
management, “treatment” is used in this context.
Tolerance of cow milk will have developed in 85% to 90% of the infants with CMA by the age of
three years. High IgE levels predict a longer persistence of allergic reactions to cow milk. In particular,
GI symptoms show a good prognosis, suggesting again an overlap between functional GI symptoms
and CMA [3,6]. However, most of the information on the natural evolution of CMA comes from
tertiary care or specialized centers and only the most severe cases are seen in these centers. This means
that data on the natural evolution of CMA at the primary healthcare level are missing.
Nutrients 2017, 9, 731 3 of 15

Table 1. Symptoms and signs related to CMA.

General
• Anaphylaxis
• Food protein induced enterocolitis syndrome (FPIES; shock-like symptoms with severe metabolic acidosis,
vomiting and diarrhea)
Gastro-Intestinal
• Failure to thrive, anorexia, refusal to feed, early satiety
• Dysphagia, dyspepsia
• Abdominal pain, colic
• Nausea, regurgitation, emesis
• Diarrhea with or without protein loss or bleeding
• Constipation with or without perianal rash
• Iron-defeiciency anemia due to occult blood loss
Respiratory
• Respiratory distress
• Runny nose, chronic coughing
• Wheezing/stridor
Dermatological
• Urticaria, atopic eczema, angioedema.

2. Methods
The PubMed and Cochrane Library databases were searched up to July 2016. The searches were
limited to human studies and to studies published in English. Only published data were considered.

3. Prevention
The allergic march describes the order in which atopic disease develops, starting with atopic
dermatitis followed by asthma to end with rhinoconjunctivitis [11]. The development of atopic disease
is influenced by environmental and genetic, thus epi-genetic, confounders.
Two meta-analyses including selected papers on one partial hydrolysate conclude that selected
partially and extensive hydrolyzed infant formula may prevent the development of atopic dermatitis
and possibly that of CMA [12,13]. Boyle et al concluded in a meta-analysis including much more
trials (37 compared to 11 and 15 [14]) that overall there was no consistent evidence that partially or
extensively hydrolysed formulas reduce risk of allergic or autoimmune outcomes in infants at high
pre-existing risk of these outcomes [14]. Odds ratios for eczema at age 0–4, compared with standard
cows’ milk formula, were 0.84 (95% confidence interval 0.67 to 1.07) for partially hydrolysed formula;
0.55 (0.28 to 1.09) for extensively hydrolysed casein based formula; and 1.12 (0.88 to 1.42) for extensively
hydrolysed whey based formula [14]. A large study with a negative outcome with a different partial
whey hydrolysate than the one included in the above mentioned two meta-analyses contributes largely
to these findings [15]. These findings also suggest that outcomes obtained with one hydrolysate may
not be extrapolated to another hydrolysate, and that findings are hydrolysate-specific. According
to Boyle et al, there is no evidence to support the health claim approved by the US Food and Drug
Administration that a partially hydrolysed formula could reduce the risk of eczema nor the conclusion
of the Cochrane review that hydrolysed formula could allergy to cows’ milk [14]. This is only partially
confirmed by the recent Cochrane review reported that in infants at high risk of allergy not exclusively
breast fed, very low-quality evidence suggests that prolonged hydrolysed formula feeding compared
with CMF feeding reduces infant allergy and infant CMA ([16] -Cochrane review withdrawn). Studies
have found no difference in childhood allergy and no difference in specific allergy, including infant and
childhood asthma, eczema and rhinitis and infant food allergy [16]. Although extensively hydrolyzed
formulas (eHF) can be used in prevention, they are not considered as first option as they are much
more expensive that partially HF (pHF). Because of their bitter taste, eHF have a poor palatability.
In theory, the allergenic epitopes are destroyed in the manufacturing process of eHF. pHF has been
developed to decrease the amount of epitopes that possibly induce sensitization, while still having
Nutrients 2017, 9, 731 4 of 15
Nutrients 2017, 9, 731 4 of 15

