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54 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, 14, 54-62

Reintroduction of Cow’s Milk in Milk-Allergic Children

Nicolaos Nicolaou1,2,*, Sophia Tsabouri3 and Kostas N. Priftis4

1
The University of Manchester, Institute of Inflammation and Repair, University Hospital of South Manchester NHS
Foundation Trust, Manchester, UK; 2St George’s University of London Medical School at University of Nicosia,
Nicosia, Cyprus; 3Child Health Department, University of Ioannina Medical School, Ioannina, Greece; 4Paediatric
Allergy and Pulmonology Units, 3rd Department of Paediatrics, University General Hospital “Attikon”, School of
Medicine, National and Kapodistrian University of Athens, Athens, Greece

Abstract: Even though cow’s milk protein allergy (CMPA) is one of the most common food allergies in childhood, its
prognosis is generally good and cow’s milk (CM) is usually reintroduced in the patient’s diet. The natural history of
CMPA shows heterogeneity and is closely related to the immunological and clinical phenotype by which CMPA presents.
Children with non-IgE-mediated CMPA tend to develop tolerance at an earlier age and at a higher percentage compared to
those with IgE-mediated disease. In subjects with severe symptoms CMPA may persist for longer or ever. Although, the
majority of children will outgrow their allergy, the individual timing of tolerance acquisition is largely unknown. Most of
the current guidelines on the diagnosis and management of CMPA suggest reevaluation of milk- allergic children every 6-
12 months, and reintroduction of CM after a negative Oral Food Challenge (OFC). However, OFC procedure is time
consuming, expensive and not without risk. Clinical variables and the measurements of sIgE levels and SPT wheal sizes to
crude (whole) CM protein and individual milk protein components may provide some useful prognostic information in the
course of CMPA. However, no clear-cut clinical or laboratory criteria exist to predict which children and at what age are
more likely to pass a repeat (reintroduction) OFC. The identification of factors that could accurately predict the outcome
of reintroduction OFC and the timing of tolerance development would be extremely useful in daily clinical practice. Until
recently, reintroduction of CM was commonly attempted when children with CMPA were more likely to have become
tolerant. Over the last years, a different approach in the management of milk and egg allergy has emerged with specific
oral tolerance induction (SOTI) as a promising method for the treatment of food allergies. Furthermore, a number of
studies have shown evidence that introduction of heated milk and egg protein into the diet of allergic patients may induce
the acquisition of tolerance. Still, the question of when and how to reintroduce cow’s milk in milk-allergic children
remains challenging and further research in this important field is necessary to provide both clinicians and anxious parents
with the desirable answer.
Keywords: Children, cow’s milk protein allergy, heated milk, prognosis, reintroduction, tolerance.

INTRODUCTION In general, CMPA has a good prognosis and CM is


usually reintroduced in the patient’s diet. The natural history
Cow’s milk protein allergy (CMPA) is one of the most of CMPA shows heterogeneity and is closely related to the
common food allergies in early childhood, affecting clinical phenotype by which it presents [8]. Children with
approximately 3% of infants and young children [1, 2]. non-IgE-mediated CMPA develop tolerance at an earlier age
CMPA presents with a spectrum of clinical phenotypes from and a higher percentage compared to those with IgE-
mild to life-threatening symptoms driven by IgE, non-IgE or mediated disease [9, 10]. Although, the majority of children
both immunologic mechanisms [3]. Oral food challenge with CMPA will outgrow their allergy, the individual timing
(OFC) and especially the double-blind placebo-controlled of tolerance acquisition is largely unknown. Most of the
food challenge (DBPCFC) is considered the gold standard current guidelines on the diagnosis and management of
for establishing allergy or tolerance to cow’s milk [4]. CMPA suggest reevaluation of milk- allergic children every
However, OFC procedure is time- consuming, expensive and 6-12 months, and reintroduction of CM after a negative OFC
not without risk. Once the diagnosis is confirmed strict [11-14]. The decision of when to perform OFC is often based
elimination of the offending allergen in diet is the mainstay on the CMPA clinical phenotype, the history of no reactions,
of management [5]. Accidental exposures are common and and a decrease in CM-Skin Prick Test (SPT) wheal size or
may result in severe reactions [6]. The quality of life in CM-specific IgE (sIgE) levels since the last clinical
children and families is significantly affected [7]. assessment in the case of IgE-mediated CMPA.
Measurement of sIgE values and SPT wheal sizes to
crude CM protein or individual milk protein components
*Address correspondence to this author at the University of Manchester,
University Hospital of South Manchester NHS Foundation Trust,
may provide some useful prognostic information in the
Manchester M23 9LT, UK; Tel: +357 99 476578; Fax: +357 25 375333; course of CMPA [15-39]. However, no clear-cut clinical or
E-mail: nic.nicolaou@gmail.com laboratory criteria exist to predict which children are more

