The natural history of cow's milk allergy in north-eastern Poland

PurposeThe rate of cow's milk allergy diminishes with age. There is not enough information concerning geographical trends in persistent cow's milk allergy in children. The objective of the study was to evaluate the prevalence of persistent cow's milk allergy in children previously diagnosed with IgE-mediated cow's milk allergy (CMA).Material/MethodsDiagnosis of cow's milk allergy was established by a medical history of symptoms associated with exposure to cow's milk, positive skin prick tests with cow's milk, the presence of milk-specific IgE, and by a positive double- or single-blind placebo-controlled food challenge with milk confirmed by a positive open-controlled milk challenge. A second oral challenge was performed after at least one year of a milk-free diet and children with a positive oral milk re-challenge were diagnosed as having a persistent CMA.ResultsTwo hundred ninety-one children, 2–14 years of age (mean 5.30±3.16 years, 95% CI, 5.02-5.62 years) completed the study. Persistent CMA was diagnosed in 79 patients (27.1%). Two hundred twelve children (72.9%) outgrew their allergy to cow's milk at a mean age of 5 years after an average time of 16.4±0.8 months on an elimination diet. Eighty percent of children below 3 years of age became milk tolerant. Milk-specific IgE (p=0.018) and history of paternal bronchial asthma and/or rhinitis (p=0.020) were associated with persistence of cow's milk allergy in regression analysis.ConclusionsAn age above 3 years, as well as features of atopy, individual and familial, may be associated with a risk of delayed tolerance to milk in children.     

Diagnostic Decision Points of Specific IgE Concentrations in Korean Children With Egg and Cow's Milk Allergies

Purpose

The purpose of this study was to evaluate the utility of specific IgE (sIgE) concentrations for the diagnosis of immediate-type egg and cow''s milk (CM) allergies in Korean children and to determine the optimal cutoff levels.

Methods

In this prospective study, children ≥12 months of age with suspected egg or CM allergy were enrolled. Food allergy was diagnosed by an open oral food challenge (OFC) or through the presence of a convincing history after ingestion of egg or CM. The cutoff levels of sIgE for egg white (EW) and CM were determined by analyzing the receiver operating characteristic curves.

Results

Out of 273 children, 52 (19.0%) were confirmed to have egg allergy. CM allergy was found in 52 (23.1%) of 225 children. The EW-sIgE concentration indicating a positive predictive value (PPV) of >90% was 28.1 kU/L in children <24 months of age and 22.9 kU/L in those ≥24 months of age. For CM-sIgE, the concentration of 31.4 kU/L in children <24 months of age and 10.1 kU/L in those ≥24 months of age indicated a >90% PPV. EW-sIgE levels of 3.45 kU/L presented a negative predictive value (NPV) of 93.6% in children <24 months of age, while 1.80 kU/L in those ≥24 months of age presented a NPV of 99.2%. The CM-sIgE levels of 0.59 kU/L in children <24 months of age and 0.94 kU/L in those ≥24 months of age showed NPVs of 100% and 96.9%.

Conclusions

Our results indicate that different diagnostic decision points (DDPs) of sIgE levels should be used for the diagnosis of egg or CM allergy in Korean children. The data also suggest that DDPs with high PPV and high NPV are useful for determining whether OFC is required in children with suspected egg or CM allergy.     

Association of STAT6 gene variants with food allergy diagnosed by double‐blind placebo‐controlled food challenges

This study describes the role of two STAT6 gene variants in food allergy using data of patients and their parents who underwent double‐blind placebo‐controlled food challenges (DBPCFCs). After quality control, 369 trios were analysed including 262 children (71.0%) with food allergy. Associations were tested by the Family based association test. The A alleles of both SNPs were associated with food allergy (P = .036 and P = .013 for rs324015 and rs1059513, respectively). Furthermore, these A alleles were associated with peanut allergy, higher sIgE levels to both peanut and cow's milk, more severe symptoms and higher eliciting doses during peanut and cow's milk DBPCFCs (all P < .05). In silico analysis indicates that the identified risk variants increase STAT6 expression which stimulates the differentiation of CD4 +  T cells to the Th2 subset. In conclusion, STAT6 variants may be involved in the pathophysiology of food allergy and their role seems to be independent of the allergenic food.     

