Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Focus on the Pathophysiological and Diagnostic Role of Viruses

Abstract

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a heterogeneous, multiorgan and potentially life-threatening drug-hypersensitivity reaction (DHR) that occurs several days or weeks after drug initiation or discontinuation. DHRs constitute an emerging issue for public health, due to population aging, growing multi-organ morbidity, and subsequent enhanced drug prescriptions. DRESS has more consistently been associated with anticonvulsants, allopurinol and antibiotics, such as sulphonamides and vancomycin, although new drugs are increasingly reported as culprit agents. Reactivation of latent infectious agents such as viruses (especially Herpesviridae) plays a key role in prompting and sustaining aberrant T-cell and eosinophil responses to drugs and pathogens, ultimately causing organ damage. However, the boundaries of the impact of viral agents in the pathophysiology of DRESS are still ill-defined. Along with growing awareness of the multifaceted aspects of immune perturbation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the ongoing SARS-CoV-2-related disease (COVID-19) pandemic, novel interest has been sparked towards DRESS and the potential interactions among antiviral and anti-drug inflammatory responses. In this review, we summarised the most recent evidence on pathophysiological mechanisms, diagnostic approaches, and clinical management of DRESS with the aim of increasing awareness on this syndrome and possibly suggesting clues for future research in this field.

Keywords: DRESS; T-cells; eosinophils; herpesvirus; reaction; viral reactivation; virus.

Figure 1

Simplified DRESS aetiopathogenesis. Flow-chart depicting the pathophysiological relationships among the main exogenous and host-related factors involved in the development of DRESS.

Figure 2

Pathogenic mechanisms for HLA-restricted, drug-induced activation of T-cells in DRESS. In this simplified depiction of HLA-restricted antigen presenting cell (APC)–T-cell interactions, the three main hypothesised mechanisms accounting for drug-induced T-cell activation in DRESS are represented. Drugs might directly interfere with HLA–T-cell receptor interactions, causing T-cell activation without the need for self peptides (p-i mechanism, left side). In this setting, drugs might activate the T-cell receptor through allosteric mechanisms or by binding HLA either inside or outside the peptide binding groove. Drugs bound to the peptide groove might cause conformational changes enabling self-peptides to be accommodated within HLA and presented to T-cells, promoting self-reactive responses (alternative peptide repertoire hypothesis, central section). Drugs can also bind self molecules through conventional hapten-carrier models (right side).

Figure 3

Potential mechanisms of heterologous immunity in DRESS. This figure depicts features of heterologous immunity with a potential pathogenic role in DRESS. Viral infections or reactivations (1–3) prompt selective pressure on a heterogeneous pool of T-cells (A). Therefore, after exposure to viruses (B), virus-reactive T-cells expand (C) and are readily available for eventual viral encounters or reactivations (D). Among virus-reactive T-cells, subpopulations harbouring T-cell receptors devoid of the ability to be activated by potential drug allergens might be selected (E), preventing the occurrence of hypersensitivity. In other cases (F), either occurring in distinct subjects or in the same subjects during distinct phases of life, virus–drug cross-reactive T-lymphocytes might be selected by viral stimulation. When challenged with culprit drugs, these cells might initiate hypersensitivity reactions, possibly including DRESS (G). Eventually, re-challenge with re-activating viruses (H, top) or chemically related drugs (H, bottom) might promote DRESS progression and/or persistence (I).