2212-3873/14 $58.00+.00 © 2014 Bentham Science Publishers


Reintroduction of Cow’s Milk in Milk-Allergic Children Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 1 55

likely to pass a repeat OFC. The identification of factors that studies [9, 18, 34] giving usually more accurate results than
could predict the likelihood of tolerance development would studies of retrospective [15, 31] design. Consistently, studies
be extremely useful in daily clinical practice. Thus, OFCs including only subjects with IgE-mediated CMPA report
with a high probability of being positive would be avoided lower resolution rates [18, 31].
and only those with an increased probability of being An early (from the 1990s) unselected prospective
negative would be carried out to confirm tolerance.
population-based study of Danish children with cow’s milk
Determining the correct timing of CM reintroduction would
protein allergy revealed a very good overall prognosis [50].
avoid unnecessary family - patient discomfort and reduce
Host et al. reported a total recovery rate of 56% at the end of
health systems costs [14].
the first year of life, 77% at 2 years, 87% at 3 years, 92% at
Until recently, reintroduction of CM was attempted when 5 years and 97% at 15 years of age [9]. Children with non-
children with CMPA were more likely to have become IgE-mediated cow’s milk allergy had a better prognosis
tolerant (outgrown their allergy) [12, 13]. Over the last years, compared to children with IgE-mediated CMPA allergy.
a different approach in the management of milk and egg Regarding the prognosis of IgE and non-IgE mediated
allergy has emerged with oral immunotherapy (OIT) and CMPA phenotype, similar findings were observed in another
specific oral tolerance induction (SOTI) as promising early study from a tertiary referral centre in Australia with
methods for the treatment of food allergies [40-45]. the percentages of tolerance development in children with
Furthermore, a number of studies have shown evidence that non-IgE- and IgE-mediated CMPA at 78% and 57%
reintroduction of heated milk and egg protein in allergic respectively [51].
patients may induce the acquisition of tolerance [46-48].
In a Finish prospective study, tolerance to cow’s milk
was developed by 44%, 69% and 77% of children by age 2,
NATURAL HISTORY OF CMPA 3 and 4 years respectively [34]. At age 2 and 4 years the
proportion of children with non-IgE-mediated CMPA who
A wide range of CMPA resolution rates (19% to 97%)
became tolerant was significantly higher compared to
has been reported from studies examining the natural history
children with IgE-mediated CMPA (59% and 93% versus 30
of CMPA in different countries (Table 1). A number of
and 59%). In an unselected Finish birth cohort study, 51% of
earlier studies [9, 49, 50] revealed a good prognosis, whereas
subjects with CMPA became tolerant by their second
some recent studies [31, 38] figured less optimistic resolution
rates suggesting a change in the natural history of CMPA birthday [10]. By the age of 5 years tolerance was developed
in all children with negative CM sIgE compared to 74% in
over time. Differences in the characteristics of the studied
the group of children with positive CM sIgE. By age 8.6
populations and in the methods followed by different
years 89% of subjects recovered their CMPA. In addition,
research groups may account for the observed variability in
children with transient sIgE sensitization recovered earlier.
reported resolution rates. Unselected population-based studies
[9, 10] tend to give a more favorable prognosis compared In Spain, Garcia-Ara. et al., followed prospectively 66
to studies of referral populations [15, 31] with prospective infants with IgE-mediated CMPA. Subjects were reassessed

Table 1. Natural history of CMPA in different populations and settings.

Authors/ Country Number of Subjects Population/Study Design Tolerance Rate


Year of Publication

Host et al., 2002 Denmark 39 (21 IgE-mediated) General Prospective birth cohort 56% by 1y, 77% by 2 y, 87% by 3 y, 92% by 5 y,
and 97% by age 15 y

Vanto et al., 2004 Finland 162 (95 IgE-mediated) Referral Prospective 44% by 2 y, 69% by 3 y, and 77% by age 4 y

Garcia-Ara et al., 2004 Spain 66 IgE-mediated Referral Prospective 68% by age 4 y

Saarinen et al., 2005 Finland 118 (75 IgE-mediated) General Prospective birth cohort 51% by 2 y, 74% by 5 y, and 85% by age 8.6 y

