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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

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

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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
could predict the likelihood of tolerance development would
be extremely useful in daily clinical practice. Thus, OFCs
with a high probability of being positive would be avoided
and only those with an increased probability of being
negative would be carried out to confirm tolerance.
Determining the correct timing of CM reintroduction would
avoid unnecessary family - patient discomfort and reduce
health systems costs [14].
Until recently, reintroduction of CM was attempted when
children with CMPA were more likely to have become
tolerant (outgrown their allergy) [12, 13]. Over the last years,
a different approach in the management of milk and egg
allergy has emerged with oral immunotherapy (OIT) and
specific oral tolerance induction (SOTI) as promising
methods for the treatment of food allergies [40-45].
Furthermore, a number of studies have shown evidence that
reintroduction of heated milk and egg protein in allergic
patients may induce the acquisition of tolerance [46-48].
NATURAL HISTORY OF CMPA
A wide range of CMPA resolution rates (19% to 97%)
has been reported from studies examining the natural history
of CMPA in different countries (Table 1). A number of
earlier studies [9, 49, 50] revealed a good prognosis, whereas
some recent studies [31, 38] figured less optimistic resolution
rates suggesting a change in the natural history of CMPA
over time. Differences in the characteristics of the studied
populations and in the methods followed by different
research groups may account for the observed variability in
reported resolution rates. Unselected population-based studies
[9, 10] tend to give a more favorable prognosis compared
to studies of referral populations [15, 31] with prospective
studies [9, 18, 34] giving usually more accurate results than
studies of retrospective [15, 31] design. Consistently, studies
including only subjects with IgE-mediated CMPA report
lower resolution rates [18, 31].
An early (from the 1990s) unselected prospective
population-based study of Danish children with cow’s milk
protein allergy revealed a very good overall prognosis [50].
Host et al. reported a total recovery rate of 56% at the end of
the first year of life, 77% at 2 years, 87% at 3 years, 92% at
5 years and 97% at 15 years of age [9]. Children with non-
IgE-mediated cow’s milk allergy had a better prognosis
compared to children with IgE-mediated CMPA allergy.
Regarding the prognosis of IgE and non-IgE mediated
CMPA phenotype, similar findings were observed in another
early study from a tertiary referral centre in Australia with
the percentages of tolerance development in children with
non-IgE- and IgE-mediated CMPA at 78% and 57%
respectively [51].
In a Finish prospective study, tolerance to cow’s milk
was developed by 44%, 69% and 77% of children by age 2,
3 and 4 years respectively [34]. At age 2 and 4 years the
proportion of children with non-IgE-mediated CMPA who
became tolerant was significantly higher compared to
children with IgE-mediated CMPA (59% and 93% versus 30
and 59%). In an unselected Finish birth cohort study, 51% of
subjects with CMPA became tolerant by their second
birthday [10]. By the age of 5 years tolerance was developed
in all children with negative CM sIgE compared to 74% in
the group of children with positive CM sIgE. By age 8.6
years 89% of subjects recovered their CMPA. In addition,
children with transient sIgE sensitization recovered earlier.
In Spain, Garcia-Ara. et al., followed prospectively 66
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
Table 2. Factors related to tolerance and persistence of CMPA.
Favor Shorter Duration and Tolerance
Clinical
Non-IgE-mediated
Later age at presentation (e.g. > 1month)
Milder symptoms (e.g. gastrointestinal)
Higher eliciting dose (e.g. > 10 mls)
Tolerance of heated milk
Absent or mild co-morbidities (e.g. asthma, rhinitis, eczema,
and other food allergies)
No family history of atopy
Laboratory
Lower levels of sIgE and/or smaller SPT wheal size to whole and individual
(e.g. casein) CM proteins at diagnosis and follow up measurements
Significant reduction in sIgE levels and/or SPT wheal size over time
Recognition of specific IgE conformational epitopes,
increased binding to IgG4 epitopes
every 6 months up to the age of 2 years and then annually
[20]. Forty-five children (68%) became tolerant over the
study period (9-99 months). In another prospective study
from Spain, 140 (82%) of 170 children with CMPA became
tolerant by age 4 years [25]. In a recent retrospective study
from Germany, 32 out of 52 (61.5%) children with CMPA
became tolerant over the analyzed period (3-142 months)
[15]. In the Milan Cow’s Milk Allergy Cohort Study
(MiCMPAC), 52.7% of children with CMPA became
tolerant by the age of 5 years [19]. The median duration of
CMPA was 23 months, while 23% of children acquired
tolerance 13 months after diagnosis and 75% after 43 months.
