Factors that predict the clinical reactivity and tolerance in children with cow's milk allergy

doi:10.1016/j.anai.2013.01.018

Annals of Allergy, Asthma & Immunology

Volume 110, Issue 4, April 2013, Pages 284-289

https://doi.org/10.1016/j.anai.2013.01.018 Get rights and content

Abstract

Background

Specific IgE (sIgE) may be used for the diagnosis of cow's milk allergy (CMA) and as a guide to perform food challenge tests in patients with CMA. The effect of genetic variants on the prognosis of food allergy is largely unknown.

Objective

To examine the performance of sIgE analysis and the utility of the genetic variants of CD14, STAT6, IL13, IL10, SPINK5, and TSLP in predicting the clinical course in children with CMA.

Methods

Serum sIgE levels of 94 children who underwent open food challenges and 54 children with anaphylaxis due to cow's milk (CM) were retrospectively analyzed between January 2002 and May 2009. The genetic polymorphisms were determined in 72 children.

Results

A total of 148 children were followed up for a median of 3.5 years, and 42 of the 94 challenge results were positive. The probability curves with 95% decision points were 2.8 kU/L for younger than 1 year, 11.1 for younger than 2 years, 11.7 for younger than 4 years, and 13.7 for younger than 6 years. Sixty-six children outgrew CMA during follow-up. Children with initial an CM sIgE level less than 6 kU/L outgrew CMA earlier than children with an initial CM sIgE level of 6 kU/L or higher (P < .001). The age of tolerance development for CM was significantly higher in children with the GG genotype at rs324015 of the STAT6 gene compared with those with the AA+AG genotype (2 years [range, 1.5-3.9 years] vs 1.2 years [range, 1.0-2.2 years]) (P = .02).

Conclusion

The decision points of sIgE obtained in different age groups may help to determine the likelihood of clinical reactivity more precisely. The results suggest that sIgE levels and STAT6 gene variants may be important determinants to predict longer persistence of CMA.

Introduction

Cow's milk allergy (CMA) is one of the most frequent food allergies in children.¹ Even though many of the children with CMA begin to tolerate milk by the age of 5 years,² in some children CMA may persist through the second decade of life. Persistence of CMA into older age has been associated with many factors, such as accompanying atopic diseases, formula feeding, and higher milk specific IgE (sIgE) levels in the first 2 years of life,[3], [4] whereas tolerance has been associated with the rate of decrease in the sIgE levels.⁵

Food challenge remains the criterion standard for both diagnosing CMA and determining tolerance to cow's milk (CM). However, food challenge can sometimes result in severe clinical symptoms and therefore should be performed with caution. Therefore, it is highly desirable to have clinical and laboratory criteria to determine the point where a food challenge can be performed with more confidence for tolerance. Efforts to establish the decision points of CM sIgE[5], [6], [7], [8], [9], [10], [11], [12] and to define clinical characteristics[13], [14] for predicting the outcome of CMA in infants and young children have been useful only to a limited extent. It appears that in addition to CM sIgE and clinical features, other factors should be considered in studying the persistence and tolerance of CMA.

Even though numerous studies have investigated the genetics of asthma and other allergic diseases, there is limited information regarding the genetic basis of food allergy. Few studies that have been performed have implicated genetic variants of the CD14, STAT6, IL13, IL10, and SPINK5 molecules to be associated with food allergy in some but not all populations.[15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]

We hypothesized that the genetic variants that have been implicated in food allergy may be a useful adjunct to sIgE levels in predicting the clinical course of CMA and may aid in determining the decision points for food challenges with higher predictive values. Therefore, together with CM sIgE, we investigated the frequency of previously described genetic variants in CD14, STAT6, IL13, IL10, and SPINK5 molecules in a group of children with IgE-mediated CMA and analyzed their association with favorable clinical outcomes. To this list, we also added TSLP, whose variants were consistently reported to be associated with atopic phenotypes in various populations but has not been investigated in food allergy.

Section snippets

Study Population

Children with IgE-mediated CMA who have been followed up at the Pediatric Allergy and Asthma Unit, Hacettepe University School of Medicine, between January 2002 and May 2009 participated in this study.²⁶ All children and their parents were interviewed, and their demographic variables and physical examination findings were recorded. The interviewing physician has made a specific effort to determine a cause and effect relationship between the ingestion of CM and development of symptoms;

Results

The characteristics of the patients are given in Table 1. The diagnosis of CMA was made with an open food challenge in 94 children and a history of anaphylaxis after CM intake in 54 children. Figure 1 shows the distribution of the children with positive and negative provocation and/or anaphylaxis based on the classification of CM sIgE measured at the time of follow-up provocation (not at the time of diagnosis when all children had a positive sIgE test result to CM).

