Renal failure and hantavirus infection in Europe

Michael Faulde1,, Dirck Sobe1, Peter Kimmig2 and Jerrold Scharninghausen3

1 Central Institute of the Armed Forces Medical Service, Koblenz, Germany, 2 Landesgesundheitsamt Baden-Württemberg, Stuttgart, Germany and 3 Department of Wildlife and Fisheries Sciences, Texas A&M University, College Station, Texas, USA

Introduction

Hantaviruses, the causative agents for haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), are serologically related viruses of the family Bunyaviridae, and have a worldwide distribution. Unlike other Bunyaviruses, hantaviruses are not known to be transmitted by an arthropod vector. The natural hosts of these viruses are small mammals. Hantavirus virions are excreted from infected rodents via saliva, urine, and faeces. Humans may become infected through inhalation of aerosols of dried excreta, inoculation through the conjunctiva, or entry through broken skin or rodent bites [1].

Human hantaviral infections are not new. During the 1950s, hantavirus carried by the striped field mouse, Apodemus agrarius, caused approximately 3000 cases of Korean haemorrhagic fever among United Nations troops participating in the Korean conflict. The aetiologic agent, defined as Hantaan virus, was first isolated in 1977 from the rodent reservoir [2]. Since then, over 20 other hantaviruses from rodent species in Asia, Europe, and the Americas have been serologically or genetically characterized. Currently, the worldwide infection rate of hantaviral disease is estimated to exceed 200 000 cases annually. The majority of these cases are HFRS which occurs in Eastern Europe and Central and East Asia.

During the last decade, it became clear that hantaviruses are widely endemic in Europe, where at least two different human-pathogenic strain types, Puumala, and Dobrava, have been reported [3–5]. In Germany, hantaviral infection is now reported as the most common endemic rodent-borne human illness, when compared with tularaemia, lymphocytic choriomeningitis, and leptospirosis. Furthermore, hantavirus is suspected to be the prevailing cause of renal failure associated with infectious diseases in Central Europe. This report aims to provide basic information on hantavirus infection associated with renal syndrome with special respect to European conditions.

Pathogenesis and clinical outcome of haemorrhagic fever with renal syndrome and nephropathia epidemica

The pathophysiological outcome of human infection with Old World hantaviruses is generally characterized by vascular dysfunction directly associated with genesis of more or less severe haemorrhagic fever with renal syndrome. Hantavirus antigen is detectable in the capillary endothelial cells of various organs, and is involved in immunopathological processes [6].

The course of hantaviral disease is usually very short, and, if the patient survives, complete recovery occurs in most cases. The incubation time is estimated to be 2–3 weeks (4–42 days) showing as broad spectrum of relatively unspecific clinical symptoms, especially when a mild or moderate course of disease occurs, thus complicating the diagnosis. Unlike the American hantaviruses responsible for HPS, the European viruses target mainly the kidneys, rather than the lungs. In rare instances, Puumala virus has been found to induce pleural complications, demonstrating that even in European hantavirus cases, acute respiratory distress syndrome may be involved in the course of the disease [7].

Severe cases of HFRS, usually associated with the Asian Hantaan virus and the European Dobrava virus, show a case fatality rate which may exceed 10%. The clinical manifestation can be differentiated into five chronological phases.

(i) The febrile phase: duration 3–7 days, associated with head, abdominal and back pain, ending up with appearance of severe proteinuria.
(ii) The hypotonic phase: duration several hours to 2 days, with first appearance of haemorrhages associated with lethal shock syndrome in most severe cases.
(iii) The oliguric phase: duration 3–7 days, associated with nausea, vomiting, and acute renal failure, often combined with hypertension due to simultaneous hypervolaemia; approximately 50% of the lethal HFRS cases appear during this phase.
(iv) The diuretic phase: duration days to weeks, indicating a good case prognosis; further clinical problems may be dehydration electrolyte shifts, and secondary infections.
(v) The convalescence phase: duration 2–3 months, usually associated with complete recovery of renal function in most cases.

Interestingly, first results obtained from serum samples of patients living in hantavirus endemic areas in Germany, who were undergoing intermittent haemodialysis treatment, revealed a significant increase in antibody prevalence of 4.2% (Würzburg area), and 4.8% (Giessen area), respectively, compared with the prevalence rate of the corresponding local population [3].