In a retrospective review of the clinical records of 807
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
the very low resolution rate of CMPA by age 4, an encouraging
finding of this study is that patients may develop tolerance
in late childhood and adolescence indicating that there is no
age limit of CMPA resolution. One of the most recent
observational studies on the natural history of CMPA in the
USA [38], estimated that approximately 50% of children
with CMPA will become tolerant by 5 years of age.
The variability in resolution rates observed in different
settings and populations does not allow for a universal
estimate regarding the natural history of CMPA at present.
PROGNOSTIC MARKERS FOR TOLERANCE VS.
PERSISTENCE IN CMPA
Several studies have looked into various clinical and
biochemical markers that could be of prognostic value for
Nicolaou et al.
Favor Longer Duration and Persistence
IgE-mediated
Earlier age at presentation (e.g. < 1month)
Severe symptoms (e.g. respiratory)
Lower eliciting dose (e.g. < 10 mls)
Intolerance of heated milk
Present and severe co-morbidities (e.g. asthma, rhinitis,
eczema, and other food allergies)
Family history of atopy
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
Non-significant reduction in sIgE levels and/or SPT wheal size over time
Recognition of specific IgE linear epitopes,
grater sIgE epitope diversity and higher affinity
Multiple sensitizations to other foods (e.g. egg, soy)
and inhalant allergens by sIgE/SPT
the development of tolerance or the persistence of CMPA [9,
15, 17, 18, 20, 26, 27, 29, 31, 33, 34, 39, 46, 52]. Age and
severity of symptoms at presentation, co-morbidities and
atopic profile, levels of allergen specific IgE and SPT wheal
sizes to whole CM and individual cow’s milk allergenic
proteins at diagnosis and follow-up assessments, are amongst
the most commonly examined factors (Table 2). Findings
vary between studies, and unfortunately no single marker has
been consistently found to be predictive of when and in
whom tolerance occurs. Some reasons for the observed
variability in the results from different studies include
different settings and populations, inclusion and diagnostic
criteria, laboratory methods applied and time points of
reassessment and duration of follow up.
Clinical Variables
The immunologic and clinical phenotype by which
CMPA presents appears to have an important role in the
development of tolerance or the persistence of the food
allergy. Children with non-IgE-mediated disease have
consistently been shown to develop tolerance earlier and
more frequently than those with IgE-mediated CMPA [9,
10]. Mild gastrointestinal and skin symptoms at presentation
are generally associated with tolerance, whereas severe
gastrointestinal or respiratory symptoms are often related to
longer duration or persistence of CMPA [18, 31].
The majority of infants diagnosed with mild CMPA
proctocolitis become tolerant before their 1st birthday and
CM is often reintroduced into their diet at the age of 9-12
months without any problems [13, 53]. Children with Milk
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
develop tolerance between their 2nd and 3rd year of life,
whereas many subjects with IgE-mediated type of CMPA
acquire tolerance after the age of 3 years [31, 34]. In the later
two types of CMPA, because of a greater risk of severe
reactions, reintroduction OFCs should be performed in a
hospital setting under the supervision of experienced
personnel [11-14]. After a negative OFC reintroduction
continues at home.
Age and severity of symptoms at 1st reaction, as well as
the amount of milk evoking the reaction may be associated
with the natural course of CMPA. Within the context of a
population-based study from Israel, Elizur et al., followed
prospectively 54 children with IgE-mediated CMPA until the
age of 4-6 years [18]. Thirty-one subjects (57.4%) outgrew
CMPA during the study period with the majority of them
(70.9%) becoming tolerant within the first 2 years. Patients’s
reacting to < 10ml of milk or in the 1st month of life were at
increased risk of not developing tolerance. The age at first
reaction was the strongest predictor of CMPA persistence as
only 30% of infants reacting in < 30 days of life developed
tolerance during the study period. Respiratory symptoms
were associated with persistence of CMPA and
gastrointestinal symptoms with development of tolerance.