sensitization,
peptides while still
of sufficient having peptides
immunogenicity of sufficient
to induce immunogenicity
oral tolerance. to induce
Only these pHF can oral
betolerance. Only
recommended
these pHF can be recommended for prevention for which there are sufficient clinical data to support
for prevention for which there are sufficient clinical data to support their efficacy, which are missing
their efficacy, which are missing for the majority of the commercialized pHFs. Some guidelines
for the majority of the commercialized pHFs. Some guidelines recommend the use of pHFs in “at risk”
recommend the use of pHFs in “at risk” infants, which are defined as infants born in a family in
infants, which are defined as infants born in a family in which at least one of the family members
which at least one of the family members (parents, brother, sister) has atopic disease. There is no
(parents, brother, sister) has atopic disease. There is no consensus if this diagnosis of atopic disease
consensus if this diagnosis of atopic disease should be “doctor confirmed” or not. As a consequence
should be “doctor confirmed” or not. As a consequence of the ongoing debate some countries (e.g.,
of the ongoing debate some countries (e.g., Japan, UK, Finland, Australia) do not recommend the use
Japan, UK, Finland, Australia) do not recommend the use of pHF to prevent allergy. There is no place
of pHF to prevent allergy. There is no place for infant formula with intact protein from different
for infant formula with intact protein from different origin in the prevention of allergic disease. Soy
origin in the prevention of allergic disease. Soy protein infant formula has no place in the prevention
protein infant formula has no place in the prevention of atopic disease.
of atopic disease.
Epidemiological data show that about half of the infants that will develop allergy are not part
Epidemiological data show that about half of the infants that will develop allergy are not part of
of this “at risk” group [17]. This is due to the fact that although the risk is lower in the non-at risk
this “at risk” group [17]. This is due to the fact that although the risk is lower in the non-at risk
group, the number of infants in the non-at risk group is much larger. In other words: guidelines
group, the number of infants in the non-at risk group is much larger. In other words: guidelines
recommend today prevention only for half of the infants that will develop atopic disease, and not for
recommend today prevention only for half of the infants that will develop atopic disease, and not for
the other half. A recent analysis from the 15 year follow-up of the two German birth cohorts GINI-plus
the other half. A recent analysis from the 15 year follow-up of the two German birth cohorts
and LISA-plus reported for the first time that parental allergic diseases increase the risk of childhood
GINI-plus and LISA-plus reported for the first time that parental allergic diseases increase the risk of
allergic diseases, especially for asthma, independent on whether the first onsets was before or after the
childhood allergic diseases, especially for asthma, independent on whether the first onsets was
birth of a child [18]. Knowledge on the long-term effects of pHF on growth and body composition
before or after the birth of a child [18]. Knowledge on the long-term effects of pHF on growth and
outcomes in healthy infants later in life is still limited [19]. There are some indications that hydrolysed
body composition outcomes in healthy infants later in life is still limited [19]. There are some
protein results in metabolic responses more distinctly different from those of human milk and different
indications that hydrolysed protein results in metabolic responses more distinctly different from
metabolic organ development compared to intact protein [19,20]. However, FDA and EFSA regulatory
those of human milk and different metabolic organ development compared to intact protein [19,20].
authorities consider a partially hydrolysed protein source as a protein source that can be used in starter
However, FDA and EFSA regulatory authorities consider a partially hydrolysed protein source as a
infant formula, irrespective of the fact if there would be some prevention of allergy or not. All studies
protein source that can be used in starter infant formula, irrespective of the fact if there would be
with pHF show no or some benefit, but never an increased risk for adverse effects. So the question
some prevention of allergy or not. All studies with pHF show no or some benefit, but never an
should be asked is pHF should not be considered as the best second choice infant feeding for every
increased risk for adverse effects. So the question should be asked is pHF should not be considered
infant, at least for those pHFs with clinical data supporting their efficacy (Figure 1), irrespective of
as the best second choice infant feeding for every infant, at least for those pHFs with clinical data
the fact if there is a preventive effect on allergy or not. Opponents to this viewpoint state that breast
supporting their efficacy (Figure 1), irrespective of the fact if there is a preventive effect on allergy or
milk contains intact protein, and a pHF does not. This is true. But: breast milk contains also proteases,
not. Opponents to this viewpoint state that breast milk contains intact protein, and a pHF does not.
digesting protein. The role of these proteases is yet unknown. And breast milk does not contain intact
This is true. But: breast milk contains also proteases, digesting protein. The role of these proteases is
cow milk protein, but contains cow milk peptides. The digestion of partially hydrolysed protein may
yet unknown. And breast milk does not contain intact cow milk protein, but contains cow milk
result in different metabolites than intact protein. Whether this is clinically relevant or not, is yet
peptides. The digestion of partially hydrolysed protein may result in different metabolites than
unknown. Overall, it is the opinion of the author that a partially hydrolysed protein may be considered
intact protein. Whether this is clinically relevant or not, is yet unknown. Overall, it is the opinion of
as an option as protein source of a starter formula for every non-exclusively breastfed infants. It then
the author that a partially hydrolysed protein may be considered as an option as protein source of a
becomes a cost/benefit discussion, which is difficult because cost of formula does vary substantially
starter formula for every non-exclusively breastfed infants. It then becomes a cost/benefit discussion,
from country to country [19].
which is difficult because cost of formula does vary substantially from country to country [19].

