Advances in understanding of the pathogenesis and therapeutic implications of drug reaction with eosinophilia and systemic symptoms: an updated review

Abstract

Drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome (DRESS/DIHS) is one type of severe cutaneous adverse reaction (SCAR). It is featured by fever, widespread skin lesions, protracted clinical course, internal organ involvement, and possibly long-term autoimmune sequelae. The presence of high-risk human leukocyte antigen (HLA) alleles, hypersensitivity reaction after culprit drug ingestion, and human herpesvirus reactivation may all contribute to its complex clinical manifestations. Some recent studies focusing on the roles of involved cytokines/chemokines and T cells co-signaling pathways in DRESS/DIHS were conducted. In addition, some predictors of disease severity and prognosis were also reported. In this review, we provided an update on the current understanding of the pathogenesis, potential biomarkers, and the relevant therapeutic rationales of DRESS/DIHS.

Keywords: DIHS; HHV-6; drug reaction with eosinophilia and systemic symptoms; eosinophilia; hypersensitivity.

Figure 1

Pathogenesis of DRESS/DIHS. The affected skin is rich in CD4⁺ and CD8⁺ T cells, regulatory T cells (Tregs), plasma dendritic cells, and type 2 innate lymphoid cells (ILC2). TARC secreted by keratinocytes and DCs would recruit type 2 T helper (Th2) cells to the skin. Through antigen presentation, drug-specific T cells are activated and produced Th2-associated cytokines including IL-4, IL-5, and IL-13. Increased IL-33 levels, which may be secreted by keratinocytes and macrophages, activate ILC2 via its receptor ST2 and promote the production of Th2-associated cytokines. The IL-5, eotaxin-1, and TARC synergistically promote the local accumulation of harmful eosinophils. Th1-associated cytokines and chemokines like IFN-γ, TNF-α, and C-X-C motif chemokine 10 (CXCL-10) have also overexpressed in some cases. Viral reactivation is another characteristic hallmark in DRESS/DIHS. The inset shows the involved signals of antigen presentation. Traditionally, the specific antigen presented by the MHC molecule is recognized by antigen-specific TCR with the aid of B7-CD28 costimulation. The costimulatory interaction between OX40L and OX40, which is presented by activated T cells, may prevent T cells from being inhibited by Tregs. The binding of PD-1 and PDL1/L2 otherwise transmit signals to inhibit T cell proliferation and cytokines production. A compromised inhibitory mechanism of Tregs and PD-1/PDL1/L2 axes can lead to the promotion of these hypersensitivity reactions. CXCL-10, C-X-C motif chemokine 10; DC, dendritic cell; DRESS/DIHS, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome; IFN-γ, interferon-γ; ILC2, type 2 innate lymphoid cells; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand 1; TARC, thymus activation-regulated chemokine; TNF-α, tumor necrosis factor-α; Treg, regulatory T cell.

Figure 2

Models of antigen presentation and T-cell activation by drugs. In the hapten/pro-hapten model, the drug (hapten) covalently binds to a larger self-peptide and forms a neoantigen which could be presented by specific HLA alleles and recognized by the specific T cell receptor. In the p-i model, the drug would bind to the HLA or TCR noncovalently, which is a processing-independent interaction and can stimulate T cell activation directly. In the altered self-peptide repertoire model, the drug may bind to either the HLA (altered HLA) or TCR (altered TCR), leading to a conformational change and altering the repertoire of self-peptides presented to T cells. APC, antigen-presenting cell; HLA, human leukocyte antigen; TCR, T cell receptor.

Figure 3

The virus-release hypothesis proposed by Pichler et al. (151) The massive p-i stimulation in DRESS/DIHS can lead to strong polyclonal T-cell expansion and activation. These p-i activated T cells are composed of cytotoxic T cells targeted at various internal organs, skin, and even virus peptide-specific T cells (may be reactive against HHV-6, CMV, EBV, etc.). These cytotoxic T cells attack organs, skin, and herpes peptide-expressing cells, causing acute symptoms of DRESS/DIHS and subsequent release of the prefabricated viruses. Therefore, viremia of various herpes viruses may be detected at a later stage. APC, antigen-presenting cell; CMV, cytomegalovirus; DRESS/DIHS, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome; EBV, Epstein–Barr virus; HHV-6, human herpesvirus-6; T_HHV-6, HHV-6 specific cytotoxic T cell; T_x, drug-stimulated T cells against various tissue.