Drug hypersensitivity reactions: review of the state of the science for prediction and diagnosis

Abstract

Drug hypersensitivity reactions (DHRs) are a type of adverse drug reaction that can occur with different classes of drugs and affect multiple organ systems and patient populations. DHRs can be classified as allergic or non-allergic based on the cellular mechanisms involved. Whereas nonallergic reactions rely mainly on the innate immune system, allergic reactions involve the generation of an adaptive immune response. Consequently, drug allergies are DHRs for which an immunological mechanism, with antibody and/or T cell, is demonstrated. Despite decades of research, methods to predict the potential for a new chemical entity to cause DHRs or to correctly attribute DHRs to a specific mechanism and a specific molecule are not well-established. This review will focus on allergic reactions induced by systemically administered low-molecular weight drugs with an emphasis on drug- and patient-specific factors that could influence the development of DHRs. Strategies for predicting and diagnosing DHRs, including potential tools based on the current state of the science, will also be discussed.

Keywords: diagnosis; drug allergy; drug hypersensitivity; prediction.

Figure 1.

Immunological overview of T cell activation and drug allergy. T cells are crucial for drug allergy and central to all immune-mediated hypersensitivity reactions. Chemically reactive drugs or drug metabolites can interact with the immune system through different modes of action. According to the hapten hypothesis, drugs bind covalently to proteins and form a new antigen. Signal 1 is the recognition of the processed antigen, presented by MHC molecules, by the TCR. The benzylpenicillin and piperacillin models of Azoury et al. (2018) and Sullivan et al. (2015) belong to this classical pathway. In addition to Signal 1, co-stimulation (Signal 2) is required to promote T cell activation and patient immunization. Thus, if danger signals are absent, Signal 2 is not initiated leading to immune tolerance. If the subject is exposed to the drug again, urticaria/angioedema/anaphylaxis can occur if drug-specific IgE/IgG are formed. Alternatively, exanthema/DRESS/SJS/DILI can occur if T cells are activated. In this context, along with the hapten hypothesis, other mechanisms of memory T cell activation are presented: PI concept, altered peptide repertoire, and heterologous immunity. HSA, human serum albumin; TF, transferrin; MPO, myeloperoxidase; Hb, hemoglobin; Lys, lysine; Cys, cysteine; His, histidine; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

Figure 2.

Strategy to identify T cell epitopes implicated in patient immunization to drugs based on an in silico approach and functional biological assays. The presence of BP on HSA was confirmed using mass spectrometry and BP‐binding sites on HSA were identified through tryptic digestion of BP‐HSA bioconjugates followed by MALDI‐MS and nano‐LC‐MS/MS analysis. 15-mer long BP‐haptenated peptides identified as potential T cell epitopes were selected using the MHC II binding prediction tool available at the IEDB. BP‐haptenated peptides were synthesized using a BP‐lysine monomer and standard Fmoc chemistry. Cocultures were established with CD4⁺ T cells from non‐allergic donors and mature autologous DCs loaded with BP‐HSA or BP‐haptenated peptides from HSA. The CD4⁺ T cell response specific for BP‐HSA or for individual BP‐haptenated peptides was measured using an ELISpot assay. BP‐HSA and BP‐haptenated peptides were recognized by naïve T cells from different healthy donors. Most donors responded to 3 peptides with BP covalently bound on lysines 159, 212, and 525. Two of these benzylpenicilloylated peptides (lysines 159 and 525) were also found to induce PBMC proliferation in patients with allergic reaction to penicillins. Thus, this strategy allows the identification of the drug-haptenated peptides involved in the immunization of patients to drugs.

Figure 3.

Retrospective analysis to understand potential to induce a DHR. This figure highlights the steps that should be followed to perform a retrospective analysis for DHR. DHR, drug hypersensitivity reaction.