Lower DBPCFC threshold dose was also a marker of
longer duration of CMPA in the Milan study (MiCMPAC),
as was co-sensitization to an increased number of inhalant
and ingested allergens and particularly soy [19]. In a
Portuguese study, immediate allergic symptoms, other food
allergies and asthma were independent risk factors for
the persistence of CMPA beyond the age of 2 years [27].
In a Finish study, exposure to CM while in maternity
hospital and development of urticaria at diagnostic challenge
were risk factors for persistent CMPA at age 2 years. Early
sensitization to egg was also a risk factor [10]. In another
Finish study, delayed and gastrointestinal symptoms during
diagnostic OFC favored the development of tolerance by age
4 years [34].
In the study by Skripak et al., coexisting asthma and
allergic rhinitis were significantly associated with a lower
likelihood of developing tolerance even when controlling for
peak CM sIgE [31]. History of other food allergies was also
associated with a worse prognosis, but no association was
observed with the presence of eczema. However, in another
USA study, children with moderate to severe atopic
dermatitis had a hazard ratio of 2 compared to those subjects
having mild or no atopic dermatitis [38].
Skin Prick Tests
Many investigators attempted to correlate CM SPT
results to the outcome of OFC in an effort to identify
simpler, safer, economical and less time-consuming
predictors. Although most studies report a higher probability
of tolerance acquisition in patients with smaller SPT weal
sizes the optimal cut-off points vary in different populations
[10, 19, 32, 34, 35, 38, 55].
In the recent study by Wood et al., subjects with SPT
weal size < 5mm had a 72% chance of developing tolerance
compared to 52% chance for those with SPT between 5-
10mm and 37% chance of those with > 10mm [38]. In the
57
study by Vanto et al., SPT < 5mm at the time of CMPA
diagnosis correctly identified 83 % of children who
developed tolerance and SPT > 5mm 71% of those with
persistent CMPA at age 4 years [34]. In the study by
Saarinen et al., SPT measured at 12- month follow up was
superior in predicting recovery at age 8.6 years compared to
SPT measured at diagnosis [10]. However, more than a third
(38%) of children who became tolerant continued to have a
positive SPT at the time tolerance was acquired with 25% of
them having a wheal size of 8mm which was shown to
always predict persistence of CMPA in another cohort [32].
In a Greek study, pre-challenge SPT < 4mm could correctly
predict a negative challenge outcome, whereas SPT > 7.5mm
had a high probability of positive challenge [35].
In the MiCMPAC study, each 1-mm increment in wheal
diameter at SPT with fresh milk (HR 1.18) and a positive
SPT to soy (HR 6.99) were the only 2 significant associates
of CMPA persistence in the multivariate analysis for
predictors of duration of disease [19]. In another Italian
study, the measurement of end point prick test (EPT) with
raw milk was suggested as a useful predictor of OFC
outcome [55]. EPT consists of seven progressive dilutions
(1/10-1/10.000.000) of fresh CM (30mg/ml) with saline
solution. EPT with the 4th dilution (1/10.0000) had the best
ratio between positive and negative predictive values (86%
and 91% respectively) and could be used to discriminate
tolerant from non-tolerant subjects.
The above findings suggest that there is no optimal SPT
cut-off value that could accurately predict the timing of
tolerance acquisition on an individual basis and that would
be applicable in every setting or population. However, an
observed reduction in SPT size in the periodic re-evaluation
of a patient with CMPA may be associated with increased
probability of passing a reintroduction OFC.
Measurements of sIgE
Measurement of milk sIgE is widely available and a
useful tool in the evaluation of patients with CMPA. A
number of studies reported that in patients who outgrew their
milk allergy the levels of whole CM sIgE and individual
milk proteins were initially lower and decreased significantly
with time compared to patients who retained their clinical
sensitivity [10, 19, 27, 29, 34, 38]. Whether quantification
and monitoring of sIgE levels to CM allergenic proteins
could be used as a reliable predictor for determining when
patients with CMPA would develop clinical tolerance has
always been a challenging question given that sIgE values
were shown to be age-dependent and higher in patients with
atopic dermatitis[29, 56].