Efficacy and safety of oral desensitization in children with cow's milk allergy according to their serum specific IgE level

BackgroundOral desensitization in children allergic to cow's milk proteins is not risk free. The analysis of factors that may influence the outcome is of utmost importance.ObjectiveTo analyze the efficacy and safety of the oral desensitization according to specific IgE (sIgE) level and adverse events during the maintenance phase.MethodsThirty-six patients allergic to cow's milk (mean age, 7 years) were included in an oral desensitization protocol. Patients were grouped according to sIgE levels (ImmunoCAP) into groups 1 (sIgE <3.5 kU/L), 2 (3.5-17 kU/L), and 3 (>17-50 kU/L). Nineteen children were included as a control group. Serum sIgE levels to cow's milk and its proteins were determined at inclusion and 6 and 12 months after finishing the desensitization protocol.ResultsThirty-three of 36 patients were successfully desensitized (200 mL): 100% of group 1 and 88% of groups 2 and 3. Desensitization was achieved in a median of 3 months (range, 1-12 months); 90% of the patients in group 1, 50% of the patients in group 2, and 30% of the patients in group 3 achieved tolerance in less than 3 months (P = .04). In the control group only 1 child tolerated milk in oral food challenge after 1 year. During the induction phase, there were 53 adverse events in 27 patients (75%). Patients of groups 2 and 3 had more severe adverse events compared with group 1. During the maintenance phase, 20 of 33 patients (60%) had an adverse event.ConclusionOral desensitization is efficacious. Tolerance is achieved earlier when sIgE is lower. Severe adverse events are frequent, especially in patients with higher sIgE levels.Trial Registrationclinicaltrials.gov Identifier: NCT01641731     

Food-specific serum immunoglobulin E measurements in children presenting with food allergy

BackgroundIn children with food allergy, multiple food-specific serum IgE levels to common food allergens are frequently measured.ObjectiveTo compare food-specific serum IgE measurements among common food allergens in children with food allergy to determine the characteristics of the measurements, their ability to discriminate between foods associated and not associated with a presenting clinical reaction, and their change over time.MethodsA retrospective analysis was conducted of food-specific serum IgE to cow's milk, egg white and yolk, peanuts, almond, and soy, for up to 3 subsequent measurements, in 291 children with food allergy. A food-specific serum IgE level lower than 0.35 kU/L was considered a negative measurement. The correlation of IgE measurements with presenting symptoms was conducted for each food in 172 children.ResultsOf 1,312 food-specific serum IgE measurements, 69.8% were positive. The median (interquartile range) IgE level for foods associated with the presenting complaint was 7.3 kU/L (2.7–31) and that for foods not associated with a clinical complaint was 2.2 kU/L (0.38–13). The difference was statistically significant (P = .01) only for cow's milk. Specific IgE levels were highest for peanuts, followed by cow's milk, eggs, soy, and almonds, and trended upward over time.ConclusionIn children presenting with clinical symptoms of a reaction to a food allergen, measurements of food-specific serum IgE to other common food allergens are commonly positive. An increase in food-specific serum IgE occurs over time.     

Role of conformational and linear epitopes in the achievement of tolerance in cow''s milk allergy