Figure [Link]
Figure Proposeddietary options
dietary according
options to breastfeeding
according and/orand/or
to breastfeeding family family
history history
of atopicofdisease.
atopic
disease.
Nutrients 2017, 9, 731 5 of 15

4. Symptoms and Diagnosis

Symptoms related to cow milk intake develop usually within the first two months after its
introduction and it is unusual for CMA to develop in a child older than one year of age [21]. Symptoms
can be separated in IgE and non-IgE mediated, and according to literature the distribution can be
estimated fifty-fifty [21]. Many infants develop symptoms in two or more organ systems. Typical IgE
mediated symptoms include urticaria, angioedema, vomiting, diarrhea and anaphylaxis. Dermatitis
and rhinitis can be IgE and non-IgE mediated. Vomiting, constipation, hemosiderosis, malabsorption,
villous atrophy, eosinophilic proctocolitis, enterocolitis and eosinophilic esophagitis are non-IgE
mediated reactions. In addition, respiratory symptoms such as chronic rhinitis and asthma may be
caused by CMA [22]. Irritability, fuzziness and colic are sometimes the only symptoms of CMA [3,23].
Whether diagnostic investigations such as IgE, specific RAST and skin prick tests should be performed
depends on local facilities and routines, but they are not routinely recommended in the guidelines [3,21].
Total IgE is not helpful in the diagnosis of CMA, but the IgE level is related to the development of
tolerance: the lower the total IgE, the more rapidly tolerance develops [21]. Specific IgE and skin
prick tests may contribute to confirm the suspected diagnosis, although false positive results do
exist. The atopy patch test, which is popular in France, has not been considered as a recommended
diagnostic test in guidelines [3,21]. Negative test results do not exclude allergy [3]. Other diagnostic
tests are only possible in specialized laboratories or indicated in very distinct clinical conditions, such
as mucosal biopsies in infants presenting with blood in their stools. There is no place for the (expensive)
determination of IgG4-antibody levels as these are considered to demonstrate contact of the immune
system with the antigens but do not suggest an allergic reaction [3,21,23].
A symptom-based score, the Cow Milk Related Symptom Score (CoMiSSTM ) has recently been
developed to raise awareness of symptoms related to the ingestion of cow milk [24]. A challenge test is
likely to be positive in 80% of patients if an initial score of more than 12 decreases to less than half with
an eHF [25]. Therefore, it is hoped that, when it is validated, the CoMiSSTM may become a valuable
diagnostic tool [24].
The majority of the guidelines accept an open challenge in infants suspected of CMA, although
a double-blind challenge test is considered to be the gold standard for diagnosing CMA [3,21,23].
Standardized procedures on how to perform a challenge test have been published (Table 2) [3,21,23].
A challenge test should always be performed under medical supervision, but it does not have to be
systematically performed in a hospital environment. Hospitalization is recommended if it is suspected
that acute, severe or unpredictable symptoms could occur [3]. Parents are often reluctant to perform a
challenge test, because it will make the allergic child sick again. In addition, the results of a challenge
are often difficult to interpret. While immediate reactions are relatively easy to pick up, delayed
reactions are more difficult to detect. A group of experts published a standardized double-blind
placebo-controlled food challenge [24]. This certainly has the merit to be scientifically sound but has
the disadvantage to be difficult to apply in daily practice in not experienced centers or at primary
health care level. Specifically for a cow's milk challenge, European experts have proposed an open
prolonged challenge: after a half day challenge under medical supervision, the patient returns home
and parents need to continue the challenge by providing a sufficient daily intake of at least 200 mL of
milk per day [3,21]. Indeed, about half of the children will develop a delayed reaction, which will only
be picked up if the parents are collaborating and the follow up is adequate. Double-blind challenge
tests cover only the first part of the challenge test, which is under medical supervision.