Discussion

Our study supports the previous observations that there is a good correlation between CM sIgE levels and clinical reactivity, with a predicted probability curve reaching 95%. Our results also suggest that the prognosis of CMA is significantly associated not only with initial CM sIgE but also with the genotype of the STAT6 gene at rs324015. The children with an initial CM sIgE level greater than 6 kU/L and those with the GG genotype at STAT6 rs324015 had a significantly higher risk of

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Food allergy (FA) affects the quality of life of millions of people worldwide and presents a significant psychological and financial burden for both national and international public health. In the past few decades, the prevalence of allergic disease has been on the rise worldwide. Identified risk factors for FA include family history, mode of delivery, variations in infant feeding practices, prior diagnosis of other atopic diseases such as eczema, and social economic status. Identifying reliable biomarkers that predict the risk of developing FA in early life would be valuable in both preventing morbidity and mortality and by making current interventions available at the earliest opportunity. There is also the potential to identify new therapeutic targets. This narrative review provides details on the genetic, epigenetic, dietary, and microbiome influences upon the development of FA and synthesizes the currently available data indicating potential biomarkers. Whereas there is a large body of research evidence available within each field of potential risk factors, there is a very limited number of studies that span multiple methodological fields, for example, including immunology, microbiome, genetic/epigenetic factors, and dietary assessment. We recommend that further collaborative research with detailed cohort phenotyping is required to identify biomarkers, and whether these vary between at-risk populations and the wider population. The low incidence of oral food challenge–confirmed FA in the general population, and the complexities of designing nutritional intervention studies will provide challenges for researchers to address in generating high-quality, reliable, and reproducible research findings.
Breastfeeding and IL-10 levels in children affected by cow's milk protein allergy: A restrospective study
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Positive family history for atopy, genetic predisposition, time of introduction of cow’s milk, the permeability of gastrointestinal tract, and environmental factors have been suggested as possible cumulative causes contributing to disease development (Fiocchi et al., 2010; Koletzko et al., 2012; Katz et al., 2010). It is becoming evident that multiple factors, through modulation of immune response, can influence the development of CMPA (Yavuz et al., 2013). On this regard, several studies have examined the possible benefits of breast-feeding in comparison to cow’s milk formula-fed on food allergy in children (Greer et al., 2008).
To assess the protective role of breast-feeding in infants with CMPA-related AEDS as well as IL-10 utility as marker of disease evolution.
64 breast-feeding children with CMPA-related AEDS (31 males and 33 females; mean age 5.56 ± 2.41 months; 21 mild AEDS; 25 moderate AEDS; 18 severe AEDS) and 60 artificial feeding babies (33 males and 27 females; mean age 6.01 ± 2.08 months; 26 mild AEDS; 19 moderate AEDS; 15 severe AEDS) were evaluated. In all patients serum IL-10 levels were detected.
Significant Score Atopic Dermatitis (SCORAD) index point differences between breastfed and not breastfed children (p < 0.001) have been detected. The serum IL-10 levels were lower in children with CMPA-related AEDS as compared to the healthy control group (p < 0.001). Moreover, a significant inverse correlation between serum IL-10 levels and SCORAD in both enrolled groups has been also noted. In particular, IL-10 levels, in both groups, were significantly lower in children with severe symptoms. Conversely, serum IL-10 levels were significantly increased in children with mild-severe symptoms in both groups. Furthermore, breastfed children, with lower severe symptoms, had higher serum IL-10 levels. Finally, serum total IgE levels were negatively correlated with serum IL-10 levels in both breastfed and non-breastfed children with CMPA-related AEDS (p < 0.001).
We reported that exclusive breast-feeding induces hyposensitization in children with CMPA-related AEDS and it is associated with minor disease severity and higher serum IL-10 levels, resulting as useful disease-monitor marker.
The Natural History of Food Allergy
2016, Journal of Allergy and Clinical Immunology: In Practice
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Routinely available assays of IgE sensitization include the skin prick test (SPT) and serum food-specific IgE levels. In general, larger SPT wheal size8,10,15,16 or higher food-specific IgE levels7,8,12,15-20 are associated with persistent food allergy. The rate of change of food-specific IgE levels21 or SPT wheal sizes16 can also help predict the likelihood that a food allergy has resolved.
