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48: Drug induced hypersensitivlty syndrome and human herpesvirus infection: an immunological and virological prospective study in 40 patients
S110 Abstracts, 5th Int. Conf. on HHV-6 & 7, 1–3 May 2006, Barcelona, Spain / Journal of Clinical Virology 37 Suppl. 1 (2006) S97–118 Primary infections with HHV-6 and HHV-7 occur in early childhood with lifelong persistence. They usually remain clinically inapparent, yet may eventually cause febrile exanthematous diseases with or without seizures. Primary infections at later ages can cause non-specific lymphadenitis or infectious mononucleosis-like syndromes. More severe diseases (e.g. acute hepatic failure, necrotizing encephalitis) in primary infection may affect immunocompromized persons. The domain of clinical attention requiring treatment is reactivated and persistently active infections at later ages. They occur preferentially in immunocompromized persons and can affect several organ systems. Such systemic and localized diseases include chronic fatigue syndrome, certain allergic, autoimmune and proliferative disorders (lupus, scleroderma, lymphadenopathy, myelodysplasia). Although a pathogenetic relationship of HHV-6 to these diseases remains obscure, persistent active virus may well add to the pathology by interfering with the immune response. HHV-6 and HHV-7 were demonstrated in interstitial peumonitis, HHV-6 in addition in myocarditis, demyelinating CNS diseases (e.g. multiple sclerosis) and in bone marrow or stem cell transplant recipients with failure of engraftment. Summary: It is especially the recurrent and persistently active infections with HHV-6 and occasionally HHV-7, which cause severe pathology and will require further study. 48 Drug induced hypersensitivity syndrome and human herpesvirus infection: an immunological and virological prospective study in 40 patients V. Descamps1 *, P. Musette2 , S. Ranger-Rogez3 . 1 Department of Dermatology, Bichat Claude Bernard Hospital, Paris, France, 2 Department of Dermatology, Charles Nicolles Hospital, Rouen, France, 3 Department of Virology, Dupuytren Hospital, Limoges, France E-mail address: [email protected] Background: Drug induced hypersensitivity syndrome is a severe drug-induced reaction. Clinical and biological manifestations associate high fever, facial edema, erythroderma, diffuse lymphadenopathy, hypereosinophilia, atypical circulating lymphocytes, abnormal results of liver function tests. Numerous other systemic manifestations may occur: pneumonitis, myocarditis, pancreatitis, nephritis, thyroiditis, meningo-encephalitis. DRESS (Drug reaction with eosinophilia and systemic symptoms) mimics viral infection. We and others demonstrated frequent reactivation of human herpesviruses (especially HHV-6) during this syndrome. The role of viral reactivation in this syndrome is debated. Objectives: We prospectively studied in a national study in France the virological and immunological characteristics in 40 consecutive patients on sequential blood and serum samples (Day 0, Day 15, Day 30, Day 180, Day 360). Study Design: The lymphocyte repertoire was analysed by immunoscope technique (ab and gd T cells). Expanded and nonexpanded lymphocyte populations were phenotyped and analysed for their cytokine secretion. Study of Human Herpesviruses (HHV-6, CMV, EBV) reactivation was done in parallel (serology, real time quantitative PCR). Results: Preliminary results demonstrated monoclonal or oligoclonal expansion of lymphocytes T in most patients. Expanded CD8+ T cells secreted IFNg, TNFa and IL2, with cutaneous homing receptors and cytotoxic properties.A bias of gd T cell repertoire similar to those observed in anti viral response, such as those described in EBV infection was demonstrated. Reactivations of HHV-6 and/or EBV were observed in many patients. Conclusions: These preliminary results suggested that immune response observed in DRESS patients was principally directed against Human Herpesvirus reactivation.