Skripak J, et al., identified CM IgE level as the most
significant and probably clinically useful marker in
predicting the resolution of CMPA [31]. By using each
patient’s highest CM sIgE level the researchers found that a
higher peak was significantly associated with a reduced
chance of developing tolerance. Children with peak CM
sIgE levels less than 5kUA/L had the best prognosis and
those with peak CM sIgE levels > 20 kU/l the worst
prognosis. As an example, by the age of 4years 57% of those
with a peak CM sIgE level < 2kUA/l became tolerant,
58 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 1
whereas significantly lower resolution percentages of 37%,
20%, 8%, 3%, and <1% were observed for those subjects
with peak CM sIgE levels in the range of 2 to 4.9 kU/l, 5 to
9.9 kU/l, 10 to 19.9 kUA/l, 20 to 49.9 kU/l, and greater than
50kUA/l respectively.
In a Finish study, 82% of subjects with CM sIgE < 2kU/l
developed tolerance whereas 71% of those with sIgE > 2kU/l
did not outgrow CMPA at age 4 years [34]. In the study by
Wood et al., a subject with level of sIgE < 2kUA/L had a
72% chance of developing tolerance compared to 52% chance
for those with sIgE between 2-10 UA/L and 23% chance for
those with sIgE > than 10 kUA/L [38]. Vassilopoulou et al.,
reported that a pre-challenge CM-sIgE < 3.94 KUA/L could
correctly predict a negative challenge outcome [35]. Ahrens
B. et al., reported that in children with an early resolution of
CMPA the levels of CM sIgE levels where lower at
diagnosis. Children with CM sIgE < 5kUA/L (the median
observed in the study) were four times more likely to
become tolerant compared to those children with levels
higher than 5kUA/L [15]. Using Kaplan-Meier calculation,
they estimated that if the CM sIgE was lower than 5kUA/L
the half-life tolerance time (the time after 50% of subjects
became tolerant) was 18 months, whereas if it was > 5kUA/L
the half-time tolerance was 33 months.
In a Spanish study, sIgE cut-off points that predicted
clinical reactivity with an accuracy of > 95% (corresponding
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
and, 9 kUA/L for casein [20]. In another study from Spain,
Martorell A et al., estimated the optimal CM and casein sIgE
cut-off points at different time points of follow-up (12, 18,
24, 36 and 48 months) [25]. These values corresponded to
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,
casein sIgE > 6.6 KUA/L was associated with prolonged
CMPA [21].
When applying cut-off points with 95% positive
predictive values (PPV) in clinical practice, OFCs with a
high probability of being positive could be avoided [57].
However, 95% PPV values are of little help in deciding
whether to perform OFC testing in patients with values
below these levels since the negative predictive value (NPV)
is approximately 50% [25]. This translates into that about
half of patients with sIgE levels below the 95% PPV cut-off
points will not pass the OFC and would not prove tolerant. In
estimating the optimal timing of reintroducing milk in the
diet of CM-allergic children, cut-off points with higher NPV
would be more useful.
The small differences and considerable overlap between
the estimated optimal cut-off values at distinct follow-up
time-points observed in different studies, do not seem to
support the utility of their application in daily clinical
practice. Thus, special caution is required when applying
such cut-off points to distinct populations.
Molecular and Genetic Markers
Within the challenging concept of molecular diagnosis or
component-resolved diagnosis (CRD) [58], employment of
microarrays including cow’s milk protein allergenic
Nicolaou et al.
components or synthetic epitopes, could determine a detailed
analysis of a patient’s sensitization (antibody recognition)
profile and facilitate more accurate diagnostic and prognostic
tools in CMPA [59]. In this view, a few studies demonstrated
significant differences in the IgE and IgG epitope-binding
pattern between subjects who developed tolerance and those
with persistent CMPA [36, 37, 52, 60]. The recognition of
IgE specific sequential (linear) as opposed to conformational
epitopes, and particularly to casein fractions was associated
with persisting disease [36, 60]. In addition, greater IgE
epitope diversity and higher affinity was observed in
children who did not develop tolerance [37].