BACKGROUND: Cow's milk (CM) is one of the leading causes of food allergy in children. However, approximately 85% of milk-allergic children become clinically tolerant to CM within the first 3 years of life. The mechanisms involved in the achievement of tolerance remain unknown. OBJECTIVE: To study whether IgE antibodies from children with persistent cow's milk allergy (CMA) differ from children who become clinically tolerant in their ability to recognize linear and conformational epitopes of alpha(s1)- and beta-casein. METHODS: Thirty-six milk-allergic children were included in the study: 11 of the children became clinically tolerant, and 25 had persistent CMA. Blood was obtained from all patients during the time they showed clinical reactions to milk challenge. Six non-milk-allergic children served as controls. Specific IgE antibodies against linear (denatured) as well as conformational (native) milk proteins were determined by probing dot-blots with patients' sera. In addition, selected decapeptides from alpha(s1)- and beta-casein, previously found to be suggestive of persistent CMA, were synthesized on a cellulose-derivatized membrane and probed with individual sera from 10 patients who outgrew CMA and from 10 patients with persistent CMA. RESULTS: Analysis of immunodot-blots showed that, in comparison to tolerant patients, milk-allergic children with persistent symptoms had a significantly higher ratio of specific IgE antibodies to linearized than to native alpha- and beta-casein (P < 0.005 and P < 0.02, respectively). Comparing the selected decapeptides, six of the 10 patients with persistent allergy recognized the peptide corresponding to amino acids 69-78 from alpha(s1)-casein while none of the patients who outgrew CMA had IgE binding to this epitope. CONCLUSION: Patients with persistent milk allergy possess higher detectable levels of IgE antibodies to linear epitopes from alpha(s1)- and beta-casein than children who have achieved tolerance. Specific IgE binding to particular linear epitopes in alpha(s1)-casein may be a predictive factor for persistence of CMA.     

Serum interleukin – 4 and tumor necrosis factor alpha concentrations in children with primary acid gastroesophageal reflux and acid gastroesophageal reflux secondary to cow's milk allergy

AimThe possible role of serum interleukin 4 (IL-4) and tumor necrosis factor alpha (TNF- α) in pathogenesis of the reflux symptoms in children with primary acid gastroesophageal reflux (GER) and acid GER secondary to cow's milk allergy (CMA).Material and methodsOut of 264 children, 76 (28.8%) patients with primary GER and 62 (23.5%) patients with GER secondary to CMA (pH – monitoring) serum IL-4 and TNF- α concentrations were assessed before treatment, 1 and 2 years after the initiation of the periodically administered pharmacotherapy.ResultsChildren with primary GER had mean IL-4 concentrations 0.17 ± 0.06 pg/ml before treatment, 0.08 ± 0.07 pg/ ml after 1-year and 0.07 ± 0.06 pg/ml after 2-years of treatment. The mean IL-4 concentrations were 1.07 ± 0.24, 0.5 ± 0.22 and 0.44 ± 0.19 pg/ml respectively in children with GER secondary to CMA.The mean serum TNF- α concentrations was 3.62 ± 1.30 pg/ml before treatment, 2.16 ± 1,35 pg/ ml after 1 year and 1.65 ± 1.16 pg/ml after 2 years of treatment in children with primary GER. In group with GER secondary to CMA mean serum TNF- α concentrations were 4.95 ± 1.88, 2.53 ± 0.80 and 2.02 ± 0.78 pg/ml respectively. Statistical analysis of the concentration of both cytokines showed their differentiation between them and in the study groups.ConclusionsThe highest mean serum IL-4 and TNF-α concentrations were observed in children with GER secondary to CMA and in children in control group (with cow's milk allergy and/or other food allergy diagnosed – CMA/FA) before the treatment administration.     

Discordance between aeroallergen specific serum IgE and skin testing in children younger than 4 years

BackgroundAtopic sensitization to aeroallergens in early life has been found to be a strong risk factor for the development of persisting asthma in young children with recurrent wheeze.ObjectiveTo assess the yield of skin prick test (SPT) compared with allergen specific serum IgE (sIgE) testing at identifying aeroallergen sensitization in atopic children younger than 4 years.MethodsConcordance between SPT and allergen-specific sIgE testing for 7 common aeroallergens was analyzed in 40 atopic inner-city children 18 to 48 months of age (mean [SD], 36 [9] months) with recurrent wheezing and family history of asthma and/or eczema.ResultsIn 80% of children one or more allergen sensitizations would have been missed if only SPT had been performed, and in 38% of children one or more sensitizations would have been missed if only sIgE testing had been performed. Agreement between the SPT and sIgE test was fair for most allergens (κ = ?0.04 to 0.50), as was correlation between sIgE levels and SPT grade (ρ = 0.21 to 0.55). Children with high total sIgE (≥300 kU/L) were more likely to have positive sIgE test results, with negative corresponding SPT results (P = .02).ConclusionOur study revealed a significant discordance between allergen-specific SPT and sIgE testing results for common aeroallergens, suggesting that both SPT and sIgE testing should be performed when diagnosing allergic sensitization in young children at high risk of asthma.Trial Registrationclinicaltrials.gov Identifier: NCT01028560     