Skripak et al., 2007 USA 807 IgE-mediated Referral Retrospective 19% by 4 y, 42% by 8 y, 64% by 12 y, and 79%
by age 16 y

Fiocchi et al., 2008 Italy 112 IgE-mediated Referral Prospective 52.7% by age 5 y

Martorell et al., 2008 Spain 170 IgE-mediated Referral Prospective 82% by age 4 y

Santos et al., 2010 Portugal 139 (66 IgE-mediated) Referral Retrospective 41% by 2 y,

Ahrens et al., 2012 Germany 52 IgE-mediated Referral Retrospective 61.5% by age 12 y

Elizur et al., 2012 Israel 54 IgE-mediated General Prospective birth cohort 57.4% by 2 y, 65% by age 4 y

Wood et al., 2013 USA 293 IgE-mediated Referral Prospective 53% by age 5.5 y

Yavuz et al., 2013 Turkey 148 IgE-mediated Referral Retrospective 20% by 2 y, 34% by 4 y, and 39% by age 6 y
56 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 1 Nicolaou et al.

Table 2. Factors related to tolerance and persistence of CMPA.

Favor Shorter Duration and Tolerance Favor Longer Duration and Persistence

Clinical

Non-IgE-mediated IgE-mediated

Later age at presentation (e.g. > 1month) Earlier age at presentation (e.g. < 1month)

Milder symptoms (e.g. gastrointestinal) Severe symptoms (e.g. respiratory)

Higher eliciting dose (e.g. > 10 mls) Lower eliciting dose (e.g. < 10 mls)

Tolerance of heated milk Intolerance of heated milk

Absent or mild co-morbidities (e.g. asthma, rhinitis, eczema, Present and severe co-morbidities (e.g. asthma, rhinitis,
and other food allergies) eczema, and other food allergies)

No family history of atopy Family history of atopy

Laboratory

Lower levels of sIgE and/or smaller SPT wheal size to whole and individual Higher levels of sIgE and/or larger SPT wheal size to whole and individual
(e.g. casein) CM proteins at diagnosis and follow up measurements (e.g. casein) CM proteins at diagnosis and follow up measurements

Significant reduction in sIgE levels and/or SPT wheal size over time Non-significant reduction in sIgE levels and/or SPT wheal size over time

Recognition of specific IgE conformational epitopes, Recognition of specific IgE linear epitopes,
increased binding to IgG4 epitopes grater sIgE epitope diversity and higher affinity

Multiple sensitizations to other foods (e.g. egg, soy)


and inhalant allergens by sIgE/SPT

every 6 months up to the age of 2 years and then annually the development of tolerance or the persistence of CMPA [9,
[20]. Forty-five children (68%) became tolerant over the 15, 17, 18, 20, 26, 27, 29, 31, 33, 34, 39, 46, 52]. Age and
study period (9-99 months). In another prospective study severity of symptoms at presentation, co-morbidities and
from Spain, 140 (82%) of 170 children with CMPA became atopic profile, levels of allergen specific IgE and SPT wheal
tolerant by age 4 years [25]. In a recent retrospective study sizes to whole CM and individual cow’s milk allergenic
from Germany, 32 out of 52 (61.5%) children with CMPA proteins at diagnosis and follow-up assessments, are amongst
became tolerant over the analyzed period (3-142 months) the most commonly examined factors (Table 2). Findings
[15]. In the Milan Cow’s Milk Allergy Cohort Study vary between studies, and unfortunately no single marker has
(MiCMPAC), 52.7% of children with CMPA became been consistently found to be predictive of when and in
tolerant by the age of 5 years [19]. The median duration of whom tolerance occurs. Some reasons for the observed
CMPA was 23 months, while 23% of children acquired variability in the results from different studies include
tolerance 13 months after diagnosis and 75% after 43 months. different settings and populations, inclusion and diagnostic
criteria, laboratory methods applied and time points of
In a retrospective review of the clinical records of 807
reassessment and duration of follow up.
patients with CMPA in the USA, Skripak et al., reported
resolution rates of 19% by age 4 years, 42% by age 8 years,
64% by age 12 years and 79% by age 16 years [31]. Despite Clinical Variables
the very low resolution rate of CMPA by age 4, an encouraging
The immunologic and clinical phenotype by which
finding of this study is that patients may develop tolerance
CMPA presents appears to have an important role in the
in late childhood and adolescence indicating that there is no
development of tolerance or the persistence of the food
age limit of CMPA resolution. One of the most recent
allergy. Children with non-IgE-mediated disease have
observational studies on the natural history of CMPA in the
USA [38], estimated that approximately 50% of children consistently been shown to develop tolerance earlier and
with CMPA will become tolerant by 5 years of age. more frequently than those with IgE-mediated CMPA [9,
10]. Mild gastrointestinal and skin symptoms at presentation
The variability in resolution rates observed in different are generally associated with tolerance, whereas severe
settings and populations does not allow for a universal gastrointestinal or respiratory symptoms are often related to
estimate regarding the natural history of CMPA at present. longer duration or persistence of CMPA [18, 31].
The majority of infants diagnosed with mild CMPA
PROGNOSTIC MARKERS FOR TOLERANCE VS. proctocolitis become tolerant before their 1st birthday and
PERSISTENCE IN CMPA CM is often reintroduced into their diet at the age of 9-12
Several studies have looked into various clinical and months without any problems [13, 53]. Children with Milk
biochemical markers that could be of prognostic value for Protein Induced Enterocolitis Syndrome [14, 54] usually
Reintroduction of Cow’s Milk in Milk-Allergic Children Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 1 57

