# Improving Safety in Food Allergen-Specific Oral Immunotherapy
## 3 Food Allergen Immunotherapy  
### Milk Oral Immunotherapy  
Cow's milk allergy (CMA) is one of the most common food allergies in infancy and early childhood. The prevalence of self-reporting CMA is estimated to be 1.2-17%, but it is much lower if only cases confirmed by oral food challenges (OFC) are considered, with a range of up to 3% [7]. The cow's milk (CM) elimination diet carries a high burden because CM is the staple food in children's diets and can cause nutritional deficit and impaired growth [8], as well as increase the risk of feeding difficulties [9]. Alongside nuts and peanuts, CM is among the most common causes of food-induced anaphylaxis [7]. Fortunately, CMA is commonly outgrown by the age of five years. For children with persistent CMA, OIT is a potential therapeutic approach that reduces reactivity or induces tolerance to CM protein [2]. Almost all of the published articles about milk OIT included children older than four years. Selected articles are listed in Table 1.  
Although the first studies on milk OIT date back to the beginning of the century, the first RCT was published by [PERSON] et al. in 2008 [10]. In this placebo-controlled RCT, the milk threshold reaction significantly increased in all children in the OIT group, with no change in the placebo group. ARs were common, but nearly 90% were transient and did not require treatment. However, it should be noted that this study did not include children with severe allergies, which may have contributed to the low rate of severe AR. In a follow-up study, desensitized children were advised to regularly consume dairy products at home. ARs were common, but the rate of reactions decreased over time, regardless of increasing milk doses. Several reactions were multisystemic but they were often linked to exercise or viral illness [11]. The first RCT with OIT among children who suffered severe CMA was published by [PERSON] et al. in 2008 [12]. Although they had severe allergies, 36% of children in the OIT group were able to consume dairy products without restrictions after one year of treatment, as opposed to none in the control group. Almost all children had ARs during OIT, mainly cutaneous or abdominal. Epinephrine was applied in 13.3% of administered doses. A more recent RCT reported similar results in 30 children with severe milk allergies [13]. The treatment efficacy for desensitization was 50%, compared to 0% in the control group, with a threshold increase of 3090%. Unfortunately, the incidence of ARs was also high. More than 80% of the children in the OIT group had ARs, while 43% needed adrenaline. As OIT in children with severe CMA was accompanied by frequent ARs, with high rates of severe reactions, [PERSON] et al. designed a study with a very low maintenance dose of milk (3 mL) [14]. After one year of treatment, unresponsiveness in the OIT group was significantly higher than in the control group. More than 50% of children tolerated 3 mL of milk, and 33% tolerated 25 mL of milk, significantly higher than the maintenance dose. ARs were more frequent at the beginning of the build-up phase, with antihistamines as the most common treatment. Therefore, low-dose-induction OIT may be a relatively safe and effective treatment method, reducing symptoms after accidental exposure to small amounts of milk. Slow low-dose OIT for different allergens (milk, egg, wheat) in children with severe food allergies also showed significant efficacy and good safety (more than 60% of children on milk OIT did not have any ARs) [15]. To further increase the safety of OIT while maintaining its effectiveness, efforts have been made to use less allergenic forms of milk. It is known that the majority of children with CMA can tolerate heated or baked milk [16]. The heating process could change the allergenicity of milk proteins through conformational changes in specific epitopes of whey protein, especially in combination with wheat flour matrix [17].