The predictive value of specific immunoglobulin E on the outcome of milk allergy.
ABSTRACT Cow's milk allergy is the most prevalent food hypersensitivity, affecting 2-3% of infants, but it tends to resolve with age. Cow's milk-specific immunoglobulin E in the serum is an important measure in the diagnosis and follow-up of infants and children with cow's milk allergy.
To examine the relation between CmsIgE and the probability of resolution of milk allergy.
CMsIgE was determined in the serum of 1800 infants and children referred for the evaluation of possible milk allergy. All children with CmslgE of 1 kU/L or above were followed at the allergy clinic and, according to their condition, underwent milk challenge. The diagnosis of cow's milk allergy was made on the basis of a significant and specific history or a positive oral food challenge. Subsequently, oral tolerance was defined as an uneventful oral challenge.
A total of 135 infants and children had milk-specific IgE greater than 1 kU/L. Forty-one percent of children still had clinical milk allergy after the age of 3 years. Sixty-eight percent of children older than 3 years with persistence of cow's milk allergy had milk-specific IgE > 3 IU/ml before the age of 1 year. Furthermore, 70% of children who at 3 years old had resolved their cow's milk allergy had milk-specific IgE that was lower than 3 IU/ml before the age of 1 year. The positive predictive value of CmsIgE > 3 IU/ml to persistent cow's milk allergy at age 3 years was 82.6% (P = 0.001), with a sensitivity of 67.9% and specificity of 70.4%.
Milk-specific IgE concentration in the first year of life can serve as a predictor of the persistence of milk allergy.
- [show abstract] [hide abstract]
ABSTRACT: IgE-mediated cow's milk proteins (CMPs) allergy shows a tendency to disappear with age. The sooner tolerance is detected, the earlier the substitute diets can be suspended and the quicker family emotional hardship is alleviated. To analyse the specific IgE levels to cow's milk and its proteins, which help to separate tolerant from no tolerant children in the follow-up of infants with allergy to cow's milk. Sixty-six infants diagnosed with IgE-mediated allergy to CMPs were included in this prospective follow-up study. Periodic reassessments were carried out every 6 months until they were 2-years old and then, annually, until tolerance arose or until the last reassessment in which tolerance had not been achieved. Non-tolerant infants were followed, at least, for a period of 3 years. In each visit, the same skin tests and determination of specific IgE (CAP System FEIA) for milk and its proteins were carried out. The open challenge test was repeated unless a clear transgression to milk, which came to be positive, had taken place within the previous 3 months in each of the follow-up visits. Specific IgE levels to milk and its proteins, in different moments of the follow-up were analysed by means of the receiver-operating characteristic curve to predict clinical reactivity. Throughout the follow-up 45 (68%) infants became tolerant. The follow-up mean for tolerant infants was 21.2 months whereas for non-tolerant infants it was 58 months. The specific IgE levels which were predictors of the clinical reactivity (positive predictive value (PPV)> or =90%), grew as the age of the infants increased: 1.5, 6 and 14 kU(A)/L for milk in the age range 13-18 and 19-24 months and in the third year, respectively. Specific IgE levels to casein: 0.6, 3 and 5 kU(A)/L, respectively, predicted clinical reactivity (PPV> or =90%) in the different analysed moments of the follow-up. The cut-off points: 2.7, 9 and 24 kU(A)/L for milk and 2, 4.2 and 9 kU(A)/L for casein, respectively, predicted clinical reactivity with an accuracy > or =95% corresponding to a specificity of 90%. Monitorization of specific IgE concentration for milk and casein by means of the CAP system in allergic children to CMPs allows us to predict, to a high degree of probability, clinical reactivity. Age factor must be taken into account to evaluate the specific IgE levels which are predictors of tolerance or clinical reactivity.Clinical & Experimental Allergy 06/2004; 34(6):866-70. · 4.79 Impact Factor
- Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2009; 123(2).
- Clinical course of cow's milk protein allergy/intoler-ance and atopic diseases in childhood. 23-8..