Table 2. Example of standardized protocol for open challenge test.

• Drop of formula on the lips

• If there is no reaction after 15 min, the formula is given orally and the dose is increased stepwise (0.5, 1, 3,
10, 30, 50 to 100 mL) every 30 min
• Additional observation for at least 2 h
Nutrients 2017, 9, 731 6 of 15

If negative, the infant should drink at least 200 m of cows’ milk-based infant formula each day
for the next 2 weeks and the parents should be contacted daily by a healthcare professional or should
contact a healthcare professional if symptoms occur so that a late reaction can be documented.

5. Treatment
The vast majority of infants with suspected CMA will be formula-fed and present with a
combination of the symptoms listed in the CoMiSS™ [24]. Guidelines recommend an elimination
diet with a whey or casein-based eHF with clinical proof of efficacy for two to four weeks
as the first option [3,23] (Table 3). The CoMiSS™ score can contribute to quantify clinical
improvement. Hydrolysates strengthen the epithelial barrier, modulate T-cell differentiation and
decrease inflammation [26]. Some studies suggest a role for hydrolysates in manipulating pathogen
recognition receptors signaling as underlying mechanism. Peptides from hydrolysates have been
shown to bind to TLR2 and TLR4 and influence cytokine production in epithelial cells and macrophages.
Current insight suggests that hydrolysates may actively participate in modulating the immune
responses in subjects with and those at risk to develop CMA [26]. If the symptoms do not improve,
then CMA is unlikely. The percentage of patients tolerating the eHF will depend on the selection of
patients. In eHFs, most of the nitrogen is present as free amino acids and peptides <1500 kDa [27].
During CMA treatment, allergenic peptides may be potentially harmful. Therefore, peptides that
have reduced allergenicity but are capable to induce tolerance are recommended. The World Allergy
Organization Diagnosis and Rationale for Action against Cow’s Milk Allergy (WAO-DRACMA)
guidelines recommend cow milk based eHF over soy infant formula in IgE-mediated CMA [10]. Amino
acid based formula (AAF) is recommended if formula-fed infants present with the rare condition of
anaphylaxis and in eosinophilic esophagitis, or when the child does not tolerate to the eHF and CMA
is a likely diagnosis (because failure of eHF has been reported) or when the cost/benefit analysis is in
favor of the AAF [3,21]. However, eHFs have been reported to be effective in adults with eosinophilic
esophagitis caused by cow milk [28]. If a strict AAF diet does not result in an improvement of the
symptoms, the patient does not suffer CMA. In case of anaphylaxis, the long-term management
of such infants should include a challenge with an eHF before cow milk is (re-)introduced. This
should be carried out after 6 to 9 months or when the infant is one year old and always in a hospital
environment [3,23].

Table 3. Recommended therapeutic options according to different guidelines for different symptoms
and signs of cow's milk allergy.

Australia [29] Dracma [10] Espghan [3]

1st choice 2nd choice 1st choice 2nd choice 1st choice 2nd choice
eHF AAF
GI syndromes eHF AAF eHF AAF
soy (if >6 months) eHF
proctocolitis eHF AAF eHF AAF
Eos Eso AAF AAF AAF
eHF AAF
Immediate FA eHF AAF/Soy eHF AAF
soy (if >6 months) eHF
FPIES eHF AAF eHF AAF eHF AAF
eHF AAF
Atopic eczema eHF AAF/Soy eHF AAF
soy eHF
urticaria eHF AAF/Soy eHF AAF
Constipation eHF AAF
Heiner syndrome AAF eHF

