Role of the endothelium in viral hemorrhagic fevers - Benh Vien ...

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esponse. Most of these diseases are worst while the virus is actively replicating in the organs and released to circulate in the blood. Only in the hantavirus diseases and in dengue HF does the classic, virusspecific immune response seem to play a role in causing the clinical manifestations, and in those diseases, immunopathology is an important part of the disease process. In the case of dengue virus, in the overwhelming majority of cases, HF follows sequential infections with different serotypes; it is not included in Table 1 because it is not one of the primary VHFs. There is now considerable information that suggests that immune enhancement and immunopathology are the major factors in the genesis of this syndrome, which is primarily a vascular permeability disease. ARENAVIRUSES Figure 1. Top, patient with hemorrhagic fever with renal syndrome showing subconjunctival hemorrhage of the bulbar conjunctivae and vascular congestion of the palpebral conjunctivae. Bottom, patient with Bolivian hemorrhagic fever, a South American arenavirus hemorrhagic fever, with diffuse mucosal bleeding. Reproduced with permission from Peters et al (1). Table 1. Viral hemorrhagic fevers Arenaviridae Lassa fever and South American HF (Argentine, Bolivian, etc.) Bunyaviridae Phlebovirus Rift Valley fever Nairovirus Crimean Congo HF Hantavirus HF with renal syndrome and Hantavirus pulmonary syndrome Filovirus Marburg HF and Ebola HF Flavivirus Yellow fever, KFD, and Omsk HF HF, hemorrhagic fever; KFD, Kyasanur Forest disease. differs, and the ways in which the viruses interact with cells are similarly different (Tables 2 and 3). PATHOGENESIS OF HF Some of these viruses cause almost no cytopathic effects, whereas others are highly destructive to the cells they infect. Pro-inflammatory cytokine induction (particularly tumor necrosis factor [TNF]-), in cases in which it has been measured, is a general finding. Disseminated intravascular coagulation (DIC) occurs in some but Crit Care Med 2002 Vol. 30, No. 5 (Suppl.) Table 2. Similarities among hemorrhagic fever viruses Similarities Vascular syndrome Dysregulation Increased permeability Diffuse damage Small RNA viruses, 1–2 10 6 d Lipid envelope Aerosol infectivity Persist in nature independently of humans Table 3. Differences among hemorrhagic fever viruses Differences Replication strategy Virion structure and morphogenesis Cytopathic effects in mammalian cells Sensitivity to antiviral effects of interferon Pathogenesis of infection Human immune response Survival strategy in nature not in others. Involvement of the liver also varies. HF is a single syndrome but not a stereotypical disease (3, 5). One of the important pathogenetic differences involves the role of the immune The arenaviruses, which cause Lassa fever in Africa and Argentine and Bolivian HF in South America, are particularly interesting; furthermore, arenavirus infections occur reasonably frequently in predictable sites, providing a pool of patients for study. Throat swabs from patients demonstrate a small amount of virus, but titers are low and inconstant. Person-to-person transmission is not very high, except possibly through sexual intercourse in convalescence, but patients develop effusions quite regularly. High-titered virus is present in the Lassa fever effusion. Arenavirus infection of the mesothelial cells on the surface of the organs bathed in the effusion suggests a direct effect of the infection on the exudation of fluid (5). Figure 2 shows the pleural surface of a patient with Lassa fever. The mesothelium is very intensely stained for viral antigen. Arenaviruses also infect the capillary endothelium of many organs in the body. The arenaviruses are not highly cytopathic, and thus, it is not clear what mechanism is involved in the alteration of vascular endothelial function or how much of the functional change is caused by direct infection and how much is from the cytokine activation that is evident in the arenaviral HF. Pro-inflammatory cytokines are elevated, and in Argentine HF, there is a correlation between mortality and the levels of TNF- and interferon (IFN) (6–8). Arenavirus infection has also been shown to cause a loss of cellular function—such as growth hormone secretion in the murine pituitary or neurohumoral transmitter secretion S269
