# Improving Safety in Food Allergen-Specific Oral Immunotherapy
## 3 Food Allergen Immunotherapy
### Milk Oral Immunotherapy
Incorporating baked milk (BM) into the diets of BM-tolerant children could induce tolerance to more allergenic (less heat-denatured) forms of milk. Children who tolerated BM but reacted to unheated milk(UM) were advised to introduce BM products into their diet, gradually introducing more allerggenic forms of milk (muuffins, pizza, rice pudding and UM). After 36 months, 48% of children who followed the BM diet became tolerant to UM. Severe ARs were not reported in children who could tolerate at least pizza, suggesting that OIT in BM-tolerant children could be a safe option [18]. Two recent RCTs have shown promising results regarding the safety of OIT with heat-processed milk [19; 20]. OIT with heated milk induced tolerance development in a safer manner than OIT with UM in children with a risk of CMA anaphylaxis, but with somewhat lower efficiency. AR rates were significantly lower in BM than in the UM group [19]. An RCT comparing BM OIT and a placebo in children with severe CMA showed that 79% of children in the BM OIT group achieved tolerance of 4 g of BM protein after one year of treatment, compared to 0% in the placebo group [20]. \begin{table}
\begin{tabular}{l l l l l l l l l l} \hline
**Reference** & **Design** & **Sample** & \multicolumn{1}{l}{**Participants**} & \multicolumn{1}{l}{**Form of**} & \multicolumn{1}{l}{**Maintenance**} & \multicolumn{1}{l}{**Efficacy**} & \multicolumn{1}{l}{**Safety**} \\  & & & & **Characteristics** & & & & & & & \\  & & & & & & & & & & & \\ \hline \multirow{4}{*}{[PERSON] et al. (2008)[10]} & Double-blind, & & & DBFCCF \textless{} 2.5 g MP & & & & & & & \\  & blind, & & N = 19 (6-17 y) & & Excluding: history & non-fat milk & 3-4 & & & & \\  & & & & powder & months & & & & \\  & & &  
\begin{table}
\begin{tabular}{l c c c c c c c c} \hline \hline
**Reference** & **Design** & **Sample** & **Participants** & **Form of** & **Duration** & **Maintenance** & **Efficacy** & **Safety** \\ \hline \multirow{4}{*}{[PERSON] et al. (2021)[18]} & & \multicolumn{2}{c}{Positive BDPCFC to} & & & & & & \\  & & N = 160 (4-10 y) & different milk form & & & & & \\  & & A = 126 & & & & & \\  & & RRM = 41 & Excluding history & & & & & \\  & & RRM = 85 & & & & & \\  & & C = 34 & & & & & \\  & & & asthma/EoE & & &  
ARs were common, but, in 98% of cases, they were mild, and less than 1% had severe reactions. Gastrointestinal side effects, which dominated, decreased during the maintenance period and mainly did not require treatment. After two years of BM OIT, 43% of children could tolerate 2 g or more of UM protein, suggesting that there may be increased efficacy with a longer treatment duration. Dose-related symptoms decreased in the second year compared to the first year, supporting the idea that safety likely increases over time with regular ingestion [22]. Alongside heat processing, the allergenicity of CM can be decreased or lost after enzymatic hydrolysis breaks down CM proteins. The effect of allergenicity depends on the final peptide fragment size. Extensively hydrolyzed formulas (eHF) with peptides < 3000 Da are intended for feeding infants with CMA. Partially hydrolyzed formulas (pHF) contain more peptides (3000-5000 Da). Although not intended for infants with CMA, pHF could potentially induce immunological changes minimalizing AR due to lower allergenicity. OIT involving pHF ingestion in a safe manner improved tolerance in children suffering from severe CMA, compared to children consuming eHF [21].