If an eHF is not available, if the infant refuses to drink it or if it is too expensive, a rice hydrolysate
or a soy infant formula are considered as second choices. Since pHF has longer peptides than eHF,
Nutrients 2017, 9, 731 7 of 15

pHF may trigger symptoms in sensitized infants (3,10,23). Therefore, a cow milk based pHF is not
suitable for treating CMA. While eHF needs to be tolerated by >90% of patients, pHF will be tolerated
by less than half of infants with CMA [3].
Thickened eHF and AAF are commercially available [30,31] to treat simultaneously CMA and
infant regurgitation. Whether an eHF is thickened or not seems not to be relevant in CMA; however,
when the challenge test is negative, the thickened eHF is more effective in reducing regurgitation than
the non-thickened [30]. Up to now allergic reactions to the thickening agent in these formulas have not
been reported.
Partial and extensively rice hydrolyzed formula are commercialized and, in some parts of the
world, soy (hydrolyzed) infant formula also exists. Since rice hydrolysates are relatively new, they
are not (yet) considered in published guidelines. The clinical efficacy of rice hydrolysates, partial and
extensive, seems excellent [32,33]. Rice hydrolysates are free of CMP allergens. Rice hydrolysates are
less expensive than cow milk based eHF. The content of arsenic in rice may be a safety issue limiting
the use of rice. There is an FDA warning against the use of rice in infants and young children regarding
rice feed thickeners and rice cereals. Therefore the arsenic content in rice based infant formula should
be determined and declared on the label [34]. The arsenic content in infant formula is reported to be
within the safety limits. Other mammalian milks such as sheep milk and goat milk are not indicated
in the treatment of CMA [3]. Infant formulas based on goat milk are on the market in a substantial
number of countries, but the high incidence of cross-reactivity in CMA patients results in the fact that
they cannot be recommended for infants with CMA [35]. Significant cross-sensitization to milk proteins
derived from kosher animals exist in patients allergic to CMP, but far less so than the milk proteins
tested from non-kosher animals [35,36]. Camel and mare milk have not been evaluated as possible
options [37–39], but ass milk in particular has been shown to be effective in treating CMA [40,41].
The DRACMA guidelines even recommend donkeys milk as third option in constipation due to CMA.
However, none of these alternative options fulfill the nutritional and compositional requirements for
infant formula and as a result they cannot be recommended in the treatment of CMA. Consumption
of unprocessed cow milk in young infants protects against respiratory infections [42]. However,
unprocessed cow milk can as well not be recommended in infants for nutritional reasons. The epitopes
in raw, cooked or baked milk differ [43] as baked milk was reported to be tolerated in patients with
eosinophilic esophagitis as presentation of CMA [43]. Although use of hypoallergenic baked milk in
oral immune therapy is a promising therapy, care must be taken before its administration in baked
milk-reactive patients because of the risk for anaphylaxis and only limited increase in challenge
threshold attained [44].
Soy infant formula has existed for longer than one century, but its popularity varies greatly [23].
The Agence Française de Sécurité Sanitaire des Aliments drew attention to the presence of isoflavones
and their unknown impact on infant health. Isoflavones have been shown to induce estradiol-like
effects in animal models [45]. The American Academy of Pediatrics reviewed the literature and
summarized that 10% to 14% of infants with CMA will become soy-sensitized, with a higher incidence
in non-IgE mediated CMA than in IgE mediated CMA [46]. According to a recent meta-analysis,
the prevalence of soy allergy was 0.5% in the general population, but the prevalence of sensitization
after the use of soy infant formula was 8.7% [47]. Therefore, it seems logic today to recommend a
clinically tested eHF as first option in the management of CMA, and to recommend rice hydrolysates
as a second option and soy as third option.
A lack of effective and approved treatment has led to strict avoidance of the culprit food proteins
being the only standard of care [2]. Several food immunotherapies are being developed; these
involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or
modified allergens to induce immune tolerance [2,48]. Oral immunotherapy is a promising but still
experimental method to treat children with cow’s milk allergy [49]. The approach generally follows
the same principles as immunotherapy of other allergic disorders and involves the administration
of small increasing doses of food during an induction phase followed by a maintenance phase with
Nutrients 2017, 9, 731 8 of 15