Performance of a component‐based allergen‐microarray in the diagnosis of cow's milk and hen's egg allergy

Background The food challenge test (FCT) is the gold standard for the diagnosis of food allergy. This procedure is time consuming, costly and can induce potentially severe symptoms. An ideal in vitro test should allow to avoid the FCT. Objective To assess the clinical performance of microarray for specific IgE (sIgE) detection in children with challenge‐proven/excluded cow's milk (CM) or hen's egg (HE) allergy. Methods One‐hundred and four children with suspected IgE‐mediated hypersensitivity to CM or HE were studied. In all patients, skin prick test, ImmunoCAP, microarray and FCT were performed. Results The microarray components Bos d 8 for CM (27/58 patients) and Gal d 1 (20/46 patients) and Gal d 2 (24/46) for HE were the most frequently recognized allergens. Using the FCT results as the reference parameter, sIgE to Bos d 8 and Gal d 1 had the highest area under the curves. These were not significantly different from those obtained using the ImmunoCAP. Use of 95% clinical decision points (CDP) for sIgE to Bos d 8 and Gal d 1 resulted in higher negative predictive values (78% and 79%, respectively) than those obtained with the ImmunoCAP (57% and 59%). Conclusions Our results show that in children with suspected CM or HE allergy, the microarray has a good ability to predict the FCT results. In a clinical application perspective, the microarray could be used as a second‐level assay, if the ImmunoCAP sIgE is <95% CDP. This approach would lead to a decrease in the number of the FCT to be performed, as well as of positive FCTs with a subsequent decrease in severe reaction risk. Cite this as: L. E. D'Urbano, K. Pellegrino, M. C. Artesani, S. Donnanno, R. Luciano, C. Riccardi, A. E. Tozzi, L. Ravà, F. De Benedetti and G. Cavagni, Clinical & Experimental Allergy, 2010 (40) 1561–1570.     

The role of cow milk allergy in increasing the severity of atopic dermatitis

Previous studies have shown that up to 33% of children with atopic dermatitis have experienced food hypersensitivity and among different kinds of food allergens Cow Milk (CM) has almost always been one of the most common food allergens in children. The aim of this study is to evaluate the cow milk allergy (CMA) as an increasing factor of severity of atopic dermatitis. One hundred and nineteen children (between 1.5 months and 12 years of age) with atopic dermatitis in the sense of Hanifin and Rajka's criteria entered this study and the severity of atopic dermatitis was identified via the SCORAD index. In order to make the diagnosis of cow milk allergy, a careful history, and a familial history of allergy was taken and the results of skin prick test (SPT) with CM and 4 other food allergen extracts, Radioallergosorbent test (RAST) with CM allergens and a food challenge test with cow milk (fresh or dried) were used. Also a total serum IgE determination and an eosinophil count (with a stool exam) were accomplished. The clinical manifestations of atopic dermatitis in patients was started from their first day of life up to 10 years of age. The family history in 83% of the patients was positive. Positive skin prick test and RAST with CM allergens were positive in 37.9% and 29.3% of cases respectively and the response to challenge test with cow milk was positive in 35 out of 40 patients and in total 44.5% had CMA according to a positive history of cow milk allergy and a positive outcome of the IgE tests (SPT and/or RAST) or a positive challenge test with CM allergens. The results showed that the most common food allergens in patients with atopic dermatitis are certainly cow milk allergens (44.5%) whereas other food allergens are tomato (29.41%), egg (28.57%), nuts (9.24%) and wheat (3.36%) according to the skin prick test. The mean total serum IgE was 307.11 +/- 6.56 IU/ml (range = 6-5000) in children with CMA and 81.04 +/- 5.97 IU/ml (range = 1-5000) in children without CMA while the mean eosinophil count was 569.52 +/- 3.02 count/ml (range = 67-8500) and 314.22 +/- 2.94 count/ml (range = 5-5000) respectively. The mean severity of atopic dermatitis according to the SCORAD index was 60.76 in children with CMA and 44.29 in children without CMA. The severity of atopic dermatitis in patients with CMA was significantly higher than patients without CMA (p < 0.0001). Also the mean total serum IgE and mean eosionophil counts in children with CMA were significantly higher than in children without CMA (P < 0.01 and p < 0.0001, respectively). It shows the important role of CM allergen proteins in the induction and in increasing the severity of AD in children.     

