Controversies in drug allergy: Testing for delayed reactions

Abstract

Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell-mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches.

Keywords: Delayed; HLA; Stevens-Johnson syndrome/toxic epidermal necrolysis; acute generalized exanthematous pustulosis; drug reaction with eosinophilia and systemic symptoms; fixed drug eruption; intradermal; oral challenge; patch; prick.

Figure 1.

A. Extended Gell & Coombs Classification of Delayed T-cell mediated adverse drug reactions. AGEP, acute generalized exanthematous pustulosis; CTL, cytotoxic T lymphocyte; CXCL8, chemokine 8; GM-CSF granulocyte-macrophage colony stimulating factor; IFN-γ (interferon-γ); IL-interleukin, PMN, polymorphonuclear neutrophil, DRESS, drug reaction with eosinophilia and systemic symptoms; Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN); Th1, helper T cell type 1; Th2, helper T cells type2: TNF-α, tumor necrosis factor-α,(adapted from Pichler et al). Frames below show representative clinical pictures: IVa (positive delayed intradermal to 1% lidocaine in patient with contact reaction to lidocaine (L) without demonstrable cross-reactivity to mepivacaine (C), IVb (maculopapular exanthem); IVc (TEN); IVd (AGEP) B. Proposed mechanisms of T-cell mediated reactions including the hapten/prohapten model, the pharmacological-interaction model and the altered peptide repertoire model that provide a proposed model for how drugs activate T cells. The hapten-prohapten model shows the drug covalently binds to a peptide either intracellularly in the endoplastic reticulum prior to peptide processing and presentation or at the cell surface The pharmacological interaction model (p-i) shows the drug non-covalently binding to the HLA-molecule and/or T-cell receptor to result in direct T-cell activation. The altered peptide repertoire model shows a drug binding non-covalently in the HLA antigen binding cleft that alters the repertoire of self-peptide ligands leading to presentation of novel peptide ligands that are recognized as foreign and elicit an immune response. TCR – T-cell receptor.

Figure 1.

A. Extended Gell & Coombs Classification of Delayed T-cell mediated adverse drug reactions. AGEP, acute generalized exanthematous pustulosis; CTL, cytotoxic T lymphocyte; CXCL8, chemokine 8; GM-CSF granulocyte-macrophage colony stimulating factor; IFN-γ (interferon-γ); IL-interleukin, PMN, polymorphonuclear neutrophil, DRESS, drug reaction with eosinophilia and systemic symptoms; Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN); Th1, helper T cell type 1; Th2, helper T cells type2: TNF-α, tumor necrosis factor-α,(adapted from Pichler et al). Frames below show representative clinical pictures: IVa (positive delayed intradermal to 1% lidocaine in patient with contact reaction to lidocaine (L) without demonstrable cross-reactivity to mepivacaine (C), IVb (maculopapular exanthem); IVc (TEN); IVd (AGEP) B. Proposed mechanisms of T-cell mediated reactions including the hapten/prohapten model, the pharmacological-interaction model and the altered peptide repertoire model that provide a proposed model for how drugs activate T cells. The hapten-prohapten model shows the drug covalently binds to a peptide either intracellularly in the endoplastic reticulum prior to peptide processing and presentation or at the cell surface The pharmacological interaction model (p-i) shows the drug non-covalently binding to the HLA-molecule and/or T-cell receptor to result in direct T-cell activation. The altered peptide repertoire model shows a drug binding non-covalently in the HLA antigen binding cleft that alters the repertoire of self-peptide ligands leading to presentation of novel peptide ligands that are recognized as foreign and elicit an immune response. TCR – T-cell receptor.