DRESS syndrome: an interaction between drugs, latent viruses, and the immune system

Abstract

Drug-induced hypersensitivity syndrome, also known as DRESS syndrome, is a serious and potentially fatal reaction that occurs in response to prolonged use (generally between 14 and 60 days) of certain drugs, and which has no predilection for gender or age group. It is believed that DRESS syndrome has a genetic basis and results from the interaction between metabolites of certain pharmacological groups, reactivation of latent viruses (especially from the Herpesviridae family), and a cellular immune response. The classic manifestation of DRESS syndrome includes a generalized rash accompanied by fever, eosinophilia, lymphadenopathy, and systemic involvement such as hepatitis, nephritis, or pneumonitis. With the continuous increase in the availability of drugs and the aging of the population, there is a favorable scenario for the development of adverse drug reactions. Physicians should be prepared for the early diagnosis of DRESS syndrome, the identification and immediate suspension of the drug involved, and also manage systemic involvement, which may require prolonged immunosuppressive therapy. This article provides an update on the clinical, physiopathological and therapeutic aspects of DRESS syndrome.

Keywords: Drug eruption; Drug hypersensitivity syndrome; Drug-related side effects and adverse reactions; Eosinophilia; Substance and drug-induced liver disease.

Figure 1

Model of the conjunction of risk factors for the occurrence of a DRESS event, in a model similar to the perfect meeting of risk factors, such as a hole in the same position in different slices of Swiss cheese, or in analogy to the meeting of perfect lenses, during refraction in an ophthalmological examination. The drug, or vaccine, needs to find a metabolic system in humans that generates a certain metabolic intermediate, which generally accumulates in excess, in the same patient, where this metabolite stimulates the proliferation of the monocytic-macrophage system, which leads to the activation of latent viruses incorporated into the host DNA. This human host must have certain genetic characteristics (HLA or cytochrome P450-CYP gain- or loss-of-function mutations), which lead to a specific type of immune response capable of generating the clinical response of DRESS.

Figure 2

Normal metabolic pathways for drug elimination and an example of the abnormal metabolism of sulfamethoxazole (SMX) in patients with HLA predisposition and loss-of-function (LOF) alterations of metabolic enzymes such as cytochrome P450 (CYP) and/or phase II (intermolecular) reactions such as defects in the glucorinization generating excess hydroxylamine/nitrous metabolites that can produce “danger” signals to the immune system, with direct cell damage and activation of innate immunity and/or presented as haptens to antigen-presenting cells.

Figure 3

Clinical and laboratory evolution of DRESS. Sequential reactivation of the Herpesviridae family, after progressive hypogammaglobulinemia, previously classically demonstrated in patients using aromatic anticonvulsants, contributing to the resurgence of clinical and laboratory manifestations, even after withdrawal of the drug that triggered DRESS.

Figure 4

Maculopapular rash in DRESS. (A) Extensive trunk involvement. (B) Detail of the lesions: erythematous papules that converge into plaques.

Figure 5

Atypical form of DRESS. Erythematous-edematous plaques with sterile vesicles and pustules.

Figure 6

DRESS (Hematoxylin & eosin, ×400). Vacuolar interface dermatitis, mild spongiosis, lymphocyte exocytosis. There is diffuse lymphocytic infiltration in the dermis, with frequent eosinophils.

Figure 7

DRESS therapeutic approach flowchart, based on the severity of the condition.