Non-IgE-Mediated Immediate Drug-Induced Hypersensitivity Reactions

Abstract

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 inflammatory pathways through immunogenic and nonimmunogenic mechanisms. The IDHSRs involve inflammatory 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 significant 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-specific IgE immunoassays have favorable specificity but low sensitivity, and the usefulness of the basophil activation test remains debatable. Lastly, no biomarker reliably differentiates between both mechanisms. Whereas non-IgE-mediated mechanisms likely predominate in IDHSRs, reclassifying most drug-related IDHSRs as non-IgE-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.

Keywords: Anaphylaxis; Anaphylaxis mechanisms; Drug allergy; Drug hypersensitivity; Infusion reaction; Mast cells; Non–IgE-mediated immediate drug hypersensitivity reactions.

Figure 1.. Mechanisms of IDHSRs:

Immunologic and non-immunologic pathways, MC-dependent and independent mechanisms, and associated mediators. *Drugs reported to trigger both IgE and non-IgE-mediated IDHSR mechanisms. **Tryptase biological roles are unclear. Elevated tryptase indicates MC and basophil involvement; however, it does not reliably distinguish between IgE- and non-IgE-mediated IDHSRs. Abbreviations: FcεRI, high-affinity IgE receptor; FcγR, Fc gamma receptor; IDHSR, immediate drug-induced hypersensitivity reactions; MC, mast cell; MRGPRX2, mas-related G-protein coupled receptor X2; NMBA, neuromuscular blocking agent; PAF, platelet-activating factor; PMNs, polymorphonuclear neutrophils.

Figure 2.. CARPA Cascade:

Pathway of complement-mediated IDHSRs. Numerous drugs can activate complement leading to C3a, C5a anaphylatoxin release, comprising signal or “hit” 1. In addition, pegylated liposomes can directly bind to pattern recognition receptors on macrophages, MCs, and basophils, comprising signal or “hit” 2. These two signals contribute to MC, basophil, and macrophage activation and mediator release resulting in end-physiologic changes. Concomitant activation of endothelial and smooth muscle directly by C3a and C5a compound these physiologic changes. Abbreviations: CARPA, complement activation-related pseudoallergy; IDHSR, immediate drug-induced hypersensitivity reactions; MC, mast cell; PAF, platelet activating factor.