Savilahti et al., observed that in subjects with CMPA
who recovered early the intensity of IgE epitope-binding was
decreased and IgG4 epitope-binding increased over time.
Based on their findings, they stated that IgE and IgG4
binding patterns to a panel of
s1-,
s2-, - and -casein
regions could aid outcome prediction with significant
accuracy [28]. Recently, Ahrens et al., demonstrated by
microarray analysis that the individual likelihood of
outgrowing CMPA is significantly associated with a low
level of sIgE to
-lactalbumin, -lactoglobulin, -casein and

s1-casein [15]. There was no significant correlation with
sIgE levels of total casein, lactoferin, -casein and -
lactalbumin. In addition, they did not observe any significant
differences between children who developed tolerance and
those with persistent disease from the detection of CM
specific IgG or IgG4 for whole CM and individual milk
proteins. Given that the prognostic value of CM sIgE was
good and similar to that of component-resolved diagnosis,
the authors supported the view that the increased laboratory
costs do not justify application of CRD measurements on a
daily basis.
There is little information on the prognostic role of
genetic variants on tolerance development in CMPA. Yavuz
et al. showed that children with CMPA and the GG genotype
at rs324015 of the STAT6 gene developed tolerance at
significantly later age compared to subjects with AA+AG
genotype, and suggested that STAT6 gene variants may be
important determinants to predict longer persistence of
CMPA [39] .
So far, no firm conclusions regarding the value of CRD
and genetic variants in the field of CMPA prognosis could be
drawn and their utility in clinical practice remains to be
assessed in further studies [59].
Predictive Models for Routine Use
Despite the absence of a single and reliable biomarker for
CMPA prognosis, predictive models based on a number of
parameters have been proposed and need further validation
in large prospective cohorts from different geographical
areas before routine use in clinical practice.
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
grater decrease in sIgE levels over a shorter period of time
was indicative of a greater likelihood of developing
tolerance. For example, in a child with milk allergy below
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
developing tolerance was .31 for a decrease of 50%, .45 for a
decrease of 75%, .66 for a decrease of 90% and .94 for a
decrease of 99% in CM sIgE levels over 12 months. The
application of this model could aid clinicians in providing
prognostic information and deciding the right timing of
subsequent reintroduction OFCs.
Wood et al., estimated that approximately 50% of
children with CMPA will become tolerant by 5 years of age
[38]. Development of tolerance was strongly associated with
lower milk sIgE levels, smaller SPT weal sizes and the
absence of severe atopic dermatitis. By using the variables of
baseline sIgE level, SPT weal size and atopic dermatitis
severity the researchers developed an algorithm to estimate
the resolution probabilities of CMPA that could be useful in
predicting the natural history of CMPA for individual
patients. However, this novel calculator model needs
validation in additional studies before general use in the
clinical setting.
REINTRODUCTION OF HEATED MILK
The standard of care focuses on strict dietary avoidance
[5] which is difficult but has been the cornerstone of food
allergy management for decades. The advice is practical
because the amount of allergen necessary to induce an
allergic reaction varies [61]and the severity of reactions is
unpredictable [62, 63]. Additionally, there has been the
theory that lack of exposure will result in deletion of
immunologic memory [46]. Thus, children diagnosed with
CMPA, were often advised by physicians to stop ingestion of
baked-milk products despite previous non-reactivity to
repeated ingestions of such foods, in the belief that this could
delay the resolution of the allergy [40]. However, it is now
thought that achievement of tolerance to a heat treated
protein may be the first step towards “outgrowing” the
allergy and inducing tolerance [46]. Hence, an alternative
approach to introducing food protein modified by high
temperature and by interactions with wheat matrix to the diet
of children with milk and egg allergy has been lately
examined.