regular intake of a maximum tolerated amount of food [50]. Most research has been conducted with
oral immunotherapy due to its efficacious and relatively safe profile but remains an investigational
treatment to be further studied before advancing into clinical practice [2,48]. Determination of IgE
and IgG4 epitope binding may contribute to select candidates for oral immune therapy [51]. Oral
immune therapy carries significant risk of allergic reactions [51]. The ability of oral immune therapy to
desensitize patients to particular foods is well-documented, although the ability to induce tolerance
has not been established [51]. Recent data suggest that oral immune therapy may induce long term
tolerance in half of the children [52]. Markers of allergy such as blood eosinophils and serum IgE
decreased and milk-specific IgG and IgG4 increased during oral immune therapy [49]. Adipokines,
leptin and resistin, which functionally are cytokines linked to Th1-type response, increase during oral
immune therapy [49]. The high frequency of allergic adverse reactions of the various approaches
highlighted the need of refinements in the strategies. A careful review of the patients who received
food oral immune therapy in controlled trials confirmed that adverse events were not rare but that
~90% of children could achieve an effective desensitization [53]. A promising strategy for preventing
IgE cross-linking and thus enhancing safety of immune therapy, while still activating T cells, is the
use of tolerogenic peptides [2]. Additional bigger, multicentric and randomized-controlled studies
must answer multiple questions including optimal dose, ideal duration of immunotherapy, degree of
protection, efficacy for different ages, severity and type of food allergy responsive to treatment [48].
The procedure remains investigational and should be performed only by trained physicians, especially
in the pediatric setting [53]. Immunotherapy for food allergy is still not ready for the clinic, but current
and upcoming studies are dedicated to collect enough evidence for the possible implementation of
allergen-SIT as a standard treatment for food allergy [2].

6. Gut Microbiota
The role of the GI microbiota in food allergy has been a topic of major interest since many years.
Oral tolerance is the consequence of a systemic absence of a response to dietary antigens. Early infancy
is a window during which gut microbiota may shape food allergy outcomes in childhood [54]. Dietary
antigens and intestinal microbiota are known to make up the majority of the antigen load in the
intestine. The GI microbiome plays a strong role in the orientation of the immune response [55].
Food allergy is associated with alterations in the gut microbiota or dysbiosis early in life that may
be predictive of disease persistence versus tolerance acquisition [56]. Qualitative and quantitative
differences in the composition of the gut microbiota between infants who will and infants who
will not develop allergy are demonstrable before the development of any clinical manifestations of
atopy [57,58]. Gut microbiome composition at age 3 to 6 months was associated with acquisition
of tolerance to milk proteins by age 8 years, with enrichment of Clostridia and Firmicutes in the
infant gut microbiome of subjects with resolved CMA [54]. Metagenome functional prediction
supported decreased fatty acid metabolism in the gut microbiome of subjects whose CMA resolved [54].
As a consequence, bacterial taxa within Clostridia and Firmicutes could be studied as probiotic
candidates for milk allergy therapy [54]. Data obtained in murine models of food allergy suggest that
microbial therapy with protolerogenic bacteria such as certain Clostridial species holds promise in
future applications for prevention or therapy of food allergy [59]. Extrapolation from in vitro data
suggests that supplementing infant formulas such as eHF with prebiotics or probiotics (Lactobacillus
(L.) rhamnosus GG, Bifidobacteria (B.) breve) may offer an additional benefit [60].

6.1. Prebiotics
Dietary supplementation with short chain galacto-oligosaccharides (scGOS), long chain
fructo-olgosaccharides (lcFOS) and/or pectin-derived acidic oligosaccharides during sensitization
effectively reduce allergic symptoms but differentially affect mucosal immune activation in
whey-sensitized mice [61]. A beneficial effect of prebiotics on the development of atopic dermatitis
in a high risk population of infants was shown for the first time in this paper [62]. Although the
Nutrients 2017, 9, 731 9 of 15