Biochemical markers of bone metabolism in children with cow's milk allergy

Introduction

Patients with cow''s milk allergy (CMA) and following a cow milk protein-free diet for a long time are potentially at risk of developing bone abnormalities. To assess the balance between bone formation and resorption processes, we determined serum concentrations of osteocalcin (OC), bone alkaline phosphatase (BALP), C-terminal telopeptide of type I collagen (CTX), fetuin-A, osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) in children with CMA.

Material and methods

The study included 50 prepubertal children with diagnosed cow''s milk allergy, who were under systematic medical and nutritional care at the Institute of Mother and Child and 40 healthy counterparts as a control group. The concentrations of bone metabolism markers were determined by immunoenzymatic assays.

Results

The diets of all investigated children were correct in terms of phosphorus and magnesium contents but deficient in terms of calcium and vitamin D. Serum OC and CTX as well as fetuin-A concentrations were similar in both studied groups. The BALP activity was significantly (p < 0.05) higher in children with cow''s milk allergy than in the controls. Serum OPG concentration was comparable in both groups, but the RANKL level was higher (p < 0.05) in CMA children than in healthy ones. Hence, the ratio of OPG/RANKL was lower in children with CMA.

Conclusions

Our study demonstrates slight disturbances in the profile of bone metabolism markers in growing children with CMA. The increase in RANKL level and decrease in OPG/RANKL ratio may contribute to intensification of bone resorption in these patients.     

Skin testing with ultra-heat-treated (UHT) cow's milk in children with cow's milk allergy

BackgroundA large proportion of cow's milk (CM)-allergic children are able to tolerate extensively heated forms of CM such as baked goods. Little is known about whether ultra-heat-treated (UHT) forms of cow's milk are immunologically similar to extensively heated cow's milk and therefore may be tolerated by these children.ObjectiveTo determine whether skin test wheal size using UHT CM was significantly different from other forms of CM and CM extracts.MethodsChildren presenting for oral food challenges with either extensively heated or unheated cow's milk underwent skin prick test (SPT) to commercial CM, UHT CM, evaporated CM, and fresh whole CM. The results were compared between groups of children.ResultsAt study exit, only 14% of children were avoiding all forms of CM, compared with 70% at study entry. No difference was seen in the mean SPT results for UHT CM between those children that could tolerate heated CM compared with those that could not. The mean SPT result for casein was significantly lower in those that could tolerate heated CM. However, within the group of heated milk–tolerant children, the mean SPT for UHT CM was significantly lower than the SPT for fresh whole CM.ConclusionUltra-heat-treated CM does not behave significantly differently from other forms of CM when evaluated by SPT in heated milk–allergic vs heated milk–tolerant children. This suggests that UHT CM is not sufficiently immunologically different from unheated CM to be tolerated by heated CM–tolerant children.     

