The prevalence of allergic diseases worldwide is rising dramatically in both developed and developing countries. These diseases include asthma; rhinitis; anaphylaxis; drug, food and insect allergy; eczema; urticaria and angioedema. This increase is especially problematic in children, who are bearing the greatest burden of the rising trend which has occurred over the last two decades.

A food allergy is "an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food". Cow's milk protein allergy (CMPA), which is also commonly referred to as cow's milk allergy (CMA), is the leading cause of food allergy in infants and children younger than three years [1]. While there is indirect data favoring an increase in CMA prevalence, knowledge of the time trend of CMA prevalence is very limited and there are no unequivocal data to suggest an increase [2].

An important differentiation in the management of milk hypersensitivities is that of allergy or intolerance [3]. Allergy is the adverse immune response to constituents within the milk, whereas intolerance is a non-allergic food sensitivity as the result of lactase deficiency, the dietary enzyme required to digest lactose, the predominant sugar in milk.

Food allergens are defined as the specific components of food or ingredients within food recognized by allergen-specific immune cells which then elicit specific immunologic reactions, resulting in characteristic symptoms. Food allergens are typically proteins, but sometimes also chemical haptens.

Food allergy symptoms commonly associated with immunoglobulin E (IgE)-mediated reactions include urticaria, angioedema, vomiting, diarrhea, eczema, rhinitis and anaphylaxis. Symptoms associated with non-IgE mediated reactions include vomiting, constipation, hemosiderosis, malabsorption, villous atrophy, eosinophilic proctocolitis, enterocoloitis and eosinophilic esophagitis. However, in some infants, irritability and colic may be the only symptoms of food allergy [4,5].

Allergy to cow's milk is due to an immunologic response to milk protein with a Danish cohort study suggesting that 54% of milk allergies are IgE-mediated, and the remaining 46% are classified as non-IgE mediated [6]. This however depends on definition of non-IgE-mediated allergy; while approximately 3-5%, a larger percentage of infants (10-15%) manifests gastrointestinal discomfort which sometimes could be classified as allergy.

The risk of developing allergic sensitization, atopic dermatitis and asthma is increased in children with a positive family history for atopy in first-degree relatives; however it has not been demonstrated that there is an increased risk for CMA if there is a positive family history.

Allergic symptoms often develop in a common sequence and pattern in what is termed the "allergic march" with progression of atopic disease from eczema to asthma, and then to allergic rhinoconjunctivitis [7]. It is thought to be the result of regional allergic response which then leads to systemic allergic inflammation. While genetic and environmental factors predispose to developing the allergic march; data support four possible interventions to prevent progression of the allergic march [8]:

Comparable international epidemiological evidence on CMA prevalence is lacking, predominantly due to methodological and geographical differences in clinical evaluation [5]. European prospective cohort studies from the last 15 years suggest that the prevalence of CMA is between 1.9% and 4.9%; this is consistent with a 2002 meta analysis of 229 articles on CMA which found that CMA is the most common food allergy in early childhood with an incidence of 2% to 3% in the first year of life [9].

Interestingly, the perception of milk allergy is much higher than confirmed CMA, with patient reports suggesting hypersensitive reactions to cow milk in preschoolers ranging between 1% and 17.5% [3]. As a result, it is desirable to undertake controlled elimination or milk challenge procedures before switching to more expensive formulae.

Most infants with CMA develop symptoms within the first month after introduction of CMP-based formula. The majority has two or more symptoms from two or more organ systems. Prognosis of CMA in infancy is good with a remission rate of approximately 85% to 90% at 3 years. In particular, gastrointestinal symptoms show a good prognosis [8]. While the majority of infants present with two or more symptoms, this may be an artifact of practitioners not identifying allergy in the presence of only a single symptom.

It is interesting to note however, that the vast majority of data come from specialized centers, and the epidemiology of CMA in primary care is unclear.

The most frequent symptoms are listed in Table 1. Except for anaphylaxis, there is not one symptom that is specific for CMA. CMA rarely develops after the age of 12 months, and most of the time develops within two months after the introduction of cow milk in the diet. CMA is also more likely if more than one organ system is involved. Recently, a symptom-based score was developed, what may contribute to diagnose CMA since an initial score >12 decreasing to <6 under elimination diet was related with a positive predictive value of 80% to have a positive challenge test (Table 2) [10,11]. A challenge test is considered as the golden standard diagnostic test, but does in fact not proof that the immune system is involved. Although a double-blind challenged test is more accurate, most guidelines accept an open challenge to confirm the diagnosis of CMA.

Where infants are formula fed, either exclusively or as a supplement to breastfeeding, it is common for pediatricians to change the formula when symptoms of intolerance occur [4]. A number of alternatives to cow's milk-based formulae exist and include [3]:

Milk formulae can be hydrolyzed in order to remove allergenic epitopes [12]. pHF have been developed with the aim of minimizing the number of sensitizing epitopes within milk proteins, while at the same time retaining peptides with sufficient size and immunogenicity to stimulate the induction of oral tolerance (and thus, they are not suitable in treatment). eHF have been extensively hydrolyzed in order to destroy allergenic epitopes; in which most of the nitrogen is in the form of free amino acids and peptides <1,500 kDa [7]. eHFs are indicated in treatment and in prevention. AAF formulae have been developed to overcome the hypersensitivity that can arise from the residual proteins in eHF. AAF are only indicated in treatment. While eHF and AAF remove allergenicity, in CMA prevention the loss of immunogenicity also prevents the immune system from developing tolerance to milk proteins [12]. As a result, pHF is commonly used for prevention of allergy. In CMA treatment, as pHFs contain larger peptides than eHF, they trigger activation of symptoms in a relatively large percentage of already sensitized infants and are therefore not recommended where there is a risk of severe CMA symptoms [12]. AAF is tolerated by >95% of those allergic to cow's milk and are therefore hypoallergenic, while pHF is tolerated by approximately 50-66% of milk allergic individuals and are therefore not considered hypoallergenic [13]. However, while pHF is not considered "hypoallergenic" by these criteria, it is acknowledged that they have a reduced allergenicity and therefore have a place, and are frequently used by practitioners, in the prevention of infant allergy. Decisions about when and how formula should be changed can vary between practitioners, and as such a number of guidelines aimed at harmonizing diagnosis and treatment strategy exist. Rice hydrolysates are safe alternatives for eHFs in the treatment of CMPA [14]. Soy infant formula has been shown to be safe [15], and to be effective in 85-90 % of the infants with CMPA [16]. Other mammalian milks are not indicated in the treatment of CMPA as most of them are nutritionally not adequate as they are no "infant formula". In some countries, goat's milk exists as commercialized infant formula and is adapted to the nutritional needs of infants. However, the cross-reactivity with CMP is about 80% [17]. As a consequence, milk from other mammalians cannot be recommended in the treatment of CMPA.

It is still difficult to diagnose CMA. Extensively hydrolyzed cow's milk protein based is the preferred treatment option. Amino acid formula should be reserved for the most difficult cases. Soy and extensive rice hydrolysate formulas are valuable second choice therapeutic options.