From bench to bedside: advances in standardized oral immunotherapy and early predictors of persistent cow’s milk allergy in children
Main Article Content
Keywords
Cow’s milk allergy; Oral immunotherapy; Pediatric food allergy; Predictive markers; Risk stratification.
Abstract
Immunoglobulin E (IgE)-mediated cow’s milk allergy (CMA) remains the most prevalent pediat-ric 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.
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7. Wood RA, Sicherer SH, Vickery BP, Jones SM, Liu AH, Fleischer DM, et al. The natural history of milk allergy in an observational cohort. J Allergy Clin Immunol. 2013;131(3):805–12. https://doi.org/10.1016/j.jaci.2012.10.060
8. Sinai T, Goldberg MR, Nachshon L, Amitzur-Levy R, Yichie T, Katz Y, et al. Reduced final height and inadequate nutritional intake in cow's milk-allergic young adults. J Allergy Clin Immunol Pract. 2019;7(2):509–15. https://doi.org/10.1016/j.jaip.2018.11.038
9. Engel ML, Warren CM, Herbert LJ, Pappalardo AA, Ramos A, Gupta RS. The psychosocial burden of pediatric food allergy in the United States: A population-based survey. J Allergy Clin Immunol Pract. 2025;13(3):630–8 e4. https://doi.org/10.1016/j.jaip.2024.12.007
10. Gunal O, Sefer AP, Utuk B, Altunbas MY, Güngören EY, Babayeva R, Eltan SB, et al. Cross-sectional analysis of health quality, treatment satisfaction and adherence in children with food allergy. Clin Exp Health Sci. 2025;15:217–25. https://doi.org/10.33808/clinexphealthsci.1589757
11. McHenry M, Begin P, Chan ES, Latrous M, Kim H. Food oral immunotherapy. Allergy Asthma Clin Immunol. 2025;20(Suppl 3):82. https://doi.org/10.1186/s13223-025-00948-5
12. Riggioni C, Oton T, Carmona L, Du Toit G, Skypala I, Santos AF. Immunotherapy and biologics in the management of IgE-mediated food allergy: Systematic review and meta-analyses of efficacy and safety. Allergy. 2024;79(8):2097–127. https://doi.org/10.1111/all.16129
13. Bognanni A, Chu DK, Firmino RT, Arasi S, Waffenschmidt S, Agarwal A, et al. World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guideline Update – XIII – Oral immunotherapy for CMA – Systematic review. World Allergy Organ J. 2022;15(9):100682. https://doi.org/10.1016/j.waojou.2022.100682
14. Pajno GB, Fernandez-Rivas M, Arasi S, Roberts G, Akdis CA, Alvaro-Lozano M, et al. EAACI guidelines on allergen immunotherapy: IgE-mediated food allergy. Allergy. 2018;73(4):799–815. https://doi.org/10.1111/all.13319
15. Wang Y, Liu S, Lu M, Guo J, Lv C, Huang L. Oral immunotherapy for cow's milk allergy in children: A systematic review and meta-analysis. Front Immunol. 2025;16:1570050. https://doi.org/10.3389/fimmu.2025.1570050
16. Begin P, Chan ES, Kim H, Wagner M, Cellier MS, Favron-Godbout C, et al. CSACI guidelines for the ethical, evidence-based and patient-oriented clinical practice of oral immunotherapy in IgE-mediated food allergy. Allergy Asthma Clin Immunol. 2020;16:20. https://doi.org/10.1186/s13223-020-0413-7
17. Esty B, Maciag MC, Bartnikas LM, Petty CR, MacGinnitie AJ, Sheehan WJ, et al. Predicting outcomes of baked egg and baked milk oral food challenges by using a ratio of food-specific IgE to total IgE. J Allergy Clin Immunol Pract. 2021;9(4):1750–2 e1. https://doi.org/10.1016/j.jaip.2020.11.004
18. Altunbas MY, Gungoren EY, Can S, Amirov R, Ozturk N, Bozkurt S, et al. Early markers of baked milk and egg tolerance in young children with IgE-mediated immediate reactions. Eur Ann Allergy Clin Immunol. 2026;58(2):86-96. https://doi.org/10.23822/EurAnnACI.1764-1489.383
19. Vitaliti G, Cimino C, Coco A, Pratico AD, Lionetti E. The immunopathogenesis of cow's milk protein allergy (CMPA). Ital J Pediatr. 2012;38:35. https://doi.org/10.1186/1824-7288-38-35
20. Carnazza M, Werner R, Tiwari RK, Geliebter J, Li XM, Yang N. The etiology of IgE-mediated food allergy: Potential therapeutics and challenges. Int J Mol Sci. 2025;26(4). https://doi.org/10.3390/ijms26041563
21. Kulis MD, Patil SU, Wambre E, Vickery BP. Immune mechanisms of oral immunotherapy. J Allergy Clin Immunol. 2018;141(2):491–8. https://doi.org/10.1016/j.jaci.2017.12.979
22. Ramsey N, Berin MC. Pathogenesis of IgE-mediated food allergy and implications for future immunotherapeutics. Pediatr Allergy Immunol. 2021;32(7):1416–25. https://doi.org/10.1111/pai.13501
23. Burks AW, Sampson HA, Plaut M, Lack G, Akdis CA. Treatment for food allergy. J Allergy Clin Immunol. 2018;141(1):1–9. https://doi.org/10.1016/j.jaci.2017.11.004
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