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      Thrombocytopenia and Acute Renal Failure in Puumala Hantavirus Infections

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          Abstract

          Low platelet counts are a novel predictive marker suitable for risk-adapted patient management.

          Abstract

          Nephropathia epidemica, caused by Puumala virus (PUUV) infection, is a form of hemorrhagic fever with renal syndrome of variable severity. Early prognostic markers for the severity of renal failure have not been established. We evaluated clinical and laboratory parameters of 15 consecutive patients with acute PUUV infection, which is endemic in the Alb-Danube region, South Germany. Severe renal failure (serum creatinine >620 µmol/L) was observed in seven patients; four required hemodialysis treatment. Low platelet count (<60 x 10 9/L), but not leukocyte count, C-reactive protein, or other parameters obtained at the initial evaluation, was significantly associated with subsequent severe renal failure (p = 0.004). Maximum serum creatinine was preceded by platelet count nadirs by a median of 4 days. Thrombocytopenia <60 x 10 9/L appears predictive of a severe course of acute renal failure in nephropathia epidemica, with potential value for risk-adapted clinical disease management.

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          Most cited references29

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          Hantavirus infections in Europe.

          Hantaviruses are enveloped RNA viruses each carried by a specific rodent species. Three hantaviruses, Puumala, Dobrava, and Saaremaa viruses, are known to cause haemorrhagic fever with renal syndrome. In Europe. Puumala causes a generally mild disease, nephropathia epidemica, which presents most commonly with fever, headache, gastrointestinal symptoms, impaired renal function, and blurred vision, whereas Dobrava infections often also have haemorrhagic complications. There are few available data about the clinical picture of confirmed Saaremaa infections, but epidemiological evidence suggests that it is less pathogenic than Dobrava, and that Saaremaa infections are more similar to nephropathia epidemica caused by Puumala. Along with its rodent host, the bank vole (Clethrionomys glareolus), Puumala is reported throughout most of Europe (excluding the Mediterranean region), whereas Dobrava, carried by the yellow-necked mouse (Apodemus flavicollis), and Saaremaa, carried by the striped field mouse (Apodemus agrarius), are reported mainly in eastern and central Europe. The diagnosis of acute hantavirus infection is based on the detection of virus-specific IgM. Whereas Puumala is distinct, Dobrava and Saaremaa are genetically and antigenically very closely related and were previously thought to be variants of the same virus. Typing of a specific hantavirus infection requires neutralisation antibody assays or reverse transcriptase PCR and sequencing.
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            Pathogenic and nonpathogenic hantaviruses differentially regulate endothelial cell responses.

            Hantaviruses cause two human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Hantaviruses infect human endothelial cells but cause little or no damage to the infected endothelium. We analyzed with Affymetrix DNA Arrays (Santa Clara, CA) the endothelial cell transcriptional responses directed by hantaviruses associated with HPS [New York-1 virus (NY-1V)], HFRS [Hantaan virus (HTNV)], or by a hantavirus not associated with human disease [Prospect Hill virus (PHV)]. Hantavirus infections induced 117 cellular genes and repressed 25 genes by >3-fold, 4 days postinfection (p.i.). Although >80% of cells were infected by each virus 1 day p.i., PHV induced or repressed 67 genes at this early time compared with three genes altered by HTNV or NY-1V. The early high-level induction of 24 IFN-stimulated genes by PHV (4- to 229-fold) represents a fundamental difference in the temporal regulation of cellular responses by pathogenic and nonpathogenic hantaviruses. Because all hantaviruses induced >23 IFN-stimulated genes at late times p.i., pathogenic hantaviruses appear to suppress early cellular IFN responses that are activated by nonpathogenic hantaviruses. At late times p.i., 13 genes were commonly induced by HTNV and NY-1V that were not induced by PHV. In contrast to NY-1V, HTNV uniquely induced a variety of chemokines and cell adhesion molecules (i.e., IL-8, IL-6, GRO-beta, ICAM), as well as two complement cascade-associated factors that may contribute to immune components of HFRS disease. NY-1V failed to induce most cellular chemokines directed by HTNV (3/14) or genes primarily activated by NF-kappaB. However, NY-1V uniquely induced beta3 integrin-linked potassium channels, which could play a role in HPS-associated vascular permeability. These studies provide a basic understanding of hantavirus-directed cellular responses that are likely to differentiate pathogenic and nonpathogenic hantaviruses, contribute to HFRS and HPS pathogenesis, and provide insight into disease mechanisms and potential therapeutic interventions.
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              Hantavirus infection of dendritic cells.

              Dendritic cells (DCs) play a pivotal role as antigen-presenting cells in the antiviral immune response. Here we show that Hantaan virus (HTNV), which belongs to the Bunyaviridae family (genus Hantavirus) and causes hemorrhagic fever with renal syndrome, productively infects human DCs in vitro. In the course of HTNV infection, DCs did not show any cytopathic effect and viral replication did not induce cell lysis or apoptosis. Furthermore, HTNV did not affect apoptosis-inducing signals that are important for the homeostatic control of mature DCs. In contrast to immunosuppressive viruses, e.g., human cytomegalovirus, HTNV activated immature DCs, resulting in upregulation of major histocompatibility complex (MHC), costimulatory, and adhesion molecules. Intriguingly, strong upregulation of MHC class I molecules and an increased intercellular cell adhesion molecule type 1 expression was also detected on HTNV-infected endothelial cells. In addition, antigen uptake by HTNV-infected DCs was reduced, another characteristic feature of DC maturation. Consistent with these findings, we observed that HTNV-infected DCs stimulated T cells as efficiently as did mature DCs. Finally, infection of DCs with HTNV induced the release of the proinflammatory cytokines tumor necrosis factor alpha and alpha interferon. Taken together, our findings indicate that hantavirus-infected DCs may significantly contribute to hantavirus-associated pathogenesis.
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                Author and article information

                Journal
                Emerg Infect Dis
                Emerging Infect. Dis
                EID
                Emerging Infectious Diseases
                Centers for Disease Control and Prevention
                1080-6040
                1080-6059
                August 2004
                : 10
                : 8
                : 1420-1425
                Affiliations
                [* ]University Hospital Ulm, Ulm, Germany,
                []Charité, Berlin, Germany
                Author notes
                Address for correspondence: Franz Maximilian Rasche, Division of Nephrology, Department of Internal Medicine II, University Hospital Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany; fax: +49-731-500-24483; email: maximilian.rasche@ 123456medizin.uni-ulm.de
                Article
                03-1069
                10.3201/eid1008.031069
                3320406
                15496243
                3f969634-9adc-4504-95f6-c8109a559938
                History
                Categories
                Research
                Research

                Infectious disease & Microbiology
                hantavirus,puumala virus,nephropathia epidemica,acute renal failure,hemodialysis,thrombocytopenia, research

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