mechanism of this effect requires further investigation, it appears likely that oligosaccharides modulate
postnatal immune development by altering bowel flora and have a potential role in primary allergy
prevention during infancy [63]. These findings were confirmed by demonstrating that early dietary
intervention with oligosaccharide prebiotics has a protective effect against both allergic manifestations
and infections [64]. Later, this effect was also shown in non-at-risk infants [63]. The observed
dual protection lasting beyond the intervention period, up to the age of five years, suggests that an
immune modulating effect through the intestinal flora modification may be the principal mechanism
of action [60,63]. This mechanism has now been demonstrated [64].
The addition of lactose to an eHF is able to positively modulate the composition of gut microbiota
by increasing the total fecal counts of L/B and decreasing that of Bacteroides/Clostridia [65]. The
positive effect is completed by the increase of median concentration of short chain fatty acids, especially
for acetic and butyric acids demonstrated by the metabolomic analysis [66]. However, the ESPGHAN
Committee on Nutrition concluded in 2011 that there was insufficient evidence to recommend the use
of prebiotics in infant formula to prevent atopic disease [67]. But, based on GRADE evidence to decision
frameworks, the WAO guideline panel suggests using prebiotic supplementation in not-exclusively
breastfed infants and not using prebiotic supplementation in exclusively breastfed infants [68]. Both
recommendations are conditional and based on very low certainty of the evidence [68].
Human milk oligosaccharides (HMOs) are a group of complex sugars that are highly abundant
in human milk, but currently not present in infant formula. Literature indicating that HMOs play a
major beneficial and facilitating role in the development of the infant’s microbiome and thus immune
development is abundant and unequivocal. However, there are over 100 different HMOs, with specific
properties and functions. HMOs are not digested by the infant and serve as metabolic substrates for
select microbes, contributing to shape the infant gut microbiome. HMOs provide a main substrate
to help shape the infant’s gut microbiota and affect the maturation of the intestinal mucosal immune
system [69]. Higher HMO diversity at the age of one month was associated with lower total and
percentage fat mass [69]. At the age of 6 months, each 1-µg/mL increase in lacto-N-fucopentaose was
associated with a 1.11-kg lower weight and a 0.85-g lower lean mass [69]. These findings support the
hypothesis that differences in HMO composition in mother's milk are associated with infant growth
and body composition [69].
HMOs act as soluble decoy receptors that block the attachment of viral, bacterial or protozoan
parasite pathogens to epithelial cell surface sugars, which may help prevent infectious diseases in the
gut and also the respiratory and urinary tracts. HMOs alter host epithelial and immune cell responses.
Secretor milk contains higher concentrations of total and fucosylated HMOs than does nonsecretor
milk. These HMO concentrations can be correlated to the health of breastfed infants in order to
investigate the protective effects of milk components [70]. HMOs have the potential to selectively
enrich the beneficial intestinal microbiota in breast-fed infants. Infants that received human milk with
low Lacto-N-fucopentaose III concentrations were more likely to become affected with cow’s milk
allergy when compared to high LNFP III-containing milk (odds ratio 6.7, 95% CI 2.0–22) [71].
Up to now, only a limited number of HMOs have been synthetized and studied in infant
formula, showing beneficial results. It is however unclear if a single HMO is more beneficial for
the infant’s immune system development than the artificial prebiotic oligosaccharides such as galacto-
and fructo-oligosaccharides.

6.2. Probiotics
The administration of probiotics may contribute to the restoration of the healthy equilibrium
of the GI microbiota and contribute to the efficacy of an elimination diet in CMA. Probiotics are
known to cross-talk with the intestinal immune cells. Probiotic bacteria have different modes of
action in the intestinal lumen: they hydrolyze peptides that are potentially antigenic to non-antigenic
peptides; they decrease the intestinal permeability and, as a consequence reduce the penetration of
antigens from the gut lumen to the systemic circulation; they stimulate the local production of IgA
Nutrients 2017, 9, 731 10 of 15