Effect of Heating on Proteins
Proteins are three-dimensional molecules held together
by electrostatic charge. Differences in allergenicity are, in
part, due to changes in the structure of the proteins when
heated, which affect the specific conformational IgE binding
sites on the protein molecule. It is recognised that heat
treatment of a protein can result in conformational changes
in epitopes by affecting hydrogen bonds within the protein
and, thus, affecting the ability of the IgE molecule to
bind [45]. Further, food processing can decrease protein
allergenicity in several ways including destruction of
predominantly conformational epitopes, with limited effect
on sequential epitopes, and chemical reactions between
proteins and fat and sugars in the food matrix that account
for limited availability of protein to the immune system [48].
Analysis of IgE-binding epitopes revealed that cow’s
milk and egg-allergic patients who lacked IgE antibodies
against certain sequential epitopes of the major allergens
were more likely to achieve tolerance compared to subjects
59
whose IgE antibodies were directed against those epitopes
[17]. Furthermore, a considerable study [47] has reported
that individuals with persistent milk allergy possessed higher
levels of IgE antibodies directed at specific sequential casein
epitopes compared with individuals who achieved tolerance
[16, 36, 64].
However, published data indicate that heating decreases
but does not completely eliminate milk allergenicity [65].
The caseins and
-lactalbumin have a higher heat stability
than the other whey proteins, -lactoglobulin and serum
albumin [66]. Namely, heating of -lactoglobulin results in
the formation of intermolecular disulfide bonds and
subsequent binding to other food proteins, making -
lactoglobulin less allergenic [67]. In addition, casein bands
were preserved in the SDS-PAGE gel even after 120 min of
boiling at 100oC. Serum albumin band became progressively
weaker after 10 min of boiling but was still visible at 120
min. In contrast,
-lactalbumin band disappeared after 30
min, -lactoglobulin disappeared after 15 min, and
lactoferrin disappeared after 10 min of boiling [42].
Humoral and Immunological Changes
From a comprehensive view, introduction of baked
products was associated with increasing levels of milk-
specific IgG4 and decreasing milk-specific IgE levels, and
SPT wheal sizes. In particular, a study [47] evaluating the
effects of heating (time and temperature) on the allergenicity
of casein and whey proteins showed that ingestion of heated
milk products was associated with a statistically significant
decrease in SPT wheal size and an increase in casein-IgG4
levels at 3 months compared with baseline. Decreasing levels
of CM sIgE, increasing levels of -lactoglobulinIgG4, and
decreasing casein and -lactoglobulin IgE/IgG4 ratios,
compared with heated milk–reactive subjects were also
noted, although these did not reach statistical significance. In
addition, the humoral changes observed in the study are in
line with reports of the effects of oral desensitization to milk
and egg white [41, 43]. These findings further support the
notion that children with CMPA are clinically and
immunologically heterogeneous, and that reactivity to heated
milk proteins is a marker of this heterogeneity.
Aside from the serologic changes noted, studies on
basophil reactivity revealed that children who reacted to
baked milk had significantly higher basophil reactivity to
stimulation with casein when compared with that seen in
children who tolerated baked milk [68]. In addition, children
tolerant of baked milk had more regulatory Tcells in the
peripheral blood at baseline; following introduction of baked
milk protein, the fraction of peripheral T regulatory cells
decreased, suggesting possible migration of these cells to the
sites of the contact with the dietary antigen (gastrointestinal
tract) [69]. Furthermore, a significantly higher percentage of
proliferating casein-specific CD25/CD271 T-cells (regulatory
T-cells involved in tolerance induction) was observed from
casein-induced peripheral blood mononuclear cell cultures
taken from extensively heated milk-tolerant children
compared to those taken from extensively heated milk-
reactive children. The study showed no significant difference
between the groups in the frequency of polyclonal T-cells or
casein-specific effector T-cells. However, casein-specific
60 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 1
regulatory T-cells correlated with the phenotype of having a
mild transient milk allergy and favourable prognosis. Hence,
induction of these regulatory T-cells is critical for the
development or oral tolerance.
The above findings suggest that ingestion of heated milk
is associated with immunologic responses to casein and,
-
lactoglobulin that favor development of tolerance.
Does it Promote Tolerance?
