Hantavirus Infection (2005)

Hantavirus has attracted more and more attention as an emerging pathogenic virus in the past decades. It causes two distinct human diseases: Hemorrhagic fever with renal syndrome (HFRS) and human pulmonary syndrome (HPS). Reports on clinical entities possibly caused by hantaviruses in China and England backdate into the first millennium and the Middle Age, respectively (1,2). However, it lasted until 1951 to 1953 during the Korean War before hantaviruses found global attention. More than 3000 United Nations and US soldiers experienced an acute febrile illness with acute renal failure and shock and a mortality rate of 7% close to a small river called Hantaan (3,4; G. Schreiner, personal communication, Washington, 1993). The causative agent, Hantaan virus (HTNV), was identified in 1978 by Lee et al. (5). Until now, 21 different hantavirus species have been described, and more than 30 genotypes are characterized and can be found all over the world (6,7). Biology and Epidemiology Morphology Hantaviruses comprise one of five genera of the virus family Bunyaviridae (8). They replicate in the cytoplasm of host cells and are composed of a spherical lipid envelope; four viral proteins; and three single-stranded, negative-sensed RNA segments designated S (small), M (medium), and L (large) that are coding for the nucleocapsid protein (NP), the surface envelope glycoproteins G1 and G2, and the RNA-dependent RNA polymerase, respectively (Figure 1). Additional minor open reading frames are present in the genomes of hantaviruses, but to date, no corresponding proteins were identified. NP, the main structural protein, is complexed with the viral RNA genome segments that form helical nucleocapsids (9). Host Range The main natural reservoir of hantaviruses is murid rodents (order Rodentia; family Muridae; subfamilies Murinae, Arvicolinae, and Sigmodontinae). Virus and host share a long period of co-evolution characterized by the absence of any hantavirus-caused disease in infected rodents (10,11). Originally, it was thought that one rodent species is the predominant host for one hantavirus species, but recently more and more studies reveal that there might be multiple rodent hosts for individual virus species and multiple viruses in a single host species (12–14). In addition, numerous studies have reported hantavirus infections to be present in animal species other than rodents, for example, in cattle, moose, cat, dog, etc. However, the question of whether these animals are infected accidentally or represent further natural reservoirs has not yet been answered (15). The distribution of single hantavirus species correlates with the geographic extension of their hosts (Table 1), and hantavirus genotypes of the same geographic area are phylogenetically related (15–17). Humans do not belong to the natural host range of hantaviruses, and infection occurs accidentally via virus-containing, aerosolized rodent excretions such as urine, feces, or saliva. People who live or work in close contact with infected rodents are at increased infection risk, and studies usually show higher percentages of seropositive individuals in such groups as compared with control subjects (18,19). Old World and New World Hantaviruses The genus Hantavirus is roughly composed of two main groups: Old World and New World hantaviruses. HFRS in humans is caused by pathogenic Old World hantaviruses that include Amur virus, Seoul virus, and HTNV, the epidemiologically most important species, with lethality rates up to 15% in Asia, as well as Dobrava virus (DOBV), Tula virus (TULV), and Puumala virus (PUUV) in Europe; the last one is the main hantavirus species in Europe and induces Nephropathia epidemica (NE), a milder variant of HFRS, with mortality rates of 0.1% (10,20). HFRS affects approximately 200,000 people each year predominantly in Asia. In 2004, 235 cases were reported in Germany according to a recent epidemiologic bulletin of the Robert-Koch Institute. The first pathogenic New World hantavirus (Sin Nombre virus) was discovered in the early 1990s in the Four Corners region of the United States (21). From this time on, numerous additional pathogenic New World hantaviruses were identified and characterized (Table 1). New World hantaviruses are the causative agent of approximately 300 cases of HPS each year in North and South America, with lethality rates up to 50%. Human hantavirus infections are assumed to occur accidentally, and men represent a dead end for the hantavirus life cycle. Transfer of virus particles from infected to uninfected people normally does not occur. One exception is the Andes hantavirus strain Sout in Argentina, of which sporadical person-to-person transmissions were reported (22,23). This finding reveals a worrying risk potential of hantaviruses for human health. Clinical Course of NE, HFRS, and HPS HFRS and HPS are partly overlapping clinical syndromes. In Europe, the hantavirus serotype Puumala causes NE, a milder variant of HFRS. Viremia occurs after initial infection of alveolar macrophages and life-threatening acute-phase symptoms are induced primarily by infection of vascular endothelial cells of the lung and the kidneys with concomitant loss of barrier function resulting in severely increased endothelial permeability. NE NE is characterized by a sudden onset with high fever, headache, backache, and abdominal pain. Transient thrombocytopenia is a typical finding in the early phase of the disease. The occurrence of conjunctival hemorrhages, palatine petechiae, and