Vincent Descamps

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.

Chromosomally integrated human herpesvirus 6: questions and answers

Chromosomally integrated human herpesvirus 6 (ciHHV‐6) is a condition in which the complete HHV‐6 genome is integrated into the host germ line genome and is vertically transmitted in a Mendelian manner. The condition is found in less than 1% of controls in the USA and UK, but has been found at a somewhat higher prevalence in transplant recipients and other patient populations in several small studies. HHV‐6 levels in whole blood that exceed 5.5 log10 copies/ml are strongly suggestive of ciHHV‐6. Monitoring DNA load in plasma and serum is unreliable, both for identifying and for monitoring subjects with ciHHV‐6 due to cell lysis and release of cellular DNA. High HHV‐6 DNA loads associated with ciHHV‐6 can lead to erroneous diagnosis of active infection. Transplant recipients with ciHHV‐6 may be at increased risk for bacterial infection and graft rejection. ciHHV‐6 can be induced to a state of active viral replication in vitro. It is not known whether ciHHV‐6 individuals are put at clinical risk by the use of drugs that have been associated with HHV‐6 reactivation in vivo or in vitro. Nonetheless, we urge careful observation when use of such drugs is indicated in individuals known to have ciHHV‐6. Little is known about whether individuals with ciHHV‐6 develop immune tolerance for viral proteins. Further research is needed to determine the role of ciHHV‐6 in disease. Copyright

A 6‐month prospective survey of cutaneous drug reactions in a hospital setting

Background  Few prospective studies are available on the incidence and analysis of the characteristics of adverse cutaneous drug reactions in hospital settings.

Twelve-Year Analysis of Severe Cases of Drug Reaction With Eosinophilia and Systemic Symptoms: A Cause of Unpredictable Multiorgan Failure

BACKGROUND Factors implicated in the severity of drug reaction with eosinophilia and systemic symptoms (DRESS) have not been identified. We retrospectively describe and analyze severe cases of DRESS defined by history of intensive care unit admission and death due to DRESS. OBSERVATIONS Of 15 patients retrospectively recruited in France, 14 were admitted to the intensive care unit and 3 died. The culprit drugs were already known to cause or trigger DRESS: allopurinol, minocycline hydrochloride, anticonvulsants, sulfonamides, and antibiotics. Visceral involvement with severe manifestations responsible for intensive care unit admission or death was variable and often multiple (pneumonitis, hepatitis, renal failure, encephalitis, hemophagocytosis, cardiac failure, and pancytopenia) and resulted in multiorgan failure in 11 patients. These severe complications sometimes developed late in DRESS. Human herpesvirus 6 infection was demonstrated in 6 of 7 patients. In addition, human herpesvirus 6 infection was demonstrated in involved viscera in 2 patients. CONCLUSIONS Severe DRESS is rare. Some specificities of visceral involvement were associated with allopurinol and minocycline. However, visceral involvement comprising multiorgan failure seemed to be unpredictable. Better knowledge of DRESS is necessary to propose specific and prompt treatment. Early demonstration of human herpesvirus 6 reactivation could be considered a prognostic factor for identifying patients at higher risk and, hence, needs to be evaluated.

Cryoglobulinemia with vasculitis associated with hepatitis C virus infection

Essential mixed cryoglobulinemia is frequently associated with chronic hepatitis. This report presents four cases of cryoglobulinemia with vasculitis associated with chronic hepatitis related to hepatitis C virus infection. Hepatitis C virus infection was ascertained in the four patients by both the presence in the serum of anti-HCV antibodies detected by the four-antigen recombinant immunoblot assay and of HCV RNA detected by polymerase chain reaction. In two patients tested, anti-HCV antibodies were not detected after centrifugation in the purified cryoglobulin but were detected in the supernatant. HCV RNA was detected in the purified cryoglobulin in all four patients and was detected in the supernatant in three patients. In one patient receiving recombinant interferon alfa, serum aminotransferases normalized and cryoglobulin disappeared; in another patient receiving recombinant interferon alfa, serum aminotransferases remained high and the cryoglobulin persisted. The presence of HCV RNA in the cryoglobulin and the parallelism of the changes of the cryoglobulinemia and of the serum aminotransferases during recombinant interferon alfa administration suggest that HCV infection is responsible for the production of cryoglobulinemia and vasculitis. It is proposed that HCV infection is a cause of cryoglobulinemia associated with chronic hepatitis.