develop tolerance between their 2nd and 3rd year of life, study by Vanto et al., SPT < 5mm at the time of CMPA
whereas many subjects with IgE-mediated type of CMPA diagnosis correctly identified 83 % of children who
acquire tolerance after the age of 3 years [31, 34]. In the later developed tolerance and SPT > 5mm 71% of those with
two types of CMPA, because of a greater risk of severe persistent CMPA at age 4 years [34]. In the study by
reactions, reintroduction OFCs should be performed in a Saarinen et al., SPT measured at 12- month follow up was
hospital setting under the supervision of experienced superior in predicting recovery at age 8.6 years compared to
personnel [11-14]. After a negative OFC reintroduction SPT measured at diagnosis [10]. However, more than a third
continues at home. (38%) of children who became tolerant continued to have a
positive SPT at the time tolerance was acquired with 25% of
Age and severity of symptoms at 1st reaction, as well as
them having a wheal size of 8mm which was shown to
the amount of milk evoking the reaction may be associated
with the natural course of CMPA. Within the context of a always predict persistence of CMPA in another cohort [32].
In a Greek study, pre-challenge SPT < 4mm could correctly
population-based study from Israel, Elizur et al., followed
predict a negative challenge outcome, whereas SPT > 7.5mm
prospectively 54 children with IgE-mediated CMPA until the
had a high probability of positive challenge [35].
age of 4-6 years [18]. Thirty-one subjects (57.4%) outgrew
CMPA during the study period with the majority of them In the MiCMPAC study, each 1-mm increment in wheal
(70.9%) becoming tolerant within the first 2 years. Patients’s diameter at SPT with fresh milk (HR 1.18) and a positive
reacting to < 10ml of milk or in the 1st month of life were at SPT to soy (HR 6.99) were the only 2 significant associates
increased risk of not developing tolerance. The age at first of CMPA persistence in the multivariate analysis for
reaction was the strongest predictor of CMPA persistence as predictors of duration of disease [19]. In another Italian
only 30% of infants reacting in < 30 days of life developed study, the measurement of end point prick test (EPT) with
tolerance during the study period. Respiratory symptoms raw milk was suggested as a useful predictor of OFC
were associated with persistence of CMPA and outcome [55]. EPT consists of seven progressive dilutions
gastrointestinal symptoms with development of tolerance. (1/10-1/10.000.000) of fresh CM (30mg/ml) with saline
Lower DBPCFC threshold dose was also a marker of solution. EPT with the 4th dilution (1/10.0000) had the best
longer duration of CMPA in the Milan study (MiCMPAC), ratio between positive and negative predictive values (86%
as was co-sensitization to an increased number of inhalant and 91% respectively) and could be used to discriminate
and ingested allergens and particularly soy [19]. In a tolerant from non-tolerant subjects.
Portuguese study, immediate allergic symptoms, other food The above findings suggest that there is no optimal SPT
allergies and asthma were independent risk factors for cut-off value that could accurately predict the timing of
the persistence of CMPA beyond the age of 2 years [27]. tolerance acquisition on an individual basis and that would
In a Finish study, exposure to CM while in maternity be applicable in every setting or population. However, an
hospital and development of urticaria at diagnostic challenge observed reduction in SPT size in the periodic re-evaluation
were risk factors for persistent CMPA at age 2 years. Early of a patient with CMPA may be associated with increased
sensitization to egg was also a risk factor [10]. In another probability of passing a reintroduction OFC.
Finish study, delayed and gastrointestinal symptoms during
diagnostic OFC favored the development of tolerance by age
4 years [34]. Measurements of sIgE
In the study by Skripak et al., coexisting asthma and Measurement of milk sIgE is widely available and a
allergic rhinitis were significantly associated with a lower useful tool in the evaluation of patients with CMPA. A
likelihood of developing tolerance even when controlling for number of studies reported that in patients who outgrew their
peak CM sIgE [31]. History of other food allergies was also milk allergy the levels of whole CM sIgE and individual
associated with a worse prognosis, but no association was milk proteins were initially lower and decreased significantly
observed with the presence of eczema. However, in another with time compared to patients who retained their clinical
USA study, children with moderate to severe atopic sensitivity [10, 19, 27, 29, 34, 38]. Whether quantification
dermatitis had a hazard ratio of 2 compared to those subjects and monitoring of sIgE levels to CM allergenic proteins
having mild or no atopic dermatitis [38]. could be used as a reliable predictor for determining when
patients with CMPA would develop clinical tolerance has
Skin Prick Tests always been a challenging question given that sIgE values
were shown to be age-dependent and higher in patients with
Many investigators attempted to correlate CM SPT atopic dermatitis[29, 56].
results to the outcome of OFC in an effort to identify
simpler, safer, economical and less time-consuming Skripak J, et al., identified CM IgE level as the most
predictors. Although most studies report a higher probability significant and probably clinically useful marker in
of tolerance acquisition in patients with smaller SPT weal predicting the resolution of CMPA [31]. By using each
sizes the optimal cut-off points vary in different populations patient’s highest CM sIgE level the researchers found that a
[10, 19, 32, 34, 35, 38, 55]. higher peak was significantly associated with a reduced
chance of developing tolerance. Children with peak CM
In the recent study by Wood et al., subjects with SPT sIgE levels less than 5kUA/L had the best prognosis and
weal size < 5mm had a 72% chance of developing tolerance those with peak CM sIgE levels > 20 kU/l the worst
compared to 52% chance for those with SPT between 5- prognosis. As an example, by the age of 4years 57% of those
10mm and 37% chance of those with > 10mm [38]. In the with a peak CM sIgE level < 2kUA/l became tolerant,
58 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 1 Nicolaou et al.

