Tools to improve the diagnosis and management of T-cell mediated adverse drug reactions

Abstract

Delayed drug T-cell immune-mediated hypersensitivity reactions have a large clinical heterogeneity varying from mild maculopapular exanthema (MPE) to severe cutaneous adverse reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and severe skin necrosis and blistering as seen in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Given the knowledge gaps related to the immunopathogenesis of these conditions, the absence of validated diagnostic tools and the significant associated morbidity and mortality, patients with SCARs often have limited drug choices. We performed a comprehensive review aiming to evaluate in vivo diagnostic tools such as delayed intradermal skin and patch testing and ex vivo/in vitro research assays such as the lymphocyte transformation test (LTT) and the enzyme-linked ImmunoSpot (ELISpot) assay. We searched through PubMed using the terms “drug allergy,” “in vivo” and “ex vivo” for original papers in the last 10 years. A detailed meticulous approach adapted to the various clinical phenotypes is recommended for the diagnostic and management of delayed drug hypersensitivity reactions. This review highlights the current diagnostic tools for the delayed drug hypersensitivity phenotypes.

Immunological Mechanisms in Cutaneous Adverse Drug Reactions

“…Among these clinical features, urticaria and anaphylaxis are typically immediate reactions caused by IgE-mediated type I hypersensitivity reactions. In contrast, exanthematous eruptions and severe cutaneous ADRs other than anaphylaxis are delayed reactions involving T-cell-mediated type IV hypersensitivity reactions ( Table 2 ) ( Roujeau, 2006 ; Limsuwan and Demoly, 2010 ; Peter et al ., 2017 ; Romano et al ., 2017 ; Wang et al ., 2018 ; Bellon, 2019 ; Lehloenya et al ., 2020 ; Vocanson et al ., 2020 ; Copaescu et al ., 2022 ; Wilkerson, 2022 ; Wuillemin et al ., 2022 ). The isolation of drug-reactive T cells and their association with human leukocyte antigen (HLA) in delayed ADRs provide further support for T cell-mediated reactions as the underlying immunological mechanism ( Pavlos et al ., 2015 ; Pirmohamed et al ., 2015 ; White et al ., 2015 ).…”

“…Various T cell subpopulations, such as cytotoxic T cells, Th1 cells, Th2 cells, Th17 cells, and Tregs, can participate in the development of severe ADRs. Subpopulations involved in the innate immune system and tissue-resident cells, including keratinocytes, can also contribute to the development of these reactions ( Roujeau, 2006 ; Limsuwan and Demoly, 2010 ; Peter et al ., 2017 ; Romano et al ., 2017 ; Wang et al ., 2018 ; Bellon, 2019 ; Lehloenya et al ., 2020 ; Vocanson et al ., 2020 ; Copaescu et al ., 2022 ; Wilkerson, 2022 ; Wuillemin et al ., 2022 ). However, the mechanism underlying neutrophilic skin inflammation, a hallmark of AGEP, remains unclear.…”

“…This condition typically occurs several days or weeks after drug initiation or discontinuation. Similar to other delayed severe ADRs, it is believed to result from T cell-mediated type IV hypersensitivity reactions ( Roujeau, 2006 ; Limsuwan and Demoly, 2010 ; Peter et al ., 2017 ; Romano et al ., 2017 ; Wang et al ., 2018 ; Bellon, 2019 ; Lehloenya et al ., 2020 ; Vocanson et al ., 2020 ; Copaescu et al ., 2022 ; Wilkerson, 2022 ; Wuillemin et al ., 2022 ). Rather than the hapten theory, the prevailing view is that the main mechanism involves a direct non-covalent interaction between drugs and MHC molecules and T cell receptors (the p-i reactions) ( Pichler, 2019 ; Sueki et al ., 2022 ; Wuillemin et al ., 2022 ).…”

“…Similar to other delayed severe ADRs, these conditions are T cell-mediated immune disorders. The interaction of drug-specific T cells, cytotoxic T cells activated by the drug, with HLA class I restriction and T cell receptors can play a key role in the immune mechanism ( Roujeau, 2006 ; Limsuwan and Demoly, 2010 ; Peter et al ., 2017 ; Romano et al ., 2017 ; Wang et al ., 2018 ; Bellon, 2019 ; Lehloenya et al ., 2020 ; Vocanson et al ., 2020 ; Copaescu et al ., 2022 ; Wilkerson, 2022 ; Wuillemin et al ., 2022 ). CD8+ T cells exhibit cytotoxicity against keratinocytes, resulting in keratinocyte apoptosis via the perforin/granzyme B, granulysin, or Fas/FasL pathway ( Saeed and Chodosh, 2016 ; Hasegawa and Abe, 2020 ; Kuijper et al ., 2020 ; Noe and Micheletti, 2020 ; Chen et al ., 2022a ).…”

Updates in SJS/TEN: collaboration, innovation, and community

“…However, there is a range of sensitivity across different drugs from 0% (allopurinol) to >50% (aromatic anticonvulsants) ( 37 , 38 ). Ex vivo and in vitro testing has had lower sensitivity than other severe cutaneous adverse drug reactions and needs more widespread validation and optimization ( 34 , 39 , 40 ). Rechallenge is contraindicated for all suspected culprit drugs and potentially cross-reactive drugs.…”