The Role of Cow Milk Allergy in Increasing the Severity of Atopic Dermatitis

Previous studies have shown that up to 33% of children with atopic dermatitis have experienced food hypersensitivity and among different kinds of food allergens Cow Milk (CM) has almost always been one of the most common food allergens in children. The aim of this study is to evaluate the cow milk allergy (CMA) as an increasing factor of severity of atopic dermatitis. One hundred and nineteen children (between 1.5 months and 12 years of age) with atopic dermatitis in the sense of Hanifin and Rajka's criteria entered this study and the severity of atopic dermatitis was identified via the SCORAD index. In order to make the diagnosis of cow milk allergy, a careful history, and a familial history of allergy was taken and the results of skin prick test (SPT) with CM and 4 other food allergen extracts, Radioallergosorbent test (RAST) with CM allergens and a food challenge test with cow milk (fresh or dried) were used. Also a total serum IgE determination and an eosinophil count (with a stool exam) were accomplished. The clinical manifestations of atopic dermatitis in patients was started from their first day of life up to 10 years of age. The family history in 83% of the patients was positive. Positive skin prick test and RAST with CM allergens were positive in 37.9% and 29.3% of cases respectively and the response to challenge test with cow milk was positive in 35 out of 40 patients and in total 44.5% had CMA according to a positive history of cow milk allergy and a positive outcome of the IgE tests (SPT and/or RAST) or a positive challenge test with CM allergens. The results showed that the most common food allergens in patients with atopic dermatitis are certainly cow milk allergens (44.5%) whereas other food allergens are tomato (29.41%), egg (28.57%), nuts (9.24%) and wheat (3.36%) according to the skin prick test. The mean total serum IgE was 307.11 ± 6.56 IU/ml (range = 6–5000) in children with CMA and 81.04 ± 5.97 IU/ml (range = 1–5000) in children without CMA while the mean eosinophil count was 569.52 ± 3.02 count/ml (range = 67–8500) and 314.22 ± 2.94 count/ml (range = 5–5000) respectively. The mean severity of atopic dermatitis according to the SCORAD index was 60.76 in children with CMA and 44.29 in children without CMA. The severity of atopic dermatitis in patients with CMA was significantly higher than patients without CMA (p < 0.0001). Also the mean total serum IgE and mean eosionophil counts in children with CMA were significantly higher than in children without CMA (P < 0.01 and p < 0.0001, respectively). It shows the important role of CM allergen proteins in the induction and in increasing the severity of AD in children.     

Coconut allergy: Characteristics of reactions and diagnostic predictors in a pediatric tertiary care center

BackgroundLittle is known on the clinical manifestations of coconut allergy. Our knowledge to date is mainly based on case reports.ObjectiveTo characterize the allergic reactions to coconut and suggest diagnostic cutoffs for specific immunoglobulin E (sIgE) and skin prick testing (SPT) to predict clinically reactive coconut allergy.MethodsMethods include retrospective chart review at an urban tertiary care center of patients with positive testing result for coconut. Probability curves were computed by logistic regression for SPT and coconut sIgE.ResultsOf 275 records reviewed, 69 patients reported coconut reactions and 206 were sensitized only or nonallergic. The reactions occurred with breastfeeding (n = 2), contact (n = 10), or oral ingestion (n = 57). Approximately 50% of oral ingestion reactions were associated with mild/moderate anaphylaxis. Clinical reactivity vs sensitization was more common in topical coconut users (2-fold) (P = .02). Although not statistically significant, there was a trend toward more coconut allergy vs sensitization in Asian and African American patients. The probability of allergy with positive SPT result was approximately 50% and with sIgE was approximately 60%. At an SPT of 9 mm wheal or sIgE of 58 kU of allergen/L, there is a 95% probability of reaction. Cosensitization with tree nuts, legumes, and seeds was common. Macadamia nut had the strongest correlation with coconut (r = 0.81, P < .001, n = 101).ConclusionAlthough the rate of reactivity to coconut in sensitized individuals is low, half of the reactions from consumption met the criteria for anaphylaxis. Clinicians should be aware of the spectrum of reactions and diagnostic use of sIgE and SPT.     

Quality of life in food allergic children: Results from 174 quality-of-life patient questionnaires

BackgroundFood allergies are becoming a global concern and pose a significant burden on allergic children and their family, with reported physical and emotional effects.ObjectiveTo investigate the effect of food allergy on patients′ quality of life (QoL), to identify any characteristics associated with worse QoL, and to directly compare the effect of food allergies on the QoL of adolescents vs younger children.MethodsChildren 0 to 17 years old with a physician-confirmed food allergy diagnosis were invited to participate by completing the validated Food Allergy Quality of Life Questionnaire (FAQLQ). The FAQLQ form for children 10 to 12 years old was completed by the parent (proxy report), whereas the FAQLQ form for adolescents was completed by the adolescent (self-report). Scores were compared using the Wilcoxon rank sum test. Independent median regressions were used to test association between potential risk factors and QoL outcomes.ResultsIn our cohort, the median FAQLQ score was significantly higher (reflecting lower QoL) in adolescents compared with children (4.7 vs 3.5, P = .007). The median social and dietary limitations score (5.2 vs 4, P = .002) and the median emotional impact score (3.8 vs 3.1, P = .02) were also higher in adolescents. Limitations in family activities because of food allergy had a negative effect on QoL.ConclusionFood allergic adolescents are affected more than younger children (based on parental report) in terms of QoL, with a direct reflection on all areas of their daily life (emotional, dietary, and social). In addition, limitations in family activities because of the child′s food allergy significantly worsen the QoL and well being of all family members.     