whereas significantly lower resolution percentages of 37%, components or synthetic epitopes, could determine a detailed
20%, 8%, 3%, and <1% were observed for those subjects analysis of a patient’s sensitization (antibody recognition)
with peak CM sIgE levels in the range of 2 to 4.9 kU/l, 5 to profile and facilitate more accurate diagnostic and prognostic
9.9 kU/l, 10 to 19.9 kUA/l, 20 to 49.9 kU/l, and greater than tools in CMPA [59]. In this view, a few studies demonstrated
50kUA/l respectively. significant differences in the IgE and IgG epitope-binding
pattern between subjects who developed tolerance and those
In a Finish study, 82% of subjects with CM sIgE < 2kU/l
with persistent CMPA [36, 37, 52, 60]. The recognition of
developed tolerance whereas 71% of those with sIgE > 2kU/l
IgE specific sequential (linear) as opposed to conformational
did not outgrow CMPA at age 4 years [34]. In the study by
epitopes, and particularly to casein fractions was associated
Wood et al., a subject with level of sIgE < 2kUA/L had a
with persisting disease [36, 60]. In addition, greater IgE
72% chance of developing tolerance compared to 52% chance
for those with sIgE between 2-10 UA/L and 23% chance for epitope diversity and higher affinity was observed in
children who did not develop tolerance [37].
those with sIgE > than 10 kUA/L [38]. Vassilopoulou et al.,
reported that a pre-challenge CM-sIgE < 3.94 KUA/L could Savilahti et al., observed that in subjects with CMPA
correctly predict a negative challenge outcome [35]. Ahrens who recovered early the intensity of IgE epitope-binding was
B. et al., reported that in children with an early resolution of decreased and IgG4 epitope-binding increased over time.
CMPA the levels of CM sIgE levels where lower at Based on their findings, they stated that IgE and IgG4
diagnosis. Children with CM sIgE < 5kUA/L (the median binding patterns to a panel of s1-, s2-, - and -casein
observed in the study) were four times more likely to regions could aid outcome prediction with significant
become tolerant compared to those children with levels accuracy [28]. Recently, Ahrens et al., demonstrated by
higher than 5kUA/L [15]. Using Kaplan-Meier calculation, microarray analysis that the individual likelihood of
they estimated that if the CM sIgE was lower than 5kUA/L outgrowing CMPA is significantly associated with a low
the half-life tolerance time (the time after 50% of subjects level of sIgE to -lactalbumin, -lactoglobulin, -casein and
became tolerant) was 18 months, whereas if it was > 5kUA/L s1-casein [15]. There was no significant correlation with
the half-time tolerance was 33 months. sIgE levels of total casein, lactoferin, -casein and -
lactalbumin. In addition, they did not observe any significant
In a Spanish study, sIgE cut-off points that predicted
differences between children who developed tolerance and
clinical reactivity with an accuracy of > 95% (corresponding
those with persistent disease from the detection of CM
to 90% specificity) at different ages (13-18, 19-24, and > 25
months) were 2.7, 9 and 24 kUA/L for cow’s milk and 2, 4.2 specific IgG or IgG4 for whole CM and individual milk
proteins. Given that the prognostic value of CM sIgE was
and, 9 kUA/L for casein [20]. In another study from Spain,
good and similar to that of component-resolved diagnosis,
Martorell A et al., estimated the optimal CM and casein sIgE
the authors supported the view that the increased laboratory
cut-off points at different time points of follow-up (12, 18,
costs do not justify application of CRD measurements on a
24, 36 and 48 months) [25]. These values corresponded to
daily basis.
2.58, 2.5, 2.7 2.26 and 5 KUA/L for CM sIgE and 0.97, 1.22, 3,
2.39 and 2.73 KUA/L for casein sIgE. In a study from Japan, There is little information on the prognostic role of
casein sIgE > 6.6 KUA/L was associated with prolonged genetic variants on tolerance development in CMPA. Yavuz
CMPA [21]. et al. showed that children with CMPA and the GG genotype
at rs324015 of the STAT6 gene developed tolerance at
When applying cut-off points with 95% positive
significantly later age compared to subjects with AA+AG
predictive values (PPV) in clinical practice, OFCs with a
high probability of being positive could be avoided [57]. genotype, and suggested that STAT6 gene variants may be
important determinants to predict longer persistence of
However, 95% PPV values are of little help in deciding
CMPA [39] .
whether to perform OFC testing in patients with values
below these levels since the negative predictive value (NPV) So far, no firm conclusions regarding the value of CRD
is approximately 50% [25]. This translates into that about and genetic variants in the field of CMPA prognosis could be
half of patients with sIgE levels below the 95% PPV cut-off drawn and their utility in clinical practice remains to be
points will not pass the OFC and would not prove tolerant. In assessed in further studies [59].
estimating the optimal timing of reintroducing milk in the
diet of CM-allergic children, cut-off points with higher NPV Predictive Models for Routine Use
would be more useful.
Despite the absence of a single and reliable biomarker for
The small differences and considerable overlap between CMPA prognosis, predictive models based on a number of
the estimated optimal cut-off values at distinct follow-up
parameters have been proposed and need further validation
time-points observed in different studies, do not seem to
in large prospective cohorts from different geographical
support the utility of their application in daily clinical
areas before routine use in clinical practice.
practice. Thus, special caution is required when applying
such cut-off points to distinct populations. Shek et al., developed a model for predicting the
likelihood of developing tolerance based on the rate of
decrease in CM sIgE levels (over a 12 month period) [29]. A
Molecular and Genetic Markers
grater decrease in sIgE levels over a shorter period of time
Within the challenging concept of molecular diagnosis or was indicative of a greater likelihood of developing
component-resolved diagnosis (CRD) [58], employment of tolerance. For example, in a child with milk allergy below
microarrays including cow’s milk protein allergenic the age of 4 years at the first challenge the probability of
Reintroduction of Cow’s Milk in Milk-Allergic Children Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 1 59