49 Sequential herpesvirus reactivation in drug-induced hypersensitivity syndrome Y. Kano *, K. Hirahara, K. Sakuma, T. Shiohara. Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan E-mail address: [email protected] Background: Drug-induced hypersensitivity syndrome (DIHS) is a multiorgan system reaction. Numerous studies have linked reactivation of human herpesvirus (HHV)-6 with the development of DIHS. Recent articles have suggested that reactivation of other herpesviruses such as Epstein–Barr virus, cytomegalovirus and HHV-7, besides HHV-6 might be involved in the development of DIHS and demonstrated that multiorgan failures such as encephalitis and pneumonitis develop despite discontinuation of the causative drugs. However, it remains unknown whether these herpesviruses reactivate from latency in an obligate order in the course of DIHS, and whether these reactivations contribute to the development of various clinical manifestations of DIHS. Objectives: Our objectives were to determine whether sequential herpesvirus reactivation could be detected in patients with DIHS and be coincident with various clinical manifestations. Study Design: Detection and quantification of viral DNA in sequential blood samples obtained from patients with severe DIHS were performed using real-time polymerase chain reaction assays. Results: Our results demonstrated that herpesviruses reactivate in a sequential order as described in patients with graft-versus-host disease (GVHD); the sequential herpesvirus reactivation is coincident with the various clinical manifestations in patients with DIHS. Conclusions: Considering the clinical similarity between DIHS and GVHD, and the common occurrence of similar sequential herpesvirus reactivation in both conditions, the sequential reactivation of herpesviruses observed in patients with DIHS may be responsible for the clinical manifestations that appear even after discontinuation of the causative drugs. 50 HHV-6 and HIV-1 co-infection ex vivo J.-C. Grivel *. Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA E-mail address: [email protected] Background: HIV infection occurs on the background of other microbial infections, which are often responsible for the different conditions that define AIDS. Often, these microbial agents promote HIV replication. However, some pathogens inhibit HIV-1 replication either in vivo or in vitro. Among them, GBV-C and measles virus that suppress HIV replication in co-infected patients in vivo, modulate the secretion of b chemokines or the expression of their receptors in vitro. Objective: Understand how herpes viruses modulate HIV replication. Study Design: Human tonsillar tissue blocks were infected ex vivo with HHV-6, HHV-7 and an X4 or an R5 HIV-1variant alone or in combination with HHV-7 or HHV-6. We monitored the replication and cytokine secretion in infected and control tissues. Results: HHV-6, by modulating the secretion of the RANTES, selectively inhibits the replication of R5 but not of X4 HIV-1 variant. This RANTES modulation is HHV-6 specific, as the other closely related HHV-7 does not upregulate b chemokine secretion. Conclusion: While infection with HHV-2 is associated with a higher sexual transmission of HIV, a strong upregulation of RANTES, as a result of HHV-6 infection, at the site of HIV infection may prevent such a transmission.
49 Sequential herpesvirus reactivation in drug-induced hypersensitivity syndrome Y. Kano *, K. Hirahara, K. Sakuma, T. Shiohara. Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan E-mail address: [email protected] Background: Drug-induced hypersensitivity syndrome (DIHS) is a multiorgan system reaction. Numerous studies have linked reactivation of human herpesvirus (HHV)-6 with the development of DIHS. Recent articles have suggested that reactivation of other herpesviruses such as Epstein–Barr virus, cytomegalovirus and HHV-7, besides HHV-6 might be involved in the development of DIHS and demonstrated that multiorgan failures such as encephalitis and pneumonitis develop despite discontinuation of the causative drugs. However, it remains unknown whether these herpesviruses reactivate from latency in an obligate order in the course of DIHS, and whether these reactivations contribute to the development of various clinical manifestations of DIHS. Objectives: Our objectives were to determine whether sequential herpesvirus reactivation could be detected in patients with DIHS and be coincident with various clinical manifestations. Study Design: Detection and quantification of viral DNA in sequential blood samples obtained from patients with severe DIHS were performed using real-time polymerase chain reaction assays. Results: Our results demonstrated that herpesviruses reactivate in a sequential order as described in patients with graft-versus-host disease (GVHD); the sequential herpesvirus reactivation is coincident with the various clinical manifestations in patients with DIHS. Conclusions: Considering the clinical similarity between DIHS and GVHD, and the common occurrence of similar sequential herpesvirus reactivation in both conditions, the sequential reactivation of herpesviruses observed in patients with DIHS may be responsible for the clinical manifestations that appear even after discontinuation of the causative drugs. 50 HHV-6 and HIV-1 co-infection ex vivo J.-C. Grivel *. Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA E-mail address: [email protected] Background: HIV infection occurs on the background of other microbial infections, which are often responsible for the different conditions that define AIDS. Often, these microbial agents promote HIV replication. However, some pathogens inhibit HIV-1 replication either in vivo or in vitro. Among them, GBV-C and measles virus that suppress HIV replication in co-infected patients in vivo, modulate the secretion of b chemokines or the expression of their receptors in vitro. Objective: Understand how herpes viruses modulate HIV replication. Study Design: Human tonsillar tissue blocks were infected ex vivo with HHV-6, HHV-7 and an X4 or an R5 HIV-1variant alone or in combination with HHV-7 or HHV-6. We monitored the replication and cytokine secretion in infected and control tissues. Results: HHV-6, by modulating the secretion of the RANTES, selectively inhibits the replication of R5 but not of X4 HIV-1 variant. This RANTES modulation is HHV-6 specific, as the other closely related HHV-7 does not upregulate b chemokine secretion. Conclusion: While infection with HHV-2 is associated with a higher sexual transmission of HIV, a strong upregulation of RANTES, as a result of HHV-6 infection, at the site of HIV infection may prevent such a transmission.