and they regulate local inflammatory responses and stimulate the differentiation and growth of the
GI mucosa [41]. Administration of L GG to children under the age of 2 years suffering from eczema
and with a challenge-proven food allergy has been shown to result in a significant decrease in the
eczema score [72]. A formula supplemented with L GG also decreased GI symptoms in infants with
eczema [73]. A cow milk challenge in allergic infants resulted in an increase of fecal IgA levels and a
decrease of the TNF-α level compared to a placebo [74]. L. GG has been shown to substantially increase
the memory B cells and stimulate interferon-γ secretion in infants with CMA and with IgE-associated
dermatitis, but not in healthy infants [75]. These findings support the hypothesis that infants with an
atopic predisposition may have an aberrant pattern of intestinal microbiota and this explains why the
beneficial effects of probiotics are only seen in this group [76]. In infants with colitis, supplementing a
casein eHF with L. GG significantly enhanced the recovery of the inflammation in the colonic mucosa
in comparison to the same hydrolysate without the probiotics [76]. In the group that received the
probiotic, fecal calprotectin and the number of infants with ongoing occult blood in stools after one
month were significantly smaller [77]. The primary goal in the treatment of CMA is, of course, for the
symptoms to disappear. However, the second, and almost equally important objective, is to acquire
oral tolerance. As an eHF supplemented with L casei CRL431 and B lactis BB-12 failed to accelerate
tolerance, this effect may be strain specific [78]. In a trial that compared an eHF without and with L
GG, a double-blind placebo-controlled food challenge (at least 1.4 × 107 CFU/100 mL) was negative
in 15/28 (53.6%) infants without L. GG and in 22/27 (81.5%, p = 0.027) with L. GG. These findings
may prove innovative in the therapeutic approach to treating infants with CMA by accelerating the
acquisition of tolerance [79].
Consumption of probiotic milk products was related to a reduced incidence of atopic eczema and
rhinoconjunctivitis, but not associated to the incidence of asthma by 36 months of age [80].
Most tolerant infants showed a significant increase in fecal butyrate levels, and those taxa that
were significantly enriched in these samples [81], exhibited specific strain-level demarcations between
tolerant and allergic infants. Data suggest that a casein eHF with L. GG promotes tolerance in infants
with CMA, in part, by influencing the strain-level bacterial community structure of the infant gut [81].
Perinatal probiotic administration is safe in long-term follow-up [82]. Children receiving L.
rhamnosus GG perinatally tended to have decreased allergy prevalence [82]. The subgroup analysis
based on the type of treatment suggested that both L. alone and L. with B. are protective against atopic
dermatitis (OR = 0.70, p = 0.004; OR = 0.62, p < 0.001). Probiotics seem to have a protective role in atopic
dermatitis prevention if these are administered during the pre- and postnatal period in both general
and allergic risk populations [82]. However, the ESPGHAN Committee on Nutrition concluded in 2011
that there was insufficient evidence to recommend probiotics to prevent atopic disease [67]. However,
considering all critical outcomes in this context, the WAO guideline panel determined that there is
a likely net benefit from using probiotics resulting primarily from prevention of eczema. The WAO
guideline panel suggests: (i) using probiotics in pregnant women at high risk for having an allergic
child; (ii) using probiotics in women who breastfeed infants at high risk of developing allergy; and
(iii) using probiotics in infants at high risk of developing allergy [83]. Probiotic compounds may
contain hidden allergens of food and may not be safe for subjects with allergy to cow milk or hen’s
egg [84,85].
Post-sensitization administration of non-digestible oligosaccharides and Bifidobacterium breve
M-16 V were shown to reduce allergic symptoms in mice [86]. Studies demonstrate that an AAF with
synbiotics is safe and well tolerated and promotes normal growth when fed to healthy full-term infants
as the sole source of nutrition and is hypoallergenic in subjects with CMA [87].

7. Conclusions
The diagnosis of CMA is still a challenge. Cow milk based eHF remains the recommended and
preferred therapeutic choice, while AAF is reserved for the most severe cases. Rice hydrolysates
and soy informant formulas are second choice options. Manipulation of the gut microbiotica may
Nutrients 2017, 9, 731 11 of 15

enhance the development of oral tolerance. Hydrolysates, in particular pHF with proven efficacy, may
become a protein source in starter infant formula. Since the efficacy of hydrolysates in the prevention
of allergic disease is debated, some guidelines recommend these formulas in infants at risk for atopic
disease, while other meta-analyses and some countries do not recommend the use of these formulas
in prevention. However, it is obvious that these formulas do not harm. Similar, although the clinical
evidence for a benefit of additional prebiotics or HMOs and/or probiotics is limited, supplementation
of hydrolysates should be considered as adverse effects have not been reported.

Conflicts of Interest: Yvan Vandenplas has participated as a clinical investigator, and/or advisory board member,
and/or consultant, and/or speaker during the last 15 years for Abbott Nutrition, Aspen, Biogaia, Biocodex,
Danone, Hero, Hypocrata (Kabrita), Nestle Nutrition Institute, Nutricia, Mead Johnson Nutrition, Merck, Orafti,
Phacobel, Sari Husada, United Pharmaceuticals (Novalac), Wyeth and Yakult.

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