Cow's milk allergy is the most common cause of food allergy in the first years of life, affecting approximately 2-3% of children . The majority of children outgrow their cow's milk allergy by 3-4 years of age . Currently, the only treatment is strict avoidance; however, a hypoallergenic substitute is necessary at this young age.
Milk of another animal source such as goat or sheep cannot be recommended as a general substitute in cow's milk allergy. For example, many proteins in goat milk show a high similarity with cow's milk proteins resulting in a cross-reactivity of 92% . Therefore, patients might react severely at first exposure. In contrast, cross-reactivity with mare's milk occurs only in about 4% . Furthermore, soy formula may provide a safe and growth-promoting
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Fig. 1. Technologies to reduce the allergenicity of a protein. Hypoallergenic formulas are produced through enzymatic hydrolysis of different sources such as bovine casein, bovine whey or soy followed by further processing such as heat treatment and/or ultrafiltration.
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Intact protein pHF eHF Amino acids
Fig. 2. Hypoallergenic formulas have been classified into 'extensively' (eHF) or 'partially' (pHF) hydrolyzed formulas according to the degree of protein hydrolysis. Hypoallergenic formulas might also be based on amino acid mixtures.
alternative for children with cow's milk allergy . However, soy is a potent allergen itself and sensitization resulting in allergic reactions might occur.
For many years hypoallergenic formulas have been used in cow's milk allergy. As shown in figure 1 hypoallergenic formulas are produced through enzymatic hydrolysis of different sources such as bovine casein, bovine whey or soy followed by further processing such as heat treatment and/or ultrafiltration . The resulting products have been classified into 'extensively' or 'partially' hydrolyzed formulas (fig. 2) according to the degree of protein hydrolysis . The degree of hydrolysis may be characterized by biochemical techniques, such as the spectrum of peptide molecular weights or the ratio of alpha amino nitrogen to total nitrogen . Assuming the theory that the shorter the peptides the less allergenic the product, much work has been done to determine the molecular weight of residual peptides in the hydrolysates . As a practical guideline for industry the appropriate cutoff for the absence of larger peptides has been determined to be approximately 1,500 Daltons .
Anaphylactic reactions have been reported not only for partially hydrolyzed formula but also for extensively hydrolyzed ones; therefore, reduction of aller-genicity should be assessed in vitro and in vivo . Residual allergenicity can be explained by the degree of hydrolysis. Peptides representing IgE-binding sites might still be present. In addition, higher-molecular-weight particles that might be allergenic can occur in hydrolyzed formula through aggregation of smaller peptides . Moreover, contamination with native proteins during production of the hypoallergenic formula is possible.
Reduction of allergenicity of dietary products may be assessed in vitro using various immunological methods, such as IgE-binding test, inhibition assays or immunoelectrophoresis methods . Especially hypoallergenic formulas used for treatment in cow's milk allergy should undergo clinical in vivo testing. Skin testing should be the first step followed by challenge tests . Suitable hypoallergenic formulas should be tolerated by at least 90% of infants with documented cow's milk allergy with 95% of confidence in doubleblind placebo-controlled food challenges. It is recommended that trials should be performed in two independent centers, and be divided into IgE-and non-IgE-mediated cases before statistical treatment . For each type of allergy >28 patients should be included in each trial . If 1 patient reacts, 46 subjects must be included and the remaining 45 must be without reactions. In order to ensure long-term tolerance a normal daily intake during a period of 3 months is recommendable. In addition, the nutritional value of the products has to be documented.
Hypoallergenic formulas might also be based on amino acid mixtures (fig. 2). These elementary diets can be considered as nonallergenic. They do not need any clinical testing provided the production is sufficiently controlled assuring no contamination . The hypoallergenicity and the nutritional value of such elementary diets have been documented .
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