developing tolerance was .31 for a decrease of 50%, .45 for a whose IgE antibodies were directed against those epitopes
decrease of 75%, .66 for a decrease of 90% and .94 for a [17]. Furthermore, a considerable study [47] has reported
decrease of 99% in CM sIgE levels over 12 months. The that individuals with persistent milk allergy possessed higher
application of this model could aid clinicians in providing levels of IgE antibodies directed at specific sequential casein
prognostic information and deciding the right timing of epitopes compared with individuals who achieved tolerance
subsequent reintroduction OFCs. [16, 36, 64].
Wood et al., estimated that approximately 50% of However, published data indicate that heating decreases
children with CMPA will become tolerant by 5 years of age but does not completely eliminate milk allergenicity [65].
[38]. Development of tolerance was strongly associated with The caseins and -lactalbumin have a higher heat stability
lower milk sIgE levels, smaller SPT weal sizes and the than the other whey proteins, -lactoglobulin and serum
absence of severe atopic dermatitis. By using the variables of albumin [66]. Namely, heating of -lactoglobulin results in
baseline sIgE level, SPT weal size and atopic dermatitis the formation of intermolecular disulfide bonds and
severity the researchers developed an algorithm to estimate subsequent binding to other food proteins, making -
the resolution probabilities of CMPA that could be useful in lactoglobulin less allergenic [67]. In addition, casein bands
predicting the natural history of CMPA for individual were preserved in the SDS-PAGE gel even after 120 min of
patients. However, this novel calculator model needs boiling at 100oC. Serum albumin band became progressively
validation in additional studies before general use in the weaker after 10 min of boiling but was still visible at 120
clinical setting. min. In contrast, -lactalbumin band disappeared after 30
min, -lactoglobulin disappeared after 15 min, and
REINTRODUCTION OF HEATED MILK lactoferrin disappeared after 10 min of boiling [42].