On a population level, it is well recognized that some IgE-mediated childhood food allergies, such as milk and egg allergies, are more likely to resolve than others, such as peanut and tree nuts allergies. Unfortunately, some studies suggest that resolution rates may have slowed compared with impressions from past decades. The clinician can apply the knowledge of the epidemiology of these allergies to describe likely patient outcomes, and direct management in a general manner. However, the ability to evaluate and predict the natural course of specific food allergies for individual patients is essential to inform personalized patient care. Data are accumulating to assist in identifying whether a child's allergy has likely resolved, informing the timing of oral food challenges or subsequent testing. Exciting recent studies are increasingly identifying early prognostic markers as well. Emerging food allergy therapies carry risks and costs. Identifying which egg-allergic patient has likely persistent allergy, and which patient with peanut allergy may experience natural resolution, is becoming an important goal to identify the best candidates for these therapies. Although more work needs to be done to identify reliable predictive markers and validate them, there is already much known about the natural course of food allergies that can be applied by the clinician to improve patient care.
Food Allergy: Epidemiology and Natural History
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However, another study reported that although filaggrin mutations do increase the likelihood of sensitization to food-specific IgE in children in the first year of life, they are not associated with an increased risk of clinical allergy among children already sensitized.20 Polymorphisms in the STAT6 gene have been associated with an increase in the age of tolerance in cow’s milk allergy,21 food sensitization,22 and risk for nut allergy.23 Although it seems likely that there is a genetic basis to food allergy development, further studies are needed to identify the specific loci involved.
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One study has shown that reactions to less than 10 ml of milk during an oral food challenge and large wheal size reactions in SPT predict a higher risk for persistence [22]. Several other studies have confirmed that low levels of milk-specific IgE and small wheals during SPTs are good indicators for resolution [23–25]. A recent observational study considered the severity of atopic dermatitis (AD) for the natural course of milk allergy and came up with a web-based calculator for the prognosis of milk allergy for infants younger than 15 months that is based on milk-specific IgE levels, SPT wheal sizes and severity of AD [26].
The first adverse reactions to cow’s milk were already described 2000 years ago. However, it was only 50 years ago that several groups started with the analysis of cow’s milk allergens. Meanwhile the spectrum of allergy eliciting proteins within cow’s milk is identified and several cow’s milk allergens have been characterized regarding their biochemical properties, fold and IgE binding epitopes. The diagnosis of cow’s milk allergy is diverse ranging from fast and cheap in vitro assays to elaborate in vivo assays. Considerable effort was spent to improve the diagnosis from an extract-based into a component resolved concept. There is still no suitable therapy available against cow’s milk allergy except avoidance. Therefore research needs to focus on the development of suitable and safe immunotherapies that do not elicit severe side effect.
Predicting outgrowth of IgE-mediated cow's milk allergy: Diagnostic tests in children under two years of age
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Previous studies have primarily used SPTs for FM to guide clinical diagnosis.4,5,15–18 Among the studies that aimed to assess the role of initial parameters on outgrowth, some evaluated the initial SPT wheal size,19 whereas others evaluated sIgE levels,8 or both.9,10 However, few studies evaluated the role of the initial SPT diameters9 or the course of tolerance acquisition with FM.20
Limited studies conducted on children <2 years old and/or involving a skin prick test (SPT) for fresh milk (FM) have examined the predictive value of allergometric tests for outgrowth of cow's milk allergy (CMA). We investigated the optimal decision points for outgrowth (ODP^fo) with SPT for commercial cow's milk extract (CE) and FM and specific immunoglobulin E (sIgE) levels for milk proteins to predict outgrowing allergy in children <2 years old.
SPTs for CE and FM, tests for sIgEs (cow's milk, casein, α-lactoalbumin, β-lactoglobulin) and oral food challenges (OFC) were performed in children referred for evaluation of suspected CMA, and 15 months after diagnosis.
Fifty-one children (median age, 7.5 months; range, 2–23 months) were enrolled. Five had a history of anaphylaxis and 26 of 48 children with a positive initial challenge underwent milk elimination. The last OFC was performed in 28 children of whom 13 reacted to milk. The initial SPT responses to CE and FM and milk sIgE levels of the patients with persistent CMA were higher at diagnosis, with ODP^fo of 7 mm, 9 mm, and 10.5 kU/L, respectively; these values remained higher with ODP^fo of 4 mm, 11 mm, and 10.5 kU/L at the last OFC.
Higher initial SPTs for FM and CE and higher initial sIgE levels for cow's milk proteins are associated with a reduced likelihood of outgrowth. Initial milk sIgE level <10.5 kU/L and initial SPT for fresh milk <9 mm are related to the acquisition of tolerance in the follow-up period.

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: Disclosures: Authors have nothing to disclose.

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Original articleSystemic allergic disorderFactors that predict the clinical reactivity and tolerance in children with cow's milk allergy

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study Population

Results

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

J Pediatr

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Immunity

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Am Acad Dermatol

Respir Med

J Allergy Clin Immunol

J Allergy Clin Immunol

The predictive value of specific immunoglobulin E levels in serum for the outcome of oral food challenges

Clin Exp Allergy

Original article
Systemic allergic disorder
Factors that predict the clinical reactivity and tolerance in children with cow's milk allergy