The clinical findings in viral hemorrhagic fever differ from those in the sepsis syndrome and should be studied and interpreted separately; this approach will sharpen therapeutic approaches and could shed light on the problems of sepsis in general. Figure 2. Pleural surface of patient with Lassa fever. in cultured neurotransmitter cells— without any detectable sign of cellular damage or interruption of the basic life functions of the cell (9). Hence, these viruses may exert reasonably selective and specific actions on function without any overt signs of cellular damage. The role of soluble mediators in VHF was first investigated in guinea pigs infected with Pichinde virus (10). (Pichinde virus is an arenavirus that does not cause disease in humans and thus provides a useful model for the laboratory study of arenavirus HF.) The lesions visible on detailed histopathologic study were not sufficient to suggest the cause of death, and the marked extension of infection beyond any zone of morphologic damage suggested that disease is associated with an alteration of function rather than overt cytopathology—and direct viral interference with endothelial cell function is a possibility (9). A role for soluble mediators presumed to be involved in the pathogenesis of septic or late hemorrhagic shock has also been considered, and several have been found to be markedly altered in Pichinde virus infections, including leukotrienes (11), plateletactivating factor (12), and endorphins (13). TNF- is also activated in the Pichinde-infected guinea pig (14). Supportive evidence for the role of soluble factors comes from the observations that cardiovascular depression is an important component of the disease in the absence of direct cardiac infection virus (15). Intensive studies of coagulation have failed to identify major isolated defects in coagulation pathways, fibrinolysis, or the presence of DIC to explain bleeding in arenavirus disease (16). In any case, bleeding is marked in the South American diseases, presumably related to vascular damage and the associated severe thrombocytopenia. Bleeding occurs less frequently in Lassa fever, but when it does, it is in a setting of mild thrombocytopenia but marked loss of platelet function measured in vitro (17, 18). RIFT VALLEY FEVER Rift Valley fever is perhaps unique in having a highly variable clinical presentation that includes VHF, encephalitis, and retinal disease (19). Development of Rift Valley fever is often associated with marked hepatitis. The pathogenesis in humans is not known, but extensive studies in monkeys have shown that an important determinant is late secretion of IFN- (20). If IFN- is detectable within 6–12 hrs of infection, the course will be mild. Later onset of the IFN response is associated with more severe disease, DIC, microangiopathic hemolytic anemia, and intravascular deposition of fibrin thrombi (21). The virus itself causes rapid cell death in all mammalian cells tested, including human endothelial cell cultures (19). It seems likely that the delay in IFN- response is sufficient to allow more extensive infection of vascular endothelium and that direct viral damage destroys the antithrombotic lining of capillaries, including the glomeruli. CRIMEAN CONGO HF Crimean Congo HF virus causes a severe HF but is not highly cytopathic. The mechanism for hemorrhage is not known, but there is clinical evidence of DIC (22). Of all the VHFs, this infection is associated with the most florid hemorrhage and also seems to be associated with the highest frequency of large ecchymoses. More detailed clotting and cytokine studies would be of considerable interest. Immunohistochemical and in situ hybridization studies have primarily focused on liver tissues and have shown involvement of hepatocytes and endothelial cells (23). The other tissues studied showed a few endothelial cells and occasional mononuclear phagocytes to be positive. There is modest cellular necrosis generally associated with the presence of antigen in hepatocytes. As with all the nonhantavirus diseases discussed here, there is marked clinical improvement at the onset of the immune response and disappearance of viremia. HANTAVIRUSES Hantaviruses from American rodents cause HPS, which is associated with a marked and abrupt increase in pulmonary capillary permeability (24). HPS is confined to the Americas. Unlike most VHFs, the disease process in HPS is mainly confined to the thoracic cavity. There is an initial febrile prodrome lasting 4–5 days. Patients subsequently develop bilateral alveolar pulmonary edema, which progresses rapidly. Patients exhibit thrombocytopenia—and this is S270 Crit Care Med 2002 Vol. 30, No. 5 (Suppl.)
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