The standard of care focuses on strict dietary avoidance


Humoral and Immunological Changes
[5] which is difficult but has been the cornerstone of food
allergy management for decades. The advice is practical From a comprehensive view, introduction of baked
because the amount of allergen necessary to induce an products was associated with increasing levels of milk-
allergic reaction varies [61]and the severity of reactions is specific IgG4 and decreasing milk-specific IgE levels, and
unpredictable [62, 63]. Additionally, there has been the SPT wheal sizes. In particular, a study [47] evaluating the
theory that lack of exposure will result in deletion of effects of heating (time and temperature) on the allergenicity
immunologic memory [46]. Thus, children diagnosed with of casein and whey proteins showed that ingestion of heated
CMPA, were often advised by physicians to stop ingestion of milk products was associated with a statistically significant
baked-milk products despite previous non-reactivity to decrease in SPT wheal size and an increase in casein-IgG4
repeated ingestions of such foods, in the belief that this could levels at 3 months compared with baseline. Decreasing levels
delay the resolution of the allergy [40]. However, it is now of CM sIgE, increasing levels of -lactoglobulinIgG4, and
thought that achievement of tolerance to a heat treated decreasing casein and -lactoglobulin IgE/IgG4 ratios,
protein may be the first step towards “outgrowing” the compared with heated milk–reactive subjects were also
allergy and inducing tolerance [46]. Hence, an alternative noted, although these did not reach statistical significance. In
approach to introducing food protein modified by high addition, the humoral changes observed in the study are in
temperature and by interactions with wheat matrix to the diet line with reports of the effects of oral desensitization to milk
of children with milk and egg allergy has been lately and egg white [41, 43]. These findings further support the
examined. notion that children with CMPA are clinically and
immunologically heterogeneous, and that reactivity to heated
Effect of Heating on Proteins milk proteins is a marker of this heterogeneity.
Aside from the serologic changes noted, studies on
Proteins are three-dimensional molecules held together
by electrostatic charge. Differences in allergenicity are, in basophil reactivity revealed that children who reacted to
baked milk had significantly higher basophil reactivity to
part, due to changes in the structure of the proteins when
stimulation with casein when compared with that seen in
heated, which affect the specific conformational IgE binding
children who tolerated baked milk [68]. In addition, children
sites on the protein molecule. It is recognised that heat
tolerant of baked milk had more regulatory Tcells in the
treatment of a protein can result in conformational changes
peripheral blood at baseline; following introduction of baked
in epitopes by affecting hydrogen bonds within the protein
and, thus, affecting the ability of the IgE molecule to milk protein, the fraction of peripheral T regulatory cells
decreased, suggesting possible migration of these cells to the
bind [45]. Further, food processing can decrease protein
sites of the contact with the dietary antigen (gastrointestinal
allergenicity in several ways including destruction of
tract) [69]. Furthermore, a significantly higher percentage of
predominantly conformational epitopes, with limited effect
proliferating casein-specific CD25/CD271 T-cells (regulatory
on sequential epitopes, and chemical reactions between
T-cells involved in tolerance induction) was observed from
proteins and fat and sugars in the food matrix that account
for limited availability of protein to the immune system [48]. casein-induced peripheral blood mononuclear cell cultures
taken from extensively heated milk-tolerant children
Analysis of IgE-binding epitopes revealed that cow’s compared to those taken from extensively heated milk-
milk and egg-allergic patients who lacked IgE antibodies reactive children. The study showed no significant difference
against certain sequential epitopes of the major allergens between the groups in the frequency of polyclonal T-cells or
were more likely to achieve tolerance compared to subjects casein-specific effector T-cells. However, casein-specific
60 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 1 Nicolaou et al.