a truncal petechial rash after 3 or 4 d is possible. Approximately 1% of patients experience severe neurologic manifestations, e.g., seizures or bladder paralysis. The hemorrhages are accompanied by oliguria, azotemia, proteinuria, and hematuria. Within 3 d, the rash disappears and the patients develop polyuria. The convalescent phase extends over several weeks, and sequelae are rare. Severe courses of NE with acute renal failure and lethal outcome range between 0.1 and 1% (24). HFRS The incubation period of HFRS is 7 to 36 d. Only 10 to 15% of cases have a severe course, with lethality rates between 6 to 15%. HFRS is characterized by systemic involvement of capillaries and venules. It induces various hemorrhagic manifestations and circulation disorders. Renal involvement is characterized by acute renal failure as a result of interstitial hemorrhage and interstitial infiltrates (24,25). The clinical course is subdivided into five phases: Febrile, hypotensive, oliguric, diuretic, and convalescent. The onset of HFRS resembles NE with high fever, backache, abdominal pain, chills, myalgia, malaise, and bradycardia over 3 to 4 d. Photophobia, pharynx enanthema, and a diffuse reddening of the face are also observed. On the third to fifth days, petechia develop initially on the palate. At the same time, conjunctival hemorrhages may appear and a temporary impairment of the visual function is reported. The urinary sediment reveals hematuria and atypical gross proteinuria (in some cases >3 g/24 h). The hypotensive phase ranges 3 to 6 d after onset of fever. Shock or hypotension may occur. Laboratory findings in this phase are leukocytosis and thrombocytopenia. Patients show a wide range of renal conditions, including acute tubulointerstitial nephritis, necrotizing glomerulonephritis, and IgA nephropathy. The oliguric phase starts at approximately day 8, and hemorrhagic manifestations become more prominent. The diuretic phase starts at approximately day 11, and the convalescent phase lasts approximately 3 wk to 6 mo. Sequelae are rare but include chronic renal failure and hypertension. In a series of 46 patients in Tampere (Finland) who had NE 3 to 7 y ago, the patients had higher GFR and filtration fraction, more proteinuria, and a higher ambulatory systolic BP compared with healthy control subjects (26). Furthermore, we studied 42 patients after NE from several areas in Germany and found hypertension or elevated serum creatinine (1.5 mg/dl) (27). Extrarenal manifestations include acute impairment of visual function, acute myopia, CNS complications with seizures, sometimes myocarditis, and severe gastrointestinal hemorrhages. In addition, thyroid, liver, and pancreas may be affected. Lung involvement but to a lesser extent than in HPS is also observed during HFRS (24,28–30). HPS The onset of HPS is characterized by flu-like symptoms such as high fever, myalgia, and headache. The patients develop acute noncardiac pulmonary edema and hypotension within 2 to 15 d. Bilateral infiltrates develop rapidly, sometimes associated with pleural effusions. Neutrophilic leukocytosis, hemoconcentration, thrombocytopenia, and circulating immunoblasts are observed. Severe courses of HPS are associated with increased lactate levels. The mortality rates of HPS are approximately 50%. Patients who survive the acute phase of the disease recover normally within 5 to 7 d without any sequelae (24). Acute renal failure is secondary as a result of shock and respiratory failure. The medical knowledge about HFRS and HPS has increased substantially in the past years, resulting in the conclusion that both syndromes are partly overlapping. The number of reports on HFRS cases with lung involvement and HPS cases with renal involvement is continuously growing, and it is conceivable that the descriptions of the clinical courses of both syndromes will further converge in the near future. Pathology of NE, HFRS, and HPS NE and HFRS Immunohistochemistry analysis of hantavirus-infected renal tissue reveals interstitial infiltrates with immune cells and interstitial hemorrhage. The most common histopathologic lesion are acute tubulointerstitial nephritis. Tubular epithelial and luminal alterations are present. Intertubular capillaries are congested, and the interstitium is broadened by edema, indicative of a generalized capillary damage. Occasionally, glomerular pathology, e.g., hypercellularity and expansion of the mesangium, are observed, and this is probably the underlying cause of gross proteinuria. Tubular, interstitial, and glomerular histologic damage are associated with the clinical severity of renal failure (Figure 2). It is of note that urinary sediment contains tubular cells with extremely enlarged nucleoli. These cells resemble uroepithelial tumor cells and spontaneously disappear after the disease has subsided (29,31). Recent work has shown that these tubular cells contain hantavirus antigen (32). HPS Immunohistochemistry analysis of HPS documents the distribution of viral antigens within the endothelium of capillaries throughout various tissues. Infected endothelial cells lack any morphologic changes and show no visible cytopathic effects (CPE). Accumulations of hantaviral antigens are observed in the pulmonary microvasculature and in dendritic cells within the lymphoid follicles of spleen and lymph nodes. In some autopsy cases, endothelial cells in the capillaries of the myocardium and the endocardium bear hantavirus antigen, contributing substantially to severe courses of HPS. Gross pathologic findings show