Insights into the Pathogenesis of Viral Haemorrhagic Fever Based on Virus Tropism and Tissue Lesions of Natural Rift Valley Fever.

Rift Valley fever phlebovirus (RVFV) infects humans and a wide range of ungulates and historically has caused devastating epidemics in Africa and the Arabian Peninsula. Lesions of naturally infected cases of Rift Valley fever (RVF) have only been described in detail in sheep with a few reports concerning cattle and humans. The most frequently observed lesion in both ruminants and humans is randomly distributed necrosis, particularly in the liver. Lesions supportive of vascular endothelial injury are also present and include mild hydropericardium, hydrothorax and ascites; marked pulmonary congestion and oedema; lymph node congestion and oedema; and haemorrhages in many tissues. Although a complete understanding of RVF pathogenesis is still lacking, antigen-presenting cells in the skin are likely the early targets of the virus. Following suppression of type I IFN production and necrosis of dermal cells, RVFV spreads systemically, resulting in infection and necrosis of other cells in a variety of organs. Failure of both the innate and adaptive immune responses to control infection is exacerbated by apoptosis of lymphocytes. An excessive pro-inflammatory cytokine and chemokine response leads to microcirculatory dysfunction. Additionally, impairment of the coagulation system results in widespread haemorrhages. Fatal outcomes result from multiorgan failure, oedema in many organs (including the lungs and brain), hypotension, and circulatory shock. Here, we summarize current understanding of RVF cellular tropism as informed by lesions caused by natural infections. We specifically examine how extant knowledge informs current understanding regarding pathogenesis of the haemorrhagic fever form of RVF, identifying opportunities for future research.

Remote-Controlled and Pulse Pressure-Guided Fluid Treatment for Adult Patients with Viral Hemorrhagic Fevers.

Circulatory shock, caused by severe intravascular volume depletion resulting from gastrointestinal losses and profound capillary leak, is a common clinical feature of viral hemorrhagic fevers, including Ebola virus disease, Marburg hemorrhagic fever, and Lassa fever. These conditions are associated with high case fatality rates, and they carry a significant risk of infection for treating personnel. Optimized fluid therapy is the cornerstone of management of these diseases, but there are few data on the extent of fluid losses and the severity of the capillary leak in patients with VHFs, and no specific guidelines for fluid resuscitation and hemodynamic monitoring exist. We propose an innovative approach for monitoring VHF patients, in particular suited for low-resource settings, facilitating optimizing fluid therapy through remote-controlled and pulse pressure-guided fluid resuscitation. This strategy would increase the capacity for adequate supportive care, while decreasing the risk for virus transmission to health personnel.

Animal models for viral haemorrhagic fever.

Viral haemorrhagic fever can be caused by one of a diverse group of viruses that come from four different families of RNA viruses. Disease severity can vary from mild self-limiting febrile illness to severe disease characterized by high fever, high-level viraemia, increased vascular permeability that can progress to shock, multi-organ failure and death. Despite the urgent need, effective treatments and preventative vaccines are currently lacking for the majority of these viruses. A number of factors preclude the effective study of these diseases in humans including the high virulence of the agents involved, the sporadic nature of outbreaks of these viruses, which are typically in geographically isolated areas with underserviced diagnostic capabilities, and the requirements for high level bio-containment. As a result, animal models that accurately mimic human disease are essential for advancing our understanding of the pathogenesis of viral haemorrhagic fevers. Moreover, animal models for viral haemorrhagic fevers are necessary to test vaccines and therapeutic intervention strategies. Here, we present an overview of the animal models that have been established for each of the haemorrhagic fever viruses and identify which aspects of human disease are modelled. Furthermore, we discuss how experimental design considerations, such as choice of species and virus strain as well as route and dose of inoculation, have an influence on animal model development. We also bring attention to some of the pitfalls that need to be avoided when extrapolating results from animal models.

Roots, Not Parachutes: Research Collaborations Combat Outbreaks.

Recent infectious disease epidemics illustrate how health systems failures anywhere can create disease vulnerabilities everywhere. We must therefore prioritize investments in health care infrastructure in outbreak-prone regions of the world. We describe how "rooted" research collaborations can establish capacity for pathogen surveillance and facilitate rapid outbreak responses.

Divergent Simian Arteriviruses Cause Simian Hemorrhagic Fever of Differing Severities in Macaques.