M. Rottem et al.
• Vol 10 • December 2008
Cow's milk allergy is the most prevalent of all food allergies and
affects 2–3% of infants worldwide. Immunoglobulin E-mediated
cow's milk allergy tends in most cases to disappear with age
[1,2]. The sooner tolerance is ascertained the earlier children
can enjoy a normal and unrestricted diet. This has substantial
importance for the normal growth and development of infants
and children and in alleviating the emotional burden of their
Oral food challenge is the gold standard for the diagnosis of
clinical food allergy and is also crucial in determining whether
the allergy has been resolved. Advising the parents of children
with known food allergy when to perform a repeat challenge is
a critical step in the follow-up of these children. Determination
of food-specific IgE levels in the serum has proved helpful,
but the exact cutoff levels are still a matter of debate. Yet,
milk-specific IgE is one of the most important measures in
the diagnosis and in the follow-up of infants and children with
food allergy [3-7]. Children with a history of food allergy are
also at greater risk of having other atopic diseases, including
asthma and rhinitis . The aim of the present study was to
examine the relation between milk-specific IgE levels in the
serum and the probability of resolution of milk allergy, as well
as the effect of other allergic conditions on the development
of such tolerance.
Subjects and Methods
All tests performed for milk-specific IgE between the years 1994
and 2006 at the immunology laboratory of HaEmek Medical
Center for children suspected of having cow's milk allergy were
seen by the pediatric allergy unit staff. The serum samples were
sent by the primary physicians in the community for infants and
children they suspected might have milk allergy. The laboratory
serves as the main immunology laboratory for the northern region
of Israel. Milk-specific IgE was assessed by the Immulite enzyme-
linked immunosorbent assay system and included total milk IgE
as well as specific IgE towards the different milk components
including alpha-lactalbuin, beta-lactoglobulin, and casein. The
detection level for milk-IgE was an IgE level higher than 0.35
kU/L. All children with cow’s milk-specific IgE of 1 kU/l or above
were brought in, examined, followed at the allergy clinic and,
depending on their condition, underwent a challenge test with
milk. The cutoff point chosen was 1 kU/L because clinical milk
allergy is extremely low at lower levels [2,5]
Data collected included gender, other allergies and atopic
conditions, family history of atopy, age at onset of symptoms, age
and symptoms with accidental exposures to milk, the reported
outcomes when milk was introduced at home, and the outcomes
of other food allergies.
The diagnosis of cow's milk allergy was made on the basis of
a history of symptoms clearly associated with exposure to milk
or a positive oral food challenge. Oral tolerance was defined as
an uneventful oral challenge in the clinic or successful home
introduction. The primary outcome of interest was acquisition
of oral tolerance. Patients who were not likely to have acquired
tolerance, on the basis of either a history of recent reactions or
elevated milk-specific IgE levels, typically did not undergo oral
challenges but continued follow-up. Diagnoses of other allergic
Background: Cow's milk allergy is the most prevalent food
hypersensitivity, affecting 2–3% of infants, but it tends to resolve
with age. Cow’s milk-specific immunoglobulin E in the serum is an
important measure in the diagnosis and follow-up of infants and
children with cow's milk allergy.
Objectives: To examine the relation between CmsIgE and the
probability of resolution of milk allergy.
Methods: CMsIgE was determined in the serum of 1800
infants and children referred for the evaluation of possible milk
allergy. All children with CmsIgE of 1 kU/L or above were followed
at the allergy clinic and, according to their condition, underwent
milk challenge. The diagnosis of cow's milk allergy was made on
the basis of a significant and specific history or a positive oral
food challenge. Subsequently, oral tolerance was defined as an
uneventful oral challenge.
Results: A total of 135 infants and children had milk-specific
IgE greater than 1 kU/L. Forty-one percent of children still had
clinical milk allergy after the age of 3 years. Sixty-eight percent of
children older than 3 years with persistence of cow's milk allergy had
milk-specific IgE > 3 IU/ml before the age of 1 year. Furthermore,
70% of children who at 3 years old had resolved their cow's milk
allergy had milk-specific IgE that was lower than 3 IU/ml before the
age of 1 year. The positive predictive value of CmsIgE > 3 IU/ml to
persistent cow's milk allergy at age 3 years was 82.6% (P = 0.001),
with a sensitivity of 67.9% and specificity of 70.4%.
Conclusions: Milk-specific IgE concentration in the first year of
life can serve as a predictor of the persistence of milk allergy.
The Predictive Value of Specific Immunoglobulin E on the Outcome
of Milk Allergy
Menachem Rottem MD1,2, Daniela Shostak BSc1 and Sylvia Foldi MD1
1Allergy Asthma and Immunology Service, HaEmek Medical Center, Afula, and 2Rappaport Faculty of Medicine,
Technion-Israel Institute of Technology, Haifa, Israel
Key words: milk allergy, immunoglobulin E, asthma, atopic dermatitis, food allergy
CmsIgE = cow’s milk-specific immunoglobulin E
Allergy and Clinical Immunology
• Vol 10 • December 2008
Milk-Specific IgE and Outcome of Milk Allergy
conditions such as atopic dermatitis, asthma and rhinitis were
based on history and clinical evaluation.