Clinical symptoms and IgE responses to common food proteins in atopic and healthy children

The appearance of symptoms suggestive of allergy through the first 4 years of life was studied prospectively in eighty-six healthy newborn babies. Blood samples were obtained at birth, at 3,8,25 and 48 months of age and analyzed for levels of total serum IgE and for IgE antibodies to some common foods. The occurrence of IgE antibodies was related to atopic manifestations and to a detailed history of infant feeding and family history of allergy. All infants with elevated cord blood IgE (more than 1.3 kU/1) developed manifestations of atopy. Specific IgE antibodies against egg, cow's milk and soy were demonstrated at 3, 8, 25 and 48 months in nine, twenty-three, six and two children respectively. Egg was a more potent sensitizing agent than cow's milk, IgE antibodies to egg being present in thirty-one samples, to cow's milk in eleven and to soy in five samples. Nine infants developed IgE antibodies to eggs or cow's milk before the introduction of these nutrients into the food. The IgE antibody levels were generally low in healthy non-atopic children and did, with one exception, not reach RAST class 1. In contrast, the levels of IgE antibodies to egg or cow's milk were higher in eleven blood samples from atopic children. We conclude that transient low IgE antibody responses to food proteins appear relatively often even in healthy infants. High concentrations of IgE antibodies however are almost exclusively seen in infants with atopic disease. Sensitization may appear early in infancy sometimes even before the offending food has been introduced into the diet.     

Utility of the ratio of food-specific IgE/total IgE in predicting symptomatic food allergy in children

BACKGROUND: Double-blind, placebo-controlled food challenges are time-consuming, expensive and not without risk to patients. Therefore, an in vitro test that could accurately diagnose food allergy would be of great value. OBJECTIVE: To evaluate the utility of the ratio of specific immunoglobulin E (IgE)/total IgE compared with specific IgE (sIgE) alone in predicting symptomatic food allergy. METHODS: We retrospectively analysed 992 controlled oral food challenges performed in 501 children (median age 13 months). The ratio of sIgE/total IgE was calculated and tested for correlation with the outcome of food challenges. Receiver operator characteristics (ROC)-curves were performed; predicted probabilities and predictive decision points were calculated. RESULTS: A significant correlation was found between the ratio and the outcome of food challenges for cow's milk (CM), hen's egg (HE), and wheat, but not for soy. The ROC and predicted probability curves as well as sensitivity and specificity of the decision points of the ratio were similar to those of sIgE levels for CM, HE and wheat. CONCLUSION: In view of the greater effort needed to determine the ratio, without benefit compared with the sIgE alone, the calculation of the ratio of sIgE/total IgE for diagnosing symptomatic food allergy offers no advantage for CM, HE, wheat or soy. For the majority of cases controlled oral food challenges still remain the method of choice.     

IgE and IgG binding epitopes on alpha-lactalbumin and beta-lactoglobulin in cow's milk allergy.