UNLABELLED: Simian hemorrhagic fever (SHF) is a highly lethal disease in captive macaques. Three distinct arteriviruses are known etiological agents of past SHF epizootics, but only one, simian hemorrhagic fever virus (SHFV), has been isolated in cell culture. The natural reservoir(s) of the three viruses have yet to be identified, but African nonhuman primates are suspected. Eleven additional divergent simian arteriviruses have been detected recently in diverse and apparently healthy African cercopithecid monkeys. Here, we report the successful isolation in MARC-145 cell culture of one of these viruses, Kibale red colobus virus 1 (KRCV-1), from serum of a naturally infected red colobus (Procolobus [Piliocolobus] rufomitratus tephrosceles) sampled in Kibale National Park, Uganda. Intramuscular (i.m.) injection of KRCV-1 into four cynomolgus macaques (Macaca fascicularis) resulted in a self-limiting nonlethal disease characterized by depressive behavioral changes, disturbance in coagulation parameters, and liver enzyme elevations. In contrast, i.m. injection of SHFV resulted in typical lethal SHF characterized by mild fever, lethargy, lymphoid depletion, lymphoid and hepatocellular necrosis, low platelet counts, increased liver enzyme concentrations, coagulation abnormalities, and increasing viral loads. As hypothesized based on the genetic and presumed antigenic distance between KRCV-1 and SHFV, all four macaques that had survived KRCV-1 injection died of SHF after subsequent SHFV injection, indicating a lack of protective heterotypic immunity. Our data indicate that SHF is a disease of macaques that in all likelihood can be caused by a number of distinct simian arteriviruses, although with different severity depending on the specific arterivirus involved. Consequently, we recommend that current screening procedures for SHFV in primate-holding facilities be modified to detect all known simian arteriviruses. IMPORTANCE: Outbreaks of simian hemorrhagic fever (SHF) have devastated captive Asian macaque colonies in the past. SHF is caused by at least three viruses of the family Arteriviridae: simian hemorrhagic fever virus (SHFV), simian hemorrhagic encephalitis virus (SHEV), and Pebjah virus (PBJV). Nine additional distant relatives of these three viruses were recently discovered in apparently healthy African nonhuman primates. We hypothesized that all simian arteriviruses are potential causes of SHF. To test this hypothesis, we inoculated cynomolgus macaques with a highly divergent simian arterivirus (Kibale red colobus virus 1 [KRCV-1]) from a wild Ugandan red colobus. Despite being only distantly related to red colobuses, all of the macaques developed disease. In contrast to SHFV-infected animals, KRCV-1-infected animals survived after a mild disease presentation. Our study advances the understanding of an important primate disease. Furthermore, our data indicate a need to include the full diversity of simian arteriviruses in nonhuman primate SHF screening assays.

Acute liver failure in dengue haemorrhagic fever.

While dengue virus infection leads to a mild to moderate elevation of liver transaminases in almost all cases, hepatic failure rarely dominates the clinical picture in adults. We present a case of dengue haemorrhagic fever in a young adult, leading to the rare complication of acute liver failure. He was managed with supportive care and discharged after 5 days. At follow-up after 1 week, he had complete recovery and no residual symptoms.

The role of platelets in the pathogenesis of viral hemorrhagic fevers.

Viral hemorrhagic fevers (VHF) are acute zoonotic diseases that, early on, seem to cause platelet destruction or dysfunction. Here we present the four major ways viruses affect platelet development and function and new evidence of molecular factors that are preferentially induced by the more pathogenic members of the families Flaviviridae, Bunyaviridae, Arenaviridae, and Filoviridae. A systematic search was performed through the main medical electronic databases using as parameters all current findings concerning platelets in VHF. Additionally, the review contains information from conference proceedings.

Infections of the developing world.

Access to critical care is rapidly growing in areas of the world where it was previously nonexistent and where infectious diseases often comprise the largest disease burden. Additionally, with crowding, mass migrations, and air travel, infectious diseases previously geographically confined are quickly spread across the planet, often in shorter time frames than disease incubation periods. Hence, critical care practitioners must be familiar with infectious diseases previously confined to the developing world. This article reviews selected tropical diseases that are seen in diverse locales and often require critical care services.

Pathogenic mechanisms involved in the hematological alterations of arenavirus-induced hemorrhagic fevers.

Viral hemorrhagic fevers (VHFs) caused by arenaviruses are acute diseases characterized by fever, headache, general malaise, impaired cellular immunity, eventual neurologic involvement, and hemostatic alterations that may ultimately lead to shock and death. The causes of the bleeding are still poorly understood. However, it is generally accepted that these causes are associated to some degree with impaired hemostasis, endothelial cell dysfunction and low platelet counts or function. In this article, we present the current knowledge about the hematological alterations present in VHF induced by arenaviruses, including new aspects on the underlying pathogenic mechanisms.

