Hantavirus infections, diagnosis and treatment

Hemorrhagic Fever with Renal Syndrome (HFRS) is a common viral illness in Asia. HFRS is caused by Hantaan virus, a member of Hantaviruses. The symptoms were firstly described as early as 1000 years ago in China, but the illness became known worldwide during the Korean war among UN soldiers as Korean hemorrhagic fever. The virus was first described in 1978 and named Hantaan virus, according to Hantaan river in Korea, where the virus was first isolated by passage in its rodent host, Apodemus agrarius (striped field mouse) (9).

Hantaviruses form a genus in the bunyaviridae family. Currently, over 20 different sero/genotypes have been reported so far from all over the world. In Asia and Europe, Hantaviruses cause HFRS or its milder form Nefropatia Epidemica (NE). In the new world they cause Hantavirus Pulmonary Syndrome (HPS).  It has been estimated that every year about 200 000 people is infected by Hantaviruses, half of them in China (10,11).

Hantaviruses as all members of Bunyaviridae have negative stranded RNA. The genome consists of three genes coding transcriptase (L), envelope proteins G1 and G2 (M) and nucleocapsid (M-segment). By electron microscopy, Hantaviruses are spherical, their diameter is 100 nm, and they have a 5 nm lipid bilayer (12,14).

Mice and rats carrying Hantaan virus secrete virus to urine, stool and saliva. The most common route of transmission to humans is aerosols, but there is evidence that bites may be another remarkable route of infection (4). HFRS is more common in rural areas than in the urban ones. The highest seasonal prevalence in Asia is during spring and summer due to the farming activities, when people have more contacts with rodents. The other high risk-groups are animal trappers, forestry workers and military personnel (9).

There are three clinical forms of HFRS described in humans: severe, moderate and mild. The severe form caused by Hantaan virus (HTNV) and Dobrava-Belgrade virus (DOBV) is common in Asia and in Eastern Europe, the moderate form, Seoul virus (SEOV), occurs only in Asia. Mortality rate is approximated to be 5 – 15% for the severe form and 1% - 2% for the milder form. The mild form of Hantavirus infections in Europe is mostly caused by Puumala virus (PUUV).

Typical course of severe HFRS infection have five phases: febrile, hypotensive, oliguric, diuretic and convalescent. The febrile phase lasts usually 3 – 7 days and is followed by a hypotensive phase which takes hours or days. When the blood pressure returns to normal oliguric phase starts lasting 3 – 7 before the urinary output increases. The diuresis phase lasts several weeks and convalescence to normal for several months. The deaths occur due to shock and multiorgan hyperfusion, or due to the uremia during the oliguric phase. (2).

Hantavirus replication occurs in the vascular endothelium. Although direct cytopathic effect can not be seen, the basic pathogenic effect of the infection is increased capillary permeability (17). Ribavirin has described to inhibit hantavirus replication (6). Clinical trials in Republic of China have shown that Ribavirin reduce the mortality when it is given during the first 5 days after the onset of illness (5).  Maintenance of intravascular volume and cardiac output with ionotropic support, as well as balance in body fluid and electrolytes, are important. In the severe cases peritoneal dialysis and hemodialysis are required (10).

Diagnosis of the infection is based on serology. IgM raises already during the first days of infection and is the best sign of acute infection. Infection is thought to leave life-long protective immunity and IgG antibodies can be measured after decades. The first method of serology was immuno-fluorescence assay (IFA) (1), with native virus grown in E6 cells or mice brain slices infected with the virus.  Whole N protein has shown to be most sensitive antigen and assays based on an recombinant technology has been introduced (7,13,15,16).

Reagena offers diagnostic tests for detection of Hantavirus specific IgM and IgG antibodies. Reagena EIA tests as well as the serodiagnostic rapid tests Reagena POC PUUMALA IgM, Reagena POC DOBRAVA-HANTAAN IgM, and the newest ReaScan tests using recombinant nucleocapsid antigens. Reascan Ab-Dect Puumala IgG rapid test can be used for screening of Puumala virus rodent carriers.

Since the risk to acquire Hantaviruses infection is higher in the countryside than in the urban areas, point-of-care diagnostic outweighs the traditional diagnostic assays which require hours or even days to perform. Reagena's POC tests are based on lateral flow membrane technology, and they enable laboratory diagnosis of Hantavirus infections without advanced laboratory facilities or highly trained personnel.

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13. Salonen, E. M., P. W. Parren, Y. F. Graus, A. Lundkvist, P. Fisicaro, O. Vapalahti, H. Kallio-Kokko, A. Vaheri, and D. R. Burton. 1998. Human recombinant Puumala virus antibodies: cross-reaction with other hantaviruses and use in diagnostics. J. Gen. Virol. 79(Apr Pt 4):659-665.

14. Schmaljohn, C.S. 1996. Bunyaviridae: the viruses and their replication. In: Fields, B.N., Knipe, D.M. Howley, P.M. (eds.) Field´s virology 3rd edn, vol.1 Philadelphia, Lippincott-Raven Publishers:1447-1471.

15. Sjolander, K. B., and A. Lundkvist. 1999. Dobrava virus infection: serological diagnosis and cross-reactions to other hantaviruses. J. Virol. Methods. 80(2):137-143.

16. Vapalahti, O., H. Kallio-Kokko, A. Narvanen, I. Julkunen, A. Lundkvist, A. Plyusnin, H. Lehvaslaiho, M. Brummer-Korvenkontio, A. Vaheri, and H. Lankinen. 1995. Human B-cell epitopes of Puumala virus nucleocapsid protein, the major antigen in early serological response. J. Med. Virol. 46(4):293-303.

17. Zaki, S. R., P. W. Greer, L. M. Coffield, C. S. Goldsmith, K. B. Nolte, K. Foucar, R. M. Feddersen, R. E. Zumwalt, G. L. Miller, A. S. Khan, et al. 1995. Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. Am. J. Pathol. 146(3):552-579.

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