Analysis was performed using SPSS version 14. Association
between the groups of children with and without clinical milk
allergy in relation to age and in comparison to their IgE level
and other clinical allergic conditions was performed by chi-square
test. Multivariate logistic regression was used to predict clinical
sensitivity in relation to age together with odds ratio, relative risk
and 95% confidence intervals.
Milk-specific IgE was determined in the serum of 1800 infants
and children aged 0–18 years referred for the evaluation of pos-
sible milk allergy by their primary physicians in the community.
The majority of children were first referred at less than 1 year of
age: Mean age at first evaluation was 10.5 months (range 5 weeks
to 11 years). Of these, 135 infants and children had milk-specific
IgE greater than 1 kU/L; 89 (66%) were males, 105 (78%) were
Jewish and 30 (22%) were Arab, similar to their distribution in
the general population in the area. Of the 135 enrolled children,
83 (62%) were over 3 years old and 52 (38%) were under 3 years
old when the study was terminated. The relation of elevated
milk IgE, age and clinical milk allergy is presented in Table 1.
As shown, 42% of children older than 3 years still had clinical
Of the 56 children with persistent clinical milk allergy over
the age of 3 years, 38 (68%) had had milk-specific IgE > 3 IU/
ml in their first year of life. In 19 (70%) of 27 children who had
lost their clinical milk allergy before age 3, milk-specific IgE was
< 3 IU/ml at or before the age of 1 year. Thus, milk-specific IgE
concentration higher than 3 IU/ml in the first year of life carries a
risk ratio of 1.69 (95% confidence level 1.19–2.43) of milk allergy
at age 3 years and above (P = 0.001) compared to milk-specific
IgE concentration of less than 3 IU/ml. The positive predictive
value was 82.6% (P = 0.001). The sensitivity of this level is 67.9%
and the specificity 70.4%. Seven (5%) of the 135 children had IgE
above 100 IU/ml before 1 year of age, which was, as expected,
clinically significant in all and had not resolved by age 3.
We next examined the correlation of milk allergy to other
allergic phenomena [Table 2]. Persistent cow’s milk allergy above
the age of 3 years significantly correlated to the presence of
other food allergies, urticaria and asthma, but not to atopic
dermatitis (P = 0.01, P = 0.02, P = 0.02, P = 0.48, respectively)
[Table 3]. The positive predictive values were 93.8%, 89.5%, and
Only two children had anaphylactic reaction to milk, and
therefore no statistical correlation could be drawn in relation to
anaphylaxis in this study.
The prevalence of milk allergy in industrial countries is 1.9–5.2%
in children under the age of 3 years, and tends to resolve with
age in most children . The ability to predict the course of
milk allergy in a specific child is important for both the parents
and the physician and determines the necessity of subjecting
the child to repeated tests and oral milk challenges. In this work
we tried to analyze whether milk-specific IgE can be helpful in
such prediction, by examining if the persistence of milk allergy
is related to the initial CMIgE in the first year of life. In addition,
we examined the relation of milk-specific IgE concentrations to
other allergic phenomena. Food allergy was diagnosed by specific
IgE and either a clear convincing history or food challenges.
A poor prognosis for milk allergy has been related to genetic
and environmental factors such as male gender, non-Caucasian
origin, asthma and smoking at home . In this study we did
not find differences related to gender or to Jewish compared to
Arab origin. Milk allergy has been associated with other allergic
manifestations, and about 30% of milk-allergic children have
atopic dermatitis . The presence of atopic dermatitis does
not apparently affect the predictive accuracy of IgE concentrations
in relation to the outcome of milk challenges . In this study
51% of children suffered from atopic dermatitis, but there was no
correlation to the milk-specific IgE concentration. However, we
found a highly significant correlation of CMsIgE level with the
presence of additional diagnoses of urticaria and asthma and to
other food allergies.
In recent years several studies have examined the possibility
of using serial or special serum CMsIgE levels for decreasing
or even avoiding the need for the complex oral challenge tests,
while keeping the predictive values intact [3,4,6,13]. However,
there is no full agreement on the validity of this approach .
