Effectiveness and safety of low‐dose oral immunotherapy protocols in paediatric milk and egg allergy

, feel safely happy and increase the threshold with ultra- low-dose allergenic food without stress. Importantly, in addition to OIT, children must have complete eczema treatment because eczema management influences food al - lergy tolerance. 6,7 Our study has several limitations. First, this study had a retro - spective, design, included a small and heterogeneous population, and lacked standardization of treatment groups, which are the features of a clinical trial. Therefore, this study's quality was lower than that of a prospective randomized controlled trial. Second, the OIT method used for each patient was determined after consulting physicians, and we cannot currently recommend a uniform OIT ap - proach for all children with food allergy. 8 Nevertheless, our study was conducted in the real-world clinical setting. Future clinical stud - ies are warranted to elucidate the role of allergen quantity in the im - mune mechanism underlying the anti-allergic response observed in humans to standardize the OIT method. We will evaluate the results of a randomized controlled trial (STITCH study, UMIN000043354) to further investigate patient-oriented allergies in the near future. 9 Third, the pre-OIT characteristics were imbalanced, and the baseline threshold of reactivity was higher for the ‘conventional’ arm. How - ever, we performed propensity score weighting analysis to adjust for this imbalance. In summary, ultra-low dose OIT was found to be more effective and safer than conventional OITs among children who were allergic to hen egg and cow milk.

immunotolerance in young children. 2 We designed several OIT protocols for children with food allergy based on shared decisionmaking.We classified the children into four OIT groups according to the four dosing strategies: super ultra-low dose (group A, starting at 1/10,000 of the initial threshold dose), ultra-low dose (group B, starting at 1/100 of the initial threshold dose), low dose (group C, starting at 1/10 of the initial threshold dose) and conventional slow dose (group D, starting just below or full of the initial threshold dose).
For groups A, B and C, the maintenance dose was 1/10 of the initial threshold dose; for group D, the maintenance dose was more than the initial threshold dose.Children who continued avoidance without OIT were the avoidance group (group E).Additional information about study methods and findings are available in the following the repository (https://doi.org/10.5281/zenodo.8377790).
We included 217 children.The median age was 6 years, and 69.6% children had atopic dermatitis.Figure 1 shows the outcomes of OIT.
The proportions of children who increased the cumulative tolerated dose were 69.7%, 88.2%, 70.6% and 56.8% in groups A, B, C and D, respectively, which was higher than the proportion in group E (26.3%; p < .05).The rate was higher in group B (88.2%) than in group D (56.8%; p < .001).The incidence rates of AEs related to OIT in groups A, B, C and D were 24.2%, 13.7%, 29.4% and 70.5%, respectively (p < .01 or p < .001).There was a significant difference in food-specific IgE level between group B (93.8%) and group E (61.1%; p < .05).In groups A, B and C (low-dose OITs), almost all AEs had minimal symptoms, such as itchy mouth/throat (27.6%, 13.7% and 23.8%), and anaphylaxis was absent.However, children in conventional OIT group D experienced many allergic symptoms (70.5%), including anaphylaxis.
Our study highlights that ultra-low dose OIT was effective and safe methods that could induce immunotolerance and increase the tolerated dose in the OFC without serious AEs compared with conventional OIT.The strength of our study was that we used various OIT strategies as active comparators.Our efficacy results were similar to those for conventional egg OIT reported in the Cochrane review. 1 Tiny doses of allergens may be sufficient to induce immunotolerance in childhood egg and milk allergy.Regarding OIT safety, a Cochrane review demonstrated 75% AE rate in egg OIT, 1 but in our study, only 13.7% receiving ultra-low dose OIT had AEs.Children with severe food allergy can be treated with ultra-low dose OIT because the starting dose is significantly lower than the threshold.
Most physicians believe that large quantities of allergenic foods are required for immune tolerance.The understanding of immune tolerance in OIT, at least in milk and egg OIT in children, needs to be revised.According to our OFC data, even children highly IgE-sensitized to cow milk had very low-dose thresholds, termed the eliciting dose or ED. 3 For example, the threshold of ED10 for cow milk with IgE 100 UA/mL was 0.07 mL of milk.Absolute avoidance of hen egg did not provide better future tolerance for hen egg allergy. 4Our physicians encourage children and their families to conduct OFC despite ultra-low doses.Food-allergic children could induce immunotolerance despite ultra-low doses (not up-dosing over eliciting dose).
Regarding AEs, anaphylaxis during OFC could lead to acute stress symptoms because of the negative experience of a traumatic event. 5e purpose of OFC is not only to evaluate the eliciting dose but also to secure a safe dose without any symptoms and without the capacity to induce allergic reactions.The final goal for children and families is that the children can enjoy eating, feel safely happy and increase the threshold with ultra-low-dose allergenic food without stress.Importantly, in addition to OIT, children must have complete eczema treatment because eczema management influences food allergy tolerance. 6,7r study has several limitations.First, this study had a retrospective, design, included a small and heterogeneous population, and lacked standardization of treatment groups, which are the features of a clinical trial.Therefore, this study's quality was lower than that of a prospective randomized controlled trial.Second, the OIT method used for each patient was determined after consulting physicians, and we cannot currently recommend a uniform OIT approach for all children with food allergy. 8Nevertheless, our study was conducted in the real-world clinical setting.Future clinical studies are warranted to elucidate the role of allergen quantity in the immune mechanism underlying the anti-allergic response observed in humans to standardize the OIT method.We will evaluate the results of a randomized controlled trial (STITCH study, UMIN000043354) to further investigate patient-oriented allergies in the near future. 9ird, the pre-OIT characteristics were imbalanced, and the baseline threshold of reactivity was higher for the 'conventional' arm.However, we performed propensity score weighting analysis to adjust for this imbalance.
In summary, ultra-low dose OIT was found to be more effective and safer than conventional OITs among children who were allergic to hen egg and cow milk.

Key messages
• Ultra-low-dose OIT was effective and safe without anaphylaxis/severe adverse events.
• Children with severe milk/egg allergy can be treated with ultra-low dose OIT.

FU
This study was funded by the National Center for Child Health and Development.K E Y WO R DS adverse events, effectiveness, food allergy, oral immunotherapy, safety AUTH O R CO NTR I B UTI O N S YM, KY and YO contributed to the study design.YM and LY analysed the data and prepared the study results.All co-authors contributed to the interpretation of the findings.YM and KY led the drafting of the manuscript.All co-authors contributed to revising the manuscript and approved the final version.