[Actual vitamin and main foodstuffs consumption by recovered patients suffered from hemorrhagic fever with renal syndrome].

Actual consumption of vitamins A, E, beta-carotene, ascorbic acid, thiamin, pyridoxine and main foodstuffs by recovered patients suffered from hemorrhagic fever with renal syndrome has been given. Frequency analysis of foodstuffs consumption was used to study actual nourishment of recovered patients. Surplus consumption of fat mainly due to the use of saturated fatty acids, deficiency of poly unsaturated fatty acids, surplus sugar consumption and predominance of proteins of animal origin over proteins of vegetable origin in ration has been revealed. Deficiency of water soluble vitamins equals to 41,6-78,7% of all examined patients, deficiency of fat water soluble vitamins is lower (21,4-38,3%).

Pathogenesis of arenavirus hemorrhagic fevers.

Viral hemorrhagic fevers (VHFs) caused by arenaviruses belong to the most devastating emerging human diseases and represent serious public health problems. Arenavirus VHFs in humans are acute diseases characterized by fever and, in severe cases, different degrees of hemorrhages associated with a shock syndrome in the terminal stage. Over the past years, much has been learned about the pathogenesis of arenaviruses at the cellular level, in particular their ability to subvert the host cell's innate antiviral defenses. Clinical studies and novel animal models have provided important new information about the interaction of hemorrhagic arenaviruses with the host's adaptive immune system, in particular virus-induced immunosuppression, and have provided the first hints towards an understanding of the terminal hemorrhagic shock syndrome. The scope of this article is to review our current knowledge on arenavirus VHF pathogenesis with an emphasis on recent developments.

Assessing changes in vascular permeability in a hamster model of viral hemorrhagic fever.

BACKGROUND: A number of RNA viruses cause viral hemorrhagic fever (VHF), in which proinflammatory mediators released from infected cells induce increased permeability of the endothelial lining of blood vessels, leading to loss of plasma volume, hypotension, multi-organ failure, shock and death. The optimal treatment of VHF should therefore include both the use of antiviral drugs to inhibit viral replication and measures to prevent or correct changes in vascular function. Although rodent models have been used to evaluate treatments for increased vascular permeability (VP) in bacterial sepsis, such studies have not been performed for VHF. RESULTS: Here, we use an established model of Pichinde virus infection of hamsters to demonstrate how changes in VP can be detected by intravenous infusion of Evans blue dye (EBD), and compare those measurements to changes in hematocrit, serum albumin concentration and serum levels of proinflammatory mediators. We show that EBD injected into sick animals in the late stage of infection is rapidly sequestered in the viscera, while in healthy animals it remains within the plasma, causing the skin to turn a marked blue color. This test could be used in live animals to detect increased VP and to assess the ability of antiviral drugs and vasoactive compounds to prevent its onset. Finally, we describe a multiplexed assay to measure levels of serum factors during the course of Pichinde arenavirus infection and demonstrate that viremia and subsequent increase in white blood cell counts precede the elaboration of inflammatory mediators, which is followed by increased VP and death. CONCLUSIONS: This level of model characterization is essential to the evaluation of novel interventions designed to control the effects of virus-induced hypercytokinemia on host vascular function in VHF, which could lead to improved survival.

Chikungunya infection in children.

Chikungunya fever is caused by Chikungunya virus (CHIK) and spread by Aedes aegypti and Aedes albopictus. The median incubation period is 2 to 4 days. Vertical transmission of disease from mother to child has also been documented. Clinical manifestations are very variable, from asymptomatic illness to severe debilitating disease. Children are among the group at maximum risk for severe manifestations of the disease and some clinical features in this group are distinct from those seen in adults. Common clinical features include: abrupt onset high grade fever, skin rashes, minor hemorrhagic manifestations, arthralgia/ arthritis, lymphadenopathy, conjunctival injection, swelling of eyelids and pharyngitis. Unusual clinical features include: neurological manifestations including seizures, altered level of consciousness, blindness due to retrobulbar neuritis and acute flaccid paralysis. Watery stools may be seen in infants. Treatment is symptomatic. Generally non- steroidal anti-inflammatory drugs are avoided. Paracetamol may be used for pain and fever. However, NSAIDS may be required for relief of severe arthralgia during convalescent phase.

