Ultra-low-dose induction phase in oral immunotherapy for children with severe peanut and walnut allergies: a multicenter observational cohort study

Abstract Background Peanut and tree nut allergies are increasing worldwide and have become a major cause of anaphylaxis in Japan. Although oral immunotherapy (OIT) is a promising treatment, conventional OIT cannot be initiated in patients with an extremely low reaction threshold because they fail to tolerate oral food challenges requiring mg-level protein ingestion. Consequently, strict avoidance remains their only option, resulting in persistent anxiety regarding accidental exposure. In this study, we introduced an ultra-low-dose induction phase before conventional OIT to evaluate whether this approach enables such patients to safely overcome allergen avoidance. Methods In this multicenter observational cohort study, we enrolled participants aged 3–15 years who were unable to start conventional OIT owing to an extremely low reaction threshold or fear related to previous anaphylactic reactions. The ultra-low-dose induction phase consisted of individually adjusted diluted allergen extracts administered as drops containing proteins at the pg-to-ng-level. The primary endpoint was the proportion of patients who successfully transitioned to conventional OIT. Secondary endpoints included changes in drop threshold doses, skin prick test wheal sizes, allergen-specific and component-specific immunoglobulin E (IgE) levels, and adverse events. Results Ten patients with peanut allergy and 11 patients with walnut allergy were enrolled, most of whom had a history of anaphylaxis. During the study period, all patients with peanut allergy and 90.9% of patients with walnut allergy successfully transitioned to conventional OIT and tolerated mg-level powder ingestion. Most evaluated indicators, including threshold protein doses in drop challenges, skin prick test wheal sizes, and component-specific IgE levels, were consistent with this outcome. Adverse reactions during home-based drop maintenance were rare (0.02% for peanuts and 0.09% for walnuts). Although higher reaction rates were observed during initial drop challenges and the in-clinic build-up phases, most reactions were mild to moderate, and adrenaline administration was not required. Conclusions The ultra-low-dose induction phase appears to be a promising treatment strategy for children with severe peanut or walnut allergies who have extremely low reaction thresholds. This approach may render conventional OIT feasible for patients who were previously unable to initiate treatment. Registration details University Hospital Medical Information Network Center; https://www.umin.ac.jp/ (R000052813).