Drug-Induced Hypersensitivity Syndrome (DIHS)/Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS): Clinical Features and Pathogenesis

Abstract

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is one example of a severe delayed T-cell-mediated adverse drug reaction. DIHS/DRESS presents with fever, widespread rash and facial edema, organ involvement, and hematological abnormalities, including eosinophilia and atypical lymphocytosis. DIHS/DRESS is associated with relapse 2 to 4 weeks after acute symptoms, often coinciding with reactivation of prevalent chronic persistent human herpesviruses such as human herpesvirus 6, EBV, and cytomegalovirus. The mortality of DIHS/DRESS is up to 10% and often related to unrecognized myocarditis and cytomegalovirus complications, with longer-term consequences that contribute to morbidity including autoimmune diseases such as thyroiditis. It is essential that all potential drug causes, including all new drugs introduced within the 8 weeks preceding onset of DIHS/DRESS symptoms, are identified. All potential drug culprits, as well as drugs that are closely related structurally to the culprit drug, should be avoided in the future. Systemic corticosteroids have remained the mainstay for the treatment of DIHS/DRESS with internal organ involvement. Steroid-sparing agents, such as cyclosporine, mycophenolate mofetil, and monthly intravenous immune globulin, have been successfully used for treatment, and careful follow-up for cytomegalovirus reactivation is recommended. Strong associations between HLA class I alleles and DIHS/DRESS predisposition include HLA-B∗13:01 and dapsone, HLA-B∗58:01 and allopurinol, and HLA-B∗32:01 and vancomycin. These have opened a pathway for prevention, risk stratification, and earlier diagnosis. Single-cell sequencing and other studies of immunopathogenesis promise to identify targeted treatment approaches.

Keywords: Autoimmune; CMV; Corticosteroids; DIHS; DRESS; EBV; Eosinophilia; HHV-6; HLA; Hypersensitivity.

Figure 1.. Timeline and clinical presentation of DRESS.

(A) Timeline of reaction onset compared to other drug reactions (FDE, Fixed drug eruption; MPE, Maculopapular exanthema; SSLR, serum sickness-like reaction; AGEP, acute generalized exanthematous pustulosis; SJS/TEN, Stevens-Johnson Syndrome/Toxic epidermal necrolysis; DILI, drug-induced liver injury). (B) Clinical presentation of DRESS across patients of different ethnicities and skin tones.

Figure 2.. Immunopathogenesis of DRESS.

(A) Symptoms, sequalae, and multiorgan involvement observed with DIHS/DRESS. (B) Cellular immunopathogenesis of DRESS in the skin with the dermis as the primary site of the inflammatory response, enriched for CD4+ and CD8+ lymphocytes, plasma dendritic cells, and monocytes. CCL17/TARC is produced by dendritic cells that recruit CCR4+ Th2 T cells to the skin. IL-5 produced by Th2 cells and ILC2 induces differentiation, activation, and migration of eosinophils to the peripheral blood and tissues. TNFα and IFN-γ (Th1) and IL-4, -5, and -13 (Th2) are elevated in acute DIHS/DRESS. Viral reactivation of human herpesviruses is also observed and Tregs are present in lesional skin. (C) Models of drug-induced T-cell activation. In the hapten model, drug or drug-derived antigen forms covalent bonds to self-proteins/peptides to form a neoantigen hapten, processed by antigen-presenting cells for presentation by HLA risk allele(s) at the cell surface for recognition by corresponding T-cell receptors (TCR). The Pharmacological-Interaction (PI) model proposes that drug-antigen forms non-covalent, labile, and processing-independent interactions with either the TCR or HLA directly inducing T-cell activation. The altered self-peptide repertoire model proposes that drug-antigen binds to either the HLA (altered HLA) or TCR (altered TCR), changing the conformation of binding such that a different repertoire of endogenous self- peptides may bind that are recognized as immunogenic. (Treg, T regulatory cell; APC, antigen- presenting cell; DC, dendritic cell; IFN, interferon; TNF, tumor necrosis factor; ILC, innate lymphoid cell; TCR, T-cell receptor; HLA, Human leukocyte antigen). Figure created using Biorender.com.

Figure 3.. HLA risk alleles and use in prediction and diagnosis of DIHS/DRESS.

(A) HLA class I and II associations with DRESS (top) and other drug-induced reactions (bottom). (B) Examples of HLA class I risk allele associations for which there are current or pre-emptive screening tests available for SCAR.^{, , -} For many drugs the near 100% NPV might apply to a specific race (e.g. HLA-B*15:02 and HLA-B*58:01 in carbamazepine SJS/TEN and allopurinol DIHS/DRESS/SJS/TEN respectively. HLA-B*58:01 may explain only 60% of allopurinol DIHS/DRESS/SJS/TEN in European populations. (C) Implications for translation of HLA-A*32:01 screening in European populations for risk of vancomycin-induced DIHS/DRESS. HLA-A*32:01 is expressed in 6.8% of the European population, of whom 20% develop DIHS/DRESS after vancomycin exposure, providing a total number needed to test (NNT) to prevent one case of 75 individuals (Cen, Centromeric; Tel, Telomeric; DILI, Drug-induced liver injury; SJS/TEN, Stevens-Johnson Syndrome/Toxic epidermal necrolysis.

Figure 4.

Analysis of 3 groups (mild, moderate, and severe cases) based on early scores to predict the risk of CMV reactivation or CMV disease and complications (Table 4). CMV reactivation including CMV disease and complications occurred most frequently in the severe group. CMV disease and complications developed exclusively in the severe group.