Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) in children is reliably associated with the presence of dengue antibody--actively or passively acquired--before the onset of illness. Limited observations by electron microscopy and fluorescent antibody testing and the recovery of virus from tissues obtained at autopsy show that dengue viruses are consistently associated with cells of mononuclear phagocyte lineage. In particular, virus is associated with Kupffer cells, pulmonary macrophages, and mononuclear cells in skin and blood. Endothelial cells fail to demonstrate necrosis or inflammatory changes. Since acute vascular permeability, shock, and hemorrhage occur late in illness, a plausible hypothesis is that phlogistic factors, resulting from interactions with elements of the immune response, are released from virus-infected mononuclear phagocytes. Such phenomena as generalized depression of mitotic activity of bone marrow cells, destruction of mature polymorphonuclear leukocytes, complement activation, and abnormal hemostasis may serve as markers of these phlogistic factors. It will be of interest to establish whether other viral hemorrhagic fevers involve the same target cells as in DHF/DSS and are mediated by similar effector mechanisms.

Antibody, Macrophages, Dengue Virus Infection, Shock, and Hemorrhage: A Pathogenetic Cascade

Pharmacology of kinins: their relevance to tissue injury and inflammation.

The severe outcome of the dengue (DEN) virus infection known as DEN hemorrhagic fever-DEN shock syndrome (DHF-DSS) is, in some cases, accompanied by liver injury. Councilman bodies observed in liver biopsies of DHF-DSS cases may correspond to hepatocytes in apoptosis. We show here that infection of the hepatoma cell line HepG2 with DEN type 1 virus induced cell death typical of apoptosis late in the virus cycle. The transcription factor NF-kappaB was activated concomitantly with viral protein synthesis and thus before the appearance of apoptotic cells. Inhibition of apoptosis was observed when DEN virus-infected cells were treated with NF-kappaB decoys, indicating the involvement of this transcription factor in induction of cell death. Thus, infected hepatocytes appear to be subject to apoptosis in vitro, and this may be a key element in the pathophysiology of hepatic failure associated with DHF-DSS.

Dengue virus replication in human hepatoma cells activates NF-kappaB which in turn induces apoptotic cell death.

Dengue is an infectious disease caused by dengue virus (DENV). In general, dengue is a self-limiting acute febrile illness followed by a phase of critical defervescence, in which patients may improve or progress to a severe form. Severe illness is characterized by hemodynamic disturbances, increased vascular permeability, hypovolemia, hypotension, and shock. Thrombocytopenia and platelet dysfunction are common in both cases and are related to the clinical outcome. Different mechanisms have been hypothesized to explain DENV-associated thrombocytopenia, including the suppression of bone marrow and the peripheral destruction of platelets. Studies have shown DENV-infected hematopoietic progenitors or bone marrow stromal cells. Moreover, anti-platelet antibodies would be involved in peripheral platelet destruction as platelets interact with endothelial cells, immune cells, and/or DENV. It is not yet clear whether platelets play a role in the viral spread. Here, we focus on the mechanisms of thrombocytopenia and platelet dysfunction in DENV infection. Because platelets participate in the inflammatory and immune response by promoting cytokine, chemokine, and inflammatory mediator secretion, their relevance as “immune-like effector cells” will be discussed. Finally, an implication for platelets in plasma leakage will be also regarded, as thrombocytopenia is associated with clinical outcome and higher mortality.

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Thrombocytopenia in Dengue: Interrelationship between Virus and the Imbalance between Coagulation and Fibrinolysis and Inflammatory Mediators

Dengue fever (DF) and dengue haemorrhagic fever (DHF) are caused by the dengue virus. The major pathophysiological hallmark that distinguishes DHF from DF is plasma leakage as a result of increased vascular permeability. Following this leakage, hypovolaemic shock occurs as a consequence of a critical plasma volume loss. Constant haematological abnormalities occurring in DHF and frequently include bone marrow suppression, leucopenia and thrombocytopenia. An enhanced immune response of the host to a secondary DV infection is a feature of DHF and leads to many consequences. These are immune complex formation, complement activation, increased histamine release and a massive release of many cytokines into the circulation, leading to shock, vasculopathy, thrombopathy and disseminated intravascular coagulation (DIC). The mechanisms underlying the bleeding in DHF are multiple. These are vasculopathy, thrombopathy and DIC. Thrombopathy consists of thrombocytopenia and platelet dysfunction. DIC is prominent in patients with shock. The most severe DIC and massive bleeding are the result of prolonged shock and cause a fatal outcome. The mechanisms of thrombopathy and DIC and the proper management of DHF are reviewed and discussed.

Talamo Rc

Papers

Evaluation of the plasma kinin system in dengue hemorrhagic fever.