Non-IgE-Mediated Immediate Drug-Induced Hypersensitivity Reactions

Immediate drug -induced hypersensitivity reactions (IDHSRs) have conventionally been attributed to an immunoglobulin E (IgE) - mediated mechanism. Nevertheless, it has now been acknowledged that IDHSRs can also occur independently of IgE involvement. Non - IgE-mediated IDHSRs encompass the activation of effector cells, both mast cell - dependent and - independent and the initiation of in fl ammatory pathways through immunogenic and nonimmunogenic mechanisms. The IDHSRs involve in fl ammatory mediators beyond histamine, including the platelet -activating factor, which activates multiple cell types, including smooth muscle, endothelium, and MC, and evidence supports its importance in IgE-mediated reactions in humans. Clinically, distinguishing IgE from non-IgE mechanisms is crucial for future treatment strategies, including drug(s) restriction, readministration approaches, and pretreatment considerations. However, this presents signi fi cant challenges because certain drugs can trigger both mechanisms, and their presentations can appear similarly, ranging from mild to life -threatening symptoms. Thus, history alone is often inadequate for differentiation, and skin tests lack a standardized approach. Moreover, drug -speci fic IgE immunoassays have favorable speci ficity but low sensitivity, and the usefulness of the basophil activation test remains debatable. Lastly, no biomarker reliably differentiates between both mechanisms. Whereas nonIgE-mediated mechanisms likely predominate in IDHSRs, reclassifying most drugrelated IDHSRs as nonIgE-mediated, with suggested prevention through dose administration adjustments, is premature and risky. Therefore, continued research and validated diagnostic tests are crucial to improving our capacity to distinguish between these mechanisms, ultimately enhancing patient care. (c) 2024 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2024;12:1109-19)