Table 1. Milk allergy in relation to age in infants and children with milk-
specific IgE > 1 IU/ml
Age (yrs)Milk allergy
> 356 (42%)27 (20%) 83 (62%)
< 341 (30%)11 (8%)52 (38%)
Total97 (72%) 38 (28%)135 (100%)
Table 2. Milk allergy and other conditions
Atopic dermatitis 69 (51)
Gastrointestinal symptoms 31 (23)
Allergic rhinitis 17 (13)
Table 3. Milk allergy and other allergic phenomena
Other food allergies 26.896.30.011.5393.8%
Urticaria 76.848 0.021.47 89.5%
Asthma 30.4 92.60.02 1.5 75.4%
Allergy and Clinical Immunology
Our work adds to the current knowledge by showing the predic-
tive value of milk-specific concentrations in children under the
age of 1 year on the outcome of milk allergy after the age of
3 years. While our results and those of others show that milk-
specific IgE concentrations are a useful predictor of challenge
outcome in patients with milk allergy  as a group, challenge
tests under specialist medical supervision are still necessary,
because the sensitivity and specificity of milk-specific IgE do not
yet allow unequivocal prediction in individual cases
Milk-specific IgE concentration in the first year of life can serve
as a predictor of the persistence of milk allergy in children.
However, their predictive value is such that oral challenges, safely
performed by an allergy specialist, remain the gold standard in
the diagnosis of food allergy and food allergy resolution.
Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of 1.
IgE-mediated cow's milk allergy. J Allergy Clin Immunol 2007;120(5):
Sampson HA. Update on food allergy. 2.
Perry TT, Matsui EC, Conover-Walker MK, Wood RA. The rela-3.
tionship of allergen-specific IgE levels and oral food challenge
outcome. J Allergy Clin Immunol 2004;114(1):127–30.
García-Ara MC, Boyano-Martínez MT, Díaz-Pena JM, Martín-Muñoz 4.
MF, Martín-Esteban M. Cow's milk-specific immunoglobulin E
levels as predictors of clinical reactivity in the follow-up of the
cow's milk allergy infants. Clin Exp Allergy 2004;34(6):866–70.
Miceli Sopo S, Radzik D, Calvani M. The predictive value of 5.
J Allergy Clin Immunol 2004;
specific immunoglobulin E levels for the first diagnosis of cow's
milk allergy. A critical analysis of pediatric literature. Pediatr
Allergy Immunol 2007;18(7):575–82.
Celik-Bilgili S, Mehl A, Verstege A, et al. The predictive value of
specific immunoglobulin E levels in serum for the outcome of
oral food challenges. Clin Exp Allergy 2005;35:268–73.
Saarinen KM, Pelkonen AS, Mäkelä MJ, Savilahti E. Clinical
course and prognosis of cow's milk allergy are dependent on
milk-specific IgE status. J Allergy Clin Immunol 2005;116(4):869–75.
Høst A, Halken S, Jacobsen HP, Christensen AE, Herskind AM,
Plesner K. Clinical course of cow's milk protein allergy/intoler-
ance and atopic diseases in childhood. Pediatr Allergy Immunol
Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of
IgE-mediated cow's milk allergy. J Allergy Clin Immunol 2007;120(5):
Tikkanen S, Kokkonen J, Juntti H, Niinimäki A. Status of chil-
dren with cow’s milk allergy in infancy by 10 years of age. Acta
Casimir GJ, Duchateau J, Gossart B, Cuvelier P, Vandaele F, Vis
HL. Atopic dermatitis: role of food and house dust mite aller-
gens. Pediatrics 1993;92:252–6.
Vassilopoulou E, Konstantinou G, Kassimos D, et al. Reintroduc-
tion of cow's milk in milk-allergic children: safety and risk fac-
tors. Int Arch Allergy Immunol 2008;146(2):156–61.
Niggemann B, Celik-Bilgili S, Ziegert M, Reibel S, Sommerfeld C,
Wahn U. Specific IgE levels do not indicate persistence or tran-
sience of food allergy in children with atopic dermatitis. J Invest
Allergol Clin Immunol 2004;14(2):98–103.
Correspondence: Dr. M. Rottem, Head, Allergy Asthma and Immu-
nology, HaEmek Medical Center, Afula 18101, Israel.
Phone: (972-4) 000-0000; Fax: (972-4) 641-5080
Allergy and Clinical Immunology