A recent study demonstrated that tolerance to baked-milk
products is a marker of mild, transient IgE-mediated cow's
milk allergy whereas baked-milk reactivity portends a more
severe, persistent phenotype [46]. Furthermore, 60% of
baked-milk-tolerant children ingesting baked milk products
will develop unheated-milk tolerance at a significantly
accelerated rate compared to subjects prescribed strict milk
avoidance.
Two studies [47, 70] reported the results from
nonrandomized clinical trials in which over 100 children
allergic to milk and over 100 children allergic to egg were
tested by oral food challenges to baked products that
contained milk or egg. In both studies, about 70% of tested
children were able to ingest baked products with milk or egg
without any immediate symptoms. Subsequently, results of
the long-term follow-up of the earlier study group [47]
revealed that subjects who incorporated dietary baked-milk
were 16 times more likely to become unheated milk-tolerant
compared to the children strictly avoiding milk (Odds Ratio
2.8, Confidence Interval, 4.8–162.7, P<.001) [46]. Likewise,
in a recent observational study, 32 (20.6%) of the 155
children with unresolved allergy, were able to tolerate
products containing baked milk at the age of five years.
Hence, supplementary studies are required to further
quantify the immune changes that occur with ingestion of
heated proteins to enable us to understand if ingestion of
heated egg or heated cow’s milk affects the natural history of
egg and cow’s milk allergies when compared with strict
avoidance.
Advantages of Using Baked Products
Inclusion of baked milk in the diet enables many foods
that were previously avoided to be included into the diet, and
this liberalization results in an improved quality of life for
the child with food allergies [71]. It is possible that regular
inclusion of products containing the baked protein reduces
the risk of reactions, due to accidental exposure to products
containing milk. Furthermore, this would facilitate the
fulfilment of nutritional requirements, reduce parental
anxiety, lessen the child’s discomfort in social situations, and
possibly provide an effective strategy to shorten the time to
achieve tolerance [7, 72].
Once tolerance to a baked product is proven, subjects are
able to include it in their diet on a regular basis. Compared
with traditional SOTI protocols, this means that there is less
cost in terms of hospital admission times and inconvenience
to the family, as there is no intense “up dosing” phase
required. This approach is potentially safer compared
with protocols, which rely on parents making up and
Nicolaou et al.
administering the appropriate diluted dose of the allergen at
home. The ability to consume baked products also moves the
child towards a more normal, less restricted diet. Given the
risk of anaphylaxis in children who react to baked-milk
products, addition of such foods should be performed under
the supervision of a physician with expertise in food allergy
[46].
SPECIFIC ORAL TOLERANCE INDUCTION (SOTI)
Specific oral tolerance induction is a promising direction
in food allergy research; however, it is clear that food oral
immunotherapy may not be possible for some patients due to
the high rate of adverse reactions and adherence to treatment.
According to current research data, the immunologic
changes induced by specific oral immunotherapy resemble
those seen during natural development of tolerance [44].
However, the long term effect of OIT approach is largely
unknown. Review of the current knowledge on desensitization
induced by oral immunotherapy will be developed in another
chapter.
CONCLUSION
The natural history of cow’s milk protein allergy is
closely related to the immunological and clinical phenotype
by which CMPA presents and shows considerable
heterogeneity between studies of different populations and
settings. While the majority of children will outgrow their
allergy, the individual timing of tolerance acquisition is
largely unknown. Clinical parameters and the measurements
of sIgE levels and SPT wheal sizes to whole CM protein and
individual milk protein components may provide some
useful prognostic information in the course of CMPA.
However, there are no precise predictors to determine when
and in whom resolution of cow’s milk allergy will occur, and
the decision for the reintroduction of cow’s milk in milk-
allergic children remains challenging. There is some
evidence to suggest that introduction of heated milk into the
diet of allergic patients may induce the acquisition of
tolerance, but further prospective studies in different
populations are necessary to confirm the utility of this
approach in daily clinical practice. Until further scientific
evidence is accumulated, regular reevaluation (every 6-
12months) of affected individuals is important and controlled
oral food challenge procedure remains the gold standard to
establish the development of tolerance to cow’s milk protein.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
Declared none.
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