Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A Multiorgan Antiviral T Cell Response

A dangerous drug reaction may be caused by a severe immune response to reactivated resident herpes viruses. Drug Sensitivity: Don’t Wake Up the Baby (Virus) The benefits of drugs almost always come with a cost. Anticonvulsants and antibiotics are no exception. Some of these commonly used drugs can cause a skin reaction so severe, appearing several weeks after use, that the patient is treated as a burn victim. Called DRESS (drug reaction with eosinophilia and systemic symptoms), this response results in death 10% of the time. A better understanding of DRESS would be a boon to diagnosis and treatment. Data from 40 DRESS patients gathered by Picard and his colleagues now move us a few steps closer to this goal. They find that the symptoms of DRESS are largely a result of activated immune cells directed at herpes virus–related antigens, which home to the skin and visceral organs. The culprit drugs may reactivate quiescent herpes viruses lurking in the patients’ genomes, triggering expansion of these misguided cells. A careful look at the T lymphocytes from 40 patients with DRESS—induced by carbamazepine, allopurinol, or sulfamethoxazole—revealed excess numbers of activated cytotoxic CD8+ T cells, which had surface proteins directing them to skin and other organs. The cells secreted cytokines such as tumor necrosis factor–α (TNF-α) and interferon-γ (IFN-γ) and expressed genes characteristic of inflammation. To get a better handle on the antigen targets of these activated T cells, the authors tested whether the patients showed viral reactivation, which had been noted before in some patients with DRESS. Not only did 76% of the patients show activation of previously quiescent Epstein-Barr virus (EBV) or human herpes viruses 6 or 7 (HHV-6, HHV-7), but a large proportion of the activated CD8 T cells in blood and affected organs carried T cell receptor sequences known to be specific for antigens from EBV. (Specific sequences for HHV-6 or HHV-7 are not available.) Cellular stimulation by antigenic peptides from EBV confirmed this result. The authors propose that DRESS is caused by an EBV (or other similar virus)–driven selection of CD8+ T lymphocytes, which in turn inappropriately attack multiple organs. They think that the culprit drugs may trigger activation of the patients’ dormant EBV by an as yet undefined mechanism, possibly directly. Indeed, they found that the three culprit drugs induce EBV production in EBV-transformed cells from DRESS patients but not from healthy controls, setting the stage for discovering just what it is that makes some people susceptible to DRESS. Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, drug-induced reaction that involves both the skin and the viscera. Evidence for reactivation of herpes family viruses has been seen in some DRESS patients. To understand the immunological components of DRESS and their relationship to viral reactivation, we prospectively assessed 40 patients exhibiting DRESS in response to carbamazepine, allopurinol, or sulfamethoxazole. Peripheral blood T lymphocytes from the patients were evaluated for phenotype, cytokine secretion, and repertoire of CD4+ and CD8+ and for viral reactivation. We found Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), or HHV-7 reactivation in 76% of the patients. In all patients, circulating CD8+ T lymphocytes were activated, exhibited increased cutaneous homing markers, and secreted large amounts of tumor necrosis factor–α and interferon-γ. The production of these cytokines was particularly high in patients with the most severe visceral involvement. In addition, expanded populations of CD8+ T lymphocytes sharing the same T cell receptor repertoire were detected in the blood, skin, liver, and lungs of patients. Nearly half of these expanded blood CD8+ T lymphocytes specifically recognized one of several EBV epitopes. Finally, we found that the culprit drugs triggered the production of EBV in patients’ EBV-transformed B lymphocytes. Thus, cutaneous and visceral symptoms of DRESS are mediated by activated CD8+ T lymphocytes, which are largely directed against herpes viruses such as EBV.