Original articleSystemic allergic disorderFactors that predict the clinical reactivity and tolerance in children with cow's milk allergy
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
References (42)
- et al.
The prevalence of food allergy: a meta-analysis
J Allergy Clin Immunol
(2007) Food allergy, part 1: immunopathogenesis and clinical disorders
J Allergy Clin Immunol
(1999)- et al.
Natural history of food hypersensitivity in children with atopic dermatitis
J Pediatr
(1989) - et al.
The natural history of IgE-mediated cow's milk allergy
J Allergy Clin Immunol
(2007) - et al.
Determination of food specific IgE levels over time can predict the development of tolerance in cow's milk and hen's egg allergy
J Allergy Clin Immunol
(2004) Utility of food-specific IgE concentrations in predicting symptomatic food allergy
J Allergy Clin Immunol
(2001)- et al.
Specific IgE levels in the diagnosis of immediate hypersensitivity to cows' milk protein in the infant
J Allergy Clin Immunol
(2001) - et al.
The predictive relationship of food-specific serum IgE concentrations to challenge outcomes for egg and milk varies by patient age
J Allergy Clin Immunol
(2007) - et al.
The relationship of allergen-specific IgE levels and oral food challenge outcome
J Allergy Clin Immunol
(2004) - et al.
Usefulness of specific IgE levels in predicting cow's milk allergy
J Allergy Clin Immunol
(2008)
The -159 C-->T polymorphism of CD14 is associated with nonatopic asthma and food allergy
J Allergy Clin Immunol
Stat6 is required for mediating responses to IL-4 and for development of Th2 cells
Immunity
Associations between specific serum IgE response and 6 variants within the genes IL4, IL13, and IL4RA in German children: the German Multicenter Atopy Study
J Allergy Clin Immunol
SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis
J Allergy Clin Immunol
Food allergy
J Allergy Clin Immunol
Work Group report: oral food challenge testing
J Allergy Clin Immunol
Consensus conference on pediatric atopic dermatitis
J Am Acad Dermatol
The role of SPINK5 in asthma related physiological events in the airway epithelium
Respir Med
IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma
J Allergy Clin Immunol
A signal transducer and activator of transcription 6 haplotype influences the regulation of serum IgE levels
J Allergy Clin Immunol
The predictive value of specific immunoglobulin E levels in serum for the outcome of oral food challenges
Clin Exp Allergy
Cited by (35)
Breastfeeding and IL-10 levels in children affected by cow's milk protein allergy: A restrospective study
2017, ImmunobiologyCitation Excerpt :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).
The Natural History of Food Allergy
2016, Journal of Allergy and Clinical Immunology: In PracticeCitation Excerpt :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.
Food Allergy: Epidemiology and Natural History
2015, Immunology and Allergy Clinics of North AmericaCitation Excerpt :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.
Cow's milk allergy: From allergens to new forms of diagnosis, therapy and prevention
2014, MethodsCitation Excerpt :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].
Predicting outgrowth of IgE-mediated cow's milk allergy: Diagnostic tests in children under two years of age
2019, Allergologia et ImmunopathologiaCitation Excerpt :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
Disclosures: Authors have nothing to disclose.