BACKGROUND: Cow's milk is one of the most common causes of food allergy in the first years of life. We recently defined IgE and IgG binding epitopes for alpha(s1)-casein, a major cow's milk allergen, and found an association between recognition of certain epitopes and clinical symptoms of cow's milk allergy (CMA). Since alpha-lactalbumin (ALA) and beta-lactoglobulin (BLG) are suspected to be significant allergens in cow's milk, we sought to determine the structure of sequential epitopes recognized by IgE antibodies to these proteins. We further sought to assess the pattern of epitope recognition in association with the clinical outcome of CMA. METHODS: According to the known amino acid sequence of ALA and BLG, 57 and 77 overlapping decapeptides (offset by two amino acids), respectively, were synthesized on a cellulose derivatized membrane. Sera from 11 patients 4-18 years of age with persistent CMA (IgE to cow's milk >100 kU(A)/l) were used to identify IgE binding epitopes. In addition, 8 patients < 3 years of age and likely to outgrow their milk allergy (IgE to cow's milk < 30 kU(A)/l) were used to investigate the differences in epitope recognition between patients with 'persistent' and those with 'transient' CMA. Seven patients 4-18 years of age were used for assessing the IgG binding regions. RESULTS: In patients with persistent allergy, four IgE binding and three IgG binding regions were identified on ALA, and seven IgE and six IgG binding epitopes were detected on BLG. The younger patients that are likely to outgrow their allergy recognized only three of these IgE binding epitopes on BLG and none on ALA. CONCLUSIONS: The presence of IgE antibodies to multiple linear allergenic epitopes may be a marker of persistent CMA. The usefulness of IgE binding to distinct epitopes on whey proteins in defining the patients that would have a lifelong CMA needs to be investigated in further studies.     

Duration of clinical reactivity in cow's milk allergy is associated with levels of specific immunoglobulin G4 and immunoglobulin A antibodies to β‐lactoglobulin

Background The development of tolerance in IgE‐mediated allergies has been associated with lower cow's milk (CM)‐specific IgE levels, increasing levels of specific IgG4 and, more contestably, IgA. Objective We investigated whether specific antibody responses to CM proteins differ over time between patients who recovered from cow's milk allergy (CMA) by the age of 3 years and those who developed tolerance only after the age of 8 years. Methods The study population comprised of 83 patients with IgE‐mediated CMA. They belonged to a cohort of 6209 healthy, full‐term infants followed prospectively for the emergence of CMA. Serum samples were available at diagnosis (median age 7 months), 1 year later (median 19 months) and at follow‐up (median 8.5 years). Age‐matched control subjects with no history of CMA (n=76) participated in the follow‐up. Serum levels of IgE antibodies to CM were measured using UniCAP. Levels of IgA, IgG1 and IgG4 antibodies to β‐lactoglobulin and α‐casein were measured using ELISA. Results Patients with persistent CMA at the age of 8 years (n=18 at diagnosis, n=16 at later time‐points) had higher CM‐specific IgE levels at all three time‐points (P<0.001) compared with patients who became tolerant by 3 years (n=55 at diagnosis, n=54 a year later, n=40 at follow‐up). They had lower serum IgA levels to β‐lactoglobulin at diagnosis (P=0.01), and lower IgG4 levels to β‐lactoglobulin (P=0.04) and α‐casein (P=0.05) at follow‐up. Conclusion High CM‐specific IgE levels predict the persistence of CMA. Development of tolerance is associated with elevated levels of β‐lactoglobulin‐specific serum IgA at the time of diagnosis, and later increasing specific IgG4 levels to β‐lactoglobulin and α‐casein. Cite this as: E. M. Savilahti, K. M. Saarinen and E. Savilahti, Clinical & Experimental Allergy, 2010 (40) 251–256.     

Combined T regulatory cell and Th2 expression profile identifies children with cow's milk allergy

The role of T regulatory cells in spontaneous recovery from cow's milk allergy (CMA) is unclear. We investigated the mRNA expression of 12 T-cell markers and the protein expression of CD4, CD25, CD127, FoxP3 after in vitro β-lactoglobulin stimulation of peripheral blood mononuclear cells from children with persisting CMA (n = 16), early recovery (n = 20) or no atopy (n = 21). Artificial neural networks with exhaustive search for all marker combinations revealed that markers FoxP3, Nfat-C2, IL-16 and GATA-3 distinguished patients with persisting CMA most accurately from other study groups. FoxP3 mRNA expression following β-lactoglobulin stimulation was highest in children with persisting CMA. Also the FoxP3 intensity in CD4⁺ CD25^highCD127^low cells was higher in children with CMA compared with non-atopic children. The expression profile of both Th2- and T regulatory cell-related genes thus reflects the clinical activity of CMA. Tolerance, in contrast, is not characterized by activation of circulating T regulatory cells.