Drug‐induced hypersensitivity syndrome associated with Epstein–Barr virus infection

Summary Association of drug‐induced hypersensitivity syndrome with viral infection is debated. Human herpesvirus 6 (HHV‐6) reactivation has been the most frequently reported infection associated with this syndrome. However, a case of cytomegalovirus (CMV) infection was recently described associated with anticonvulsant‐induced hypersensitivity syndrome. We report a case of severe allopurinol‐induced hypersensitivity syndrome with pancreatitis associated with Epstein–Barr virus (EBV) infection. Active EBV infection was demonstrated in two consecutive serum samples by the presence of anti‐EBV early antigen (EA) IgM antibodies and an increase in anti‐EBV EA IgG antibodies, whereas no anti‐EBV nuclear antigen IgG antibodies were detected. EBV DNA was detected by polymerase chain reaction (PCR) in peripheral blood mononuclear cells. Reactivation of HHV‐6 was suggested only by the presence of anti‐HHV‐6 IgM antibodies, but HHV‐6 DNA was not detected by PCR in the serum. Other viral investigations showed previous infection (CMV, rubella, measles, parvovirus B19), immunization after vaccination (hepatitis B virus), or absence of previous infection (hepatitis C virus, human immunodeficiency virus). We suggest that EBV infection may participate in some cases, as do the other herpesviruses HHV‐6 or CMV, in the development of drug‐induced hypersensitivity syndrome.

CD30+ T-cell lymphoma in a patient with psoriasis treated with ciclosporin and infliximab

Summary There is a known relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies. These lymphomas are mainly B‐cell nonHodgkins lymphomas associated with Epstein–Barr virus. Most cases concern classical immunosuppressive treatments including ciclosporin and methotrexate. A relationship between the new antitumour necrosis factor (TNF)‐α agents and lymphoproliferative malignancies is debated. Patients with psoriasis on immunosuppressive therapies, mainly ciclosporin, are considered to have a low risk of developing lymphoid proliferation. We report a patient with erythrodermic psoriasis treated with ciclosporin and infliximab who developed a CD30+ T‐cell lymphoma. This lymphoma regressed after stopping these treatments. In this case, the anti‐TNF‐α agent may have played a role in association with ciclosporin in the development of the lymphoproliferative disorder. Whereas the combination of anti‐TNF‐α therapies with methotrexate has been well studied, their combination with ciclosporin has been evaluated only in a few patients. Psoriatic patients who may require anti‐TNF‐α treatment have often been or will be treated with ciclosporin. The combination of ciclosporin and anti‐TNF‐α warrants further investigation.

Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma

The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the ‘combination test’ enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.

Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus 6 replication in vitro

Amoxicillin is known to induce exanthema in patients with EBV-induced infectious mononucleosis. It is widely recognized that the reactivation of herpesviruses, including HHV-6 (Human Herpesvirus 6) and EBV (Epstein Barr virus) is associated with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). We report 7 cases of amoxicillin-induced flare in patients with DRESS induced by other drugs and investigate whether amoxicillin may have a direct effect on HHV-6 replication in vitro. 7 cases of DRESS with amoxicillin-induced flare were retrospectively analysed. The influence of amoxicillin on HHV-6 HST strain replication was studied in vitro in a human T lymphoblastoid MT4 cell line. The viral replication was quantified by immunofluorescence assay and by real-time polymerase chain reaction (PCR). Comparisons were performed using the Students t test. Amoxicillin-induced flare was observed in 7 patients with DRESS induced by other drugs. In two cases HHV-6 reactivation was studied and was demonstrated by PCR. Amoxicillin neither modified cell viability nor cell proliferation for the range of tested concentrations. Amoxicillin increased the replication of HHV-6 at 25 microg*mL-1 and 50 microg*mL-1. Amoxicillin may induce a flare of DRESS, possibly by acting directly on herpesvirus replication.

A three-year-analysis of fixed drug eruptions in hospital settings in France

Fixed drug eruption (FDE) is one of the most typical cutaneous drug adverse reactions. This localized drug-induced reaction is characterized by its relapse at the same sites. Few large series of FDE are reported. The aim of this study was to retrospectively collect and analyse well informed cases observed in a hospital setting. This study involved 17 academic clinical centers. A French nation-wide retrospective multicentric study was carried out on a 3-year-period from 2005 to 2007 by collecting data in seventeen departments of dermatology in France. Diagnosis of FDE was based essentially on clinical findings, at times confirmed by pathological data and patch-testing. Records were reviewed for demographics, causative drugs, localization, severity, and patch-tests, when available. Fifty nine cases were analysed. Patients were 59-years-old on average, with a female predilection. The most common drug was paracetamol, followed by the non-steroidal anti inflammatory drugs. The time between drug intake and skin symptoms was, on average, two days. Beside these classical characteristics, some original findings were found including, a frequent non pigmentation course and a sex-dependent pattern of distribution. Women often had lesions on the hands and feet, and men on the genitalia. Given the fact that skin pigmentation is an inconstant feature of FDE, its French name (erythème pigmenté fixe) should be reconsidered. The sex-dependent distribution could help our understanding of the pathophysiology of fixed drug eruption.