How Mechanism Knowledge Can Help to Management of Drug Hypersensitivity

Abstract

To describe the mechanisms involved in the heterogeneous drug hypersensitivity reactions and how a better understanding of them can help in the correct diagnosis, the improvement of the in vitro diagnostic methods, and the management of the reaction. We know that drug hypersensitivity reactions are mediated by different mechanisms and until now some drugs have been reported to be able to activate the immune system by a single mechanism while other drugs can be involved in different mechanisms. Moreover, studies show that important clinical aspects such as risk factors, predictability, and cross-reactivity may depend on the drug action mechanism. In this way, recent genetic association studies have shown different human leukocyte antigen (HLA) associations with hypersensitivity reactions depending on the drug and/or the mechanism involved. Mechanistically, drug hypersensitivity reactions (DHRs) are classified as allergic and non-allergic reactions. Allergic reactions have been further classified into reactions mediated by IgE, IgG, or IgM; immune complex/complement activation; and T cells. Non allergic reactions can be associated to nonspecific histamine release, bradykinin increase, complement activation, or changes in the metabolism of arachidonic acid. More recently, a classification based on the mode of action of drugs has been proposed, suggesting three mechanisms involved in DHRs: (i) drugs that bind covalently on macromolecules (e.g., proteins) (allergic/immune reaction); (ii) drugs that bind on immune receptors like HLA and T cell receptors (pharmacological interaction, p-i reactions); and (iii) drugs with the ability to stimulate or inhibit receptors or enzymes of inflammatory cells (pseudo-allergy). An extended knowledge on the mechanisms involved in the heterogeneous DHRs can help to understand differences in sensitization patterns, uncommon clinical manifestations, dependence on drug dose, predictability, and cross-reactivity. For that, a better understanding of them can help in the correct diagnosis and the management of the reaction.