that the lungs of patients with HPS are dense, rubbery, and heavy, usually weighing twice as much as the average lung. The pathologic lesions are primarily vascular with variable degrees of generalized capillary dilation and edema. Frequently, the lungs reveal a mild to moderate interstitial pneumonitis with variable degrees of congestion, edema, and mononuclear cell infiltration (33). Pathophysiology of Hantavirus Infection The main factor that determines the course and the severity of HFRS and HPS is the degree of increased permeability of infected endothelium that shows no histologic signs of damage and no visible CPE. At present, it is poorly understood how pathogenic hantaviruses induce the capillary leakage during the acute phase of the two syndromes and why some hantavirus species are nonpathogenic. Genetic Predisposition Patients with certain HLA antigens seem to have a genetic predisposition for severe courses of HFRS and HPS. Patients who bear HLA-B8, DRB1*0301, C4A*Q0, or DQ2 alleles seem to have a significantly higher risk for a severe course of NE (34–36), and the HLA-B35 allele was associated with severe courses of HPS (37). The mechanisms that are involved in these genetic predispositions are unknown. Hantavirus Replication Cycle Hantavirus replication takes place in macrophages and vascular endothelial cells, especially in the lung and the kidney (10,38). For pathogenic hantaviruses, the entry into host cells occurs by attachment to αVβ3 integrin on the cellular surface and subsequent endocytosis (39,40). The virion envelope fuses with the endosome membrane in a pH-dependent way, and nucleocapsids are released into the cytoplasm. Thereafter, the viral RNA-dependent RNA polymerase directs transcription of viral genes and replication of the viral RNA genome segments. The viral NP and RNA polymerase mRNA are translated at free ribosomes, whereas the glycoprotein mRNA is translated into the endoplasmic reticulum. G1 and G2 glycoproteins are transported to the Golgi complex for final glycosylation. Large intracellular inclusion bodies, probably composed of NP, are formed in the cytoplasm. It is assumed that hantavirions are formed at the membranes of the Golgi complex, followed by budding into the Golgi cisternae, migration in secretory vesicles to the plasma membrane, and release by exocytosis. Several in vitro studies have shown that this hantaviral life cycle does not induce any visible CPE in endothelial cells. Host cells are not lysed by infection with pathogenic hantaviruses, and no increased permeability is induced in endothelial cell cultures (41,42). Apoptosis and of genes in cells that were infected with pathogenic hantaviruses was reported for and human kidney in there is no for cell in infected endothelial cells These that increased endothelial permeability during HFRS and HPS might be the result of the infection with pathogenic hantaviruses in with additional that are for the in and that are not present in in vitro cell In this it is assumed that in the infected cells and immune mechanisms may a in the of vascular Infection with hantaviruses induces immune in host cells, whereas pathogenic hantaviruses seem to be to these to a certain of are and genes are The of the protein is in cells that are infected with pathogenic hantaviruses in with hantaviruses. of e.g., HLA are the more after infection with pathogenic than with hantaviruses mechanisms that are induced during hantavirus infection include of the of the and e.g., with elevated of complex and higher during NE caused by cells, as and cells in and in of of and of and are assumed to into hantavirus-infected The immune a hantavirus infection via a and a cellular In the course of the immune all of are during HFRS and HPS. of serum and the main of the were during the acute phase of both syndromes and were found to be increased before and during the acute phase of HFRS. It is conceivable that in hantavirus by of and that permeability of infected it was not to a between and HFRS severity of viral NP, and G2 are during and after the acute phase of HFRS and whereas the hantavirus NP is as the viral antigen the most of hantaviruses, is also predominantly viral NP and during the acute phase of HFRS and whereas further can be observed during the early convalescent phase cells are the predominant in the course of the cellular immune to a hantavirus infection and are assumed to important in virus and of were observed at the onset of HFRS and HPS and were also found in the lungs of patients who from HPS. The severity of disease correlates with the number of were identified in all three viral structural whereas NP to be the predominant protein of and of and are in variable to the immune during a hantavirus It is assumed that an important in vascular during HFRS and HPS. such as are to endothelial permeability in the course of natural immune e.g., during migration the vascular elevated plasma of and were at the onset of the acute phase of HFRS and HPS of seem to with a severe course of NE of especially of in the area of the was reported during HFRS and in the lungs of patients with increased of and cells were observed (37). Hantaviruses are also to dendritic cells, resulting in of e.g., and that also to increased endothelial permeability In vitro infection of human lung endothelial cells with or Nombre virus increased of and protein recent in vitro by et al. that increased permeability of endothelial cells is significantly in cells in with uninfected cells. 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