Fibroblastic reticular cell infection by hemorrhagic fever viruses.

Viral hemorrhagic fevers (VHFs) often cause high mortality with high infectivity, multiorgan failure, shock and hemorrhagic diathesis. Fibroblastic reticular cells (FRCs) within secondary lymphoid organs provide a supporting scaffold to T-lymphocyte areas. These cells regulate the movement of various immune cells and soluble molecules that promote T-lymphocyte homeostasis. We previously reported Ebola virus infection of FRCs, but ascribed little significance to this finding. Here, we studied infection of FRCs by Ebola, Marburg and Lassa viruses. We demonstrate that FRCs, or the extracellular 'conduit' of the fibroblastic reticulum of nonhuman primates, are targets of Ebola, Marburg and Lassa viruses. Furthermore, we observed that FRC damage correlates temporally and spatially with lymphocyte damage and that FRCs serve as nidi of fibrin deposition. In addition, we show that nonhuman primate FRCs express p75 NGF receptor and tissue transglutaminase. Our data suggest that viral infection of FRCs may be crucial to the immunological dysfunction and coagulopathy characteristic of VHFs. We further propose that p75 NGF receptor and tissue transglutaminase may be involved in FRC-associated dysfunction during the course of infection.

Animal models of highly pathogenic RNA viral infections: hemorrhagic fever viruses.

A diverse group of highly pathogenic RNA viruses cause a severe multisystemic illness in humans commonly referred to as viral hemorrhagic fever (VHF). Although they can vary widely in clinical presentation, all VHFs share certain features that include intense fever, malaise, bleeding and shock. Effective antiviral therapies for most of the VHFs are lacking. Complicating development of intervention strategies is the relative infrequency and unpredictability of VHF outbreaks making human clinical trials extremely challenging or unfeasible. Therefore, animal models that can recapitulate human disease are essential to the development of effective antivirals and vaccines. In general, a good animal model of VHF will demonstrate systemic dispersion of the virus through infection of mononuclear phagocytes and dendritic cells, which induces the release of inflammatory mediators that increase vascular permeability and facilitate coagulation. The culmination of this process leads to significant loss of plasma volume and terminal hypovolemic shock. Although it is clear that nonhuman primate models are the most faithful to human disease, the more accessible and less costly rodent models, including those based on infection with related surrogate viruses, can reproduce certain components of VHF and can serve as suitable preclinical models for initial development of effective countermeasures. Such models are sufficient for testing of drugs that directly block viral replication, but may be inadequate for evaluating therapies that depend for their success on the activation or inhibition of host responses.

[Strokes caused by infection in the tropics]. / Ictus de causa infecciosa en el trópico.

INTRODUCTION: Almost three out of every four people in the world who suffer a fatal stroke live in developing countries. A number of different tropical diseases may appear in Europe in the coming years as a consequence of the demographic change that is being brought about by migratory flows. We review the main infectious causes of strokes in the tropics. DEVELOPMENT: There are estimated to be 500 million cases of malaria every year. Cerebral malaria can cause cerebral oedema, diffuse or focal compromise of the subcortical white matter and cortical, cerebellar and pontine infarctions. Chagas disease is an independent risk factor for stroke in South America. At least 20 million people have the chronic form of Chagas disease. The main prognostic factors for Chagas-related stroke are the presence of apical aneurysms, arrhythmia and heart failure. Vascular complications of neurocysticercosis include transient ischemic attacks, ischemic strokes due to angiitis and intracranial haemorrhages. The frequency of cerebral infarction associated with neurocysticercosis varies between 2% and 12%. Gnathostomiasis is a cause of subarachnoid haemorrhage in south-east Asia. Other less common causes of stroke are viral haemorrhagic fevers due to arenavirus and flavivirus. CONCLUSIONS: Several diseases that are endemic in the tropics can be responsible for up to 10% of the cases of strokes in adults.

Emerging roles of tissue factor in viral hemorrhagic fever.

Activation of coagulation by tissue factor (TF) is frequently observed in sepsis syndrome and is documented in certain viral hemorrhagic fevers. Coagulation protease complexes signal by activating the G-protein coupled, protease-activated receptors that regulate inflammation. Blockade of TF attenuates lethality in experimental models of Ebola virus infection but - similar to findings in bacterial sepsis - reduction of inflammation, rather than attenuation of coagulation, predicts survival of treated animals. Thus, targeting TF appears to aid the antiviral immune response in hemorrhagic fevers, and further studies are encouraged to define how TF-dependent signaling regulates immunity.