regulatory T-cells correlated with the phenotype of having a administering the appropriate diluted dose of the allergen at
mild transient milk allergy and favourable prognosis. Hence, home. The ability to consume baked products also moves the
induction of these regulatory T-cells is critical for the child towards a more normal, less restricted diet. Given the
development or oral tolerance. risk of anaphylaxis in children who react to baked-milk
The above findings suggest that ingestion of heated milk products, addition of such foods should be performed under
the supervision of a physician with expertise in food allergy
is associated with immunologic responses to casein and, -
[46].
lactoglobulin that favor development of tolerance.

SPECIFIC ORAL TOLERANCE INDUCTION (SOTI)


Does it Promote Tolerance?
Specific oral tolerance induction is a promising direction
A recent study demonstrated that tolerance to baked-milk
in food allergy research; however, it is clear that food oral
products is a marker of mild, transient IgE-mediated cow's
immunotherapy may not be possible for some patients due to
milk allergy whereas baked-milk reactivity portends a more
the high rate of adverse reactions and adherence to treatment.
severe, persistent phenotype [46]. Furthermore, 60% of
According to current research data, the immunologic
baked-milk-tolerant children ingesting baked milk products
will develop unheated-milk tolerance at a significantly changes induced by specific oral immunotherapy resemble
those seen during natural development of tolerance [44].
accelerated rate compared to subjects prescribed strict milk
However, the long term effect of OIT approach is largely
avoidance.
unknown. Review of the current knowledge on desensitization
Two studies [47, 70] reported the results from induced by oral immunotherapy will be developed in another
nonrandomized clinical trials in which over 100 children chapter.
allergic to milk and over 100 children allergic to egg were
tested by oral food challenges to baked products that
CONCLUSION
contained milk or egg. In both studies, about 70% of tested
children were able to ingest baked products with milk or egg The natural history of cow’s milk protein allergy is
without any immediate symptoms. Subsequently, results of closely related to the immunological and clinical phenotype
the long-term follow-up of the earlier study group [47] by which CMPA presents and shows considerable
revealed that subjects who incorporated dietary baked-milk heterogeneity between studies of different populations and
were 16 times more likely to become unheated milk-tolerant settings. While the majority of children will outgrow their
compared to the children strictly avoiding milk (Odds Ratio allergy, the individual timing of tolerance acquisition is
2.8, Confidence Interval, 4.8–162.7, P<.001) [46]. Likewise, largely unknown. Clinical parameters and the measurements
in a recent observational study, 32 (20.6%) of the 155 of sIgE levels and SPT wheal sizes to whole CM protein and
children with unresolved allergy, were able to tolerate individual milk protein components may provide some
products containing baked milk at the age of five years. useful prognostic information in the course of CMPA.
However, there are no precise predictors to determine when
Hence, supplementary studies are required to further
and in whom resolution of cow’s milk allergy will occur, and
quantify the immune changes that occur with ingestion of
the decision for the reintroduction of cow’s milk in milk-
heated proteins to enable us to understand if ingestion of
allergic children remains challenging. There is some
heated egg or heated cow’s milk affects the natural history of
egg and cow’s milk allergies when compared with strict evidence to suggest that introduction of heated milk into the
diet of allergic patients may induce the acquisition of
avoidance.
tolerance, but further prospective studies in different
populations are necessary to confirm the utility of this
Advantages of Using Baked Products approach in daily clinical practice. Until further scientific
Inclusion of baked milk in the diet enables many foods evidence is accumulated, regular reevaluation (every 6-
that were previously avoided to be included into the diet, and 12months) of affected individuals is important and controlled
this liberalization results in an improved quality of life for oral food challenge procedure remains the gold standard to
the child with food allergies [71]. It is possible that regular establish the development of tolerance to cow’s milk protein.
inclusion of products containing the baked protein reduces
the risk of reactions, due to accidental exposure to products CONFLICT OF INTEREST
containing milk. Furthermore, this would facilitate the
The author(s) confirm that this article content has no
fulfilment of nutritional requirements, reduce parental
conflict of interest.
anxiety, lessen the child’s discomfort in social situations, and
possibly provide an effective strategy to shorten the time to
achieve tolerance [7, 72]. ACKNOWLEDGEMENTS
Once tolerance to a baked product is proven, subjects are Declared none.
able to include it in their diet on a regular basis. Compared
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Received: 28 August, 2013 Accepted: 17 January, 2014