From bench to bedside: advances in standardized oral immunotherapy and early predictors of persistent cow's milk allergy in children.

Abstract

Immunoglobulin E (IgE)-mediated cow's milk allergy (CMA) remains the most prevalent pediatric food allergy and a major cause of early-life anaphylaxis, with a substantial proportion of children developing persistent disease despite traditional avoidance-based management. Oral immunotherapy (OIT) has emerged as a proactive strategy that modulates the allergic immune response through controlled and sustained allergen exposure, shifting immunity from T-helper (Th) 2-dominant pathways toward a more regulatory and tolerogenic profile. Current evidence from randomized trials and real-world cohorts demonstrates that cow's milk oral immunotherapy (CM-OIT) achieves desensitization in most treated children, reduces accidental reaction risk, and improves quality of life, although sustained unresponsiveness remains variable and protocol-dependent. Marked heterogeneity exists across protocols regarding dosing, antigen formulation, maintenance targets, and escalation speed, reflecting differing therapeutic philosophies rather than standardized practice. Safety concerns, including dose-related reactions and rare cases of eosinophilic esophagitis, underscore the need for careful patient selection, optimization of comorbid atopic diseases, and shared decision-making. Advances in precision immunology, including component-resolved diagnostics, epitope mapping, basophil activation testing, and emerging transcriptomic and microbiome signatures, now enable the earlier identification of children at high risk of persistent CMA who may benefit most from OIT, while low-risk phenotypes can be safely observed. Adjunctive biologic therapy, particularly anti-IgE agents, has improved tolerability and expanded eligibility in high-risk patients. This review synthesizes current evidence on efficacy, safety, biomarkers, protocols, and adjunctive strategies, emphasizing a personalized, risk-adapted approach to CM-OIT and outlining future directions toward standardized formulations, biomarker-guided stratification, and integrated biologic-assisted immunomodulation.