Classification of Drug Hypersensitivity into Allergic, p-i, and Pseudo-Allergic Forms

Abstract

Drug hypersensitivity reactions (DHR) are clinically and functionally heterogeneous. Different subclassifications based on timing of symptom appearance or type of immune mechanism have been proposed. Here, we show that the mode of action of drugs leading to immune/inflammatory cell stimulation is a further decisive factor in understanding and managing DHR. Three mechanisms can be delineated: (a) some drugs have or gain the ability to bind covalently to proteins, form new antigens, and thus elicit immune reactions to hapten-carrier complexes (allergic/immune reaction); (b) a substantial part of immune-mediated DHR is due to a typical off-target activity of drugs on immune receptors like HLA and TCR (pharmacological interaction with immune receptors, p-i reactions); such p-i reactions are linked to severe DHR; and (c) symptoms of DHR can also appear if the drug stimulates or inhibits receptors or enzymes of inflammatory cells (pseudo-allergy). These three distinct ways of stimulations of immune or inflammatory cells differ substantially in clinical manifestations, time of appearance, dose dependence, predictability, and cross-reactivity, and thus need to be differentiated.

Drug Hypersensitivity and Desensitizations: Mechanisms and New Approaches

“…This phenotype typically includes the mast cell activation IgE mediated endotype, driven by epitope-specific IgE with mast cells as the main players. Other endotypes include direct complement activation [1,18], HSRs mediated by cyclooxygenase-1 inhibition in Aspirin Exacerbated Respiratory Disease (AERD) and Aspirin Exacerbated Cutaneous Disease (AECD) [19,20], or reactions due to some drugs with THIQ (tetrahydroisoquinoline)motifs which signal through the human G-protein-coupled receptor (MrgprX2) may also induce histamine release are included in the mast cell activation endotype [21,22]. In the past, symptoms such as fever, chills, and pain were not typically associated with allergic reactions, however, they have been reported during HSRs to monoclonals, oxaliplatin, and taxanes [3,6,9,23].…”

“…Recent studies have shown that small molecule drugs may induce systemic non-IgE mediated reactions through the activation of human MC G-protein coupled receptor (MrgprX2) [21,22]. The IgE mediated pathway is the one that is best defined: patients who are predisposed to developing an allergic reaction switch their allergen specific antibodies from IgM to IgE after several exposures.…”

All‐trans‐retinoic acid activated mast cells via Mas‐related G‐protein‐coupled receptor‐X2 in retinoid dermatitis

“…A strong relationship between ATRA and skin mast cells has been confirmed, as mast cell‐deficient Kit W‐sh/W‐sh mice did not show as serious dermatitis as WT mice . Mast cell‐mediated drug hypersensitivity mainly consists of allergic/immune reaction, pharmacological interaction with immune receptors (p‐i reactions), and pseudoallergy . The most frequent form is the IgE‐mediated type I allergic reaction, which occurs rapidly and is induced by antigens via prior exposure.…”

Recent Advances in Clinical Allergy and Immunology

“…Three distinct ways by which stimulation of immune or inflammatory cells associated with typical clinical manifestations, time of appearance, dose dependence, predictability, and cross-reactivity have been identified: (a) an allergic/immune reaction; (b) pharmacological interaction with immune receptors (P-I reactions), and (c) pseudo-allergic reaction (Fig. 2) [81]. Multiple drug hypersensitivity is characterized by long-lasting hypersensitivity reactions to different drugs as a consequence of a massive T cell stimulation that first presents with exanthema or drug rash with eosinophilia and systemic symptoms, while upon the second stimulus, erythroderma, Stevens-Johnson syndrome/toxic epidermal necrolysis, hepatitis, and agranulocytosis may develop [82].…”