A relatively mild form of HFRS in northern and western Europe, associated with Puumala virus, only rarely involves haemorrhage. This disease produces a case fatality rate of <0.2% and should be suspected if the following four criteria can be diagnosed: sudden onset of illness, fever >38°C, back and/or head and/or abdominal pain, and proteinuria and/or haematuria with polyuria >2000 ml/day and an increase of serum creatinine [6].

Diagnosis and treatment

Since symptoms linked to HFRS are usually not pathoGognomonic, further specific laboratory work-up is necessary for case confirmation. Laboratory diagnosis may be conducted either by direct or indirect methods. Direct methods include virus culture and RT–PCR. Indirect methods include serologic means for antigen or antibody detection. Immunofluorescence assays (IFAs) and enzyme-linked immunosorbent assays (ELISAs) are widely commercially available to determine specific anti-hantavirus IgM and/or IgG antibodies, respectively. Usually, a strong antibody response occurs during the course of the disease with an IgM antibody titer peaking between 8 and 25 days after onset of illness. IgG antibodies can be detected in approximately 60% of HFRS cases until the 14th day [6,7].


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Table 1. Overview of systematic relationship between rodent host and hantaviruses related to human disease

 
Immunologically, hantaviruses are cross-reactive, and can be serologically differentiated into two major subgroups: the Hantaan (HTN)-like, and the Puumala (PUU)-like hantaviruses, respectively. According to recommendations released by the World Health Organization, antigens of both viruses must be used for correct serologic hantavirus testing in order to cover all strain types. Depending upon their cross-reactivity, HTN-specific tests also may detect infection with Dobrava and Seoul virus, whereas PUU-specific test systems show cross-reactivity with both Tula and the New World Sin Nombre virus [3,8].

Rapid diagnosis is of great importance since it enhances patient management and allows early treatment of hantaviral disease. HFRS is primarily treated symptomatically. Specific therapeutical regimens include the use of Ribavirin. This antiviral drug is considered to be of significant value if administered during the early stages of disease. At present, licensed vaccines are not yet commercially available. Recently, first encouraging studies have been made with a new hantavirus vaccine [9].

Epidemiological aspects and transmission modes in Europe

Although hantaviruses are distributed worldwide, the specific virus strains or species and their geographic distribution are often unknown. Additionally, various hantavirus strains, such as Tula virus (Central Europe), and Prospect Hill virus (North America) have not yet been linked to human disease.

Hantaviral infection rates may reach 200/100 000 in hyperendemic areas [8]. Environmental destruction, poor hygienic conditions, and rodent population cycles are linked with increased human exposure. These factors led to hyperendemic disease transmission in the Balkans, increasing from seven confirmed cases (January to October) in the Bosnia and Herzegowina area during 1994 to 347 confirmed cases in 1995 [11]. In Germany, the seroprevalence rate within the overall population was estimated to range between 1% and 2%, increasing up to 3% in known endemic areas. Seropositivity rates up to 9.1% in forest workers and between 10% and 30% in rodents could be ascertained against PUU antigen in the Suebian Alb area, a mountainous region located in southwestern Germany. Using RT-PCR, 10% positivity for Tula virus (TUL) in common voles (Microtus arvalis), and 9% positivity for PUU in red bank voles (Clethrionomys glareolus) could be determined, respectively [12]. Prevalence rates tend to be lower in western Europe, but higher in northern, eastern and south-eastern Europe. For example, a seroprevalence rate exceeding 40% was detectable in areas of northern Sweden [1,3].

Contracting hantavirus depends upon direct contact between humans and infectious rodent excrements, thus defining risk groups. Significantly higher risk of infection than in general population was reported among forest workers, hunters, muskrat hunters, soldiers, employees on horse farms, and mammalogists [3,13,14]. The population dynamics of rodents in Europe vary geographically within and between host species, and these differences are reflected in the seasonal and multiannual patterns of human epidemiology. In the north, human epidemics peak in late autumn when, depending on the species, rodents may invade human settlements, while in southern Europe epidemics peak during the summer period, obviously related to crop harvesting and increased outdoor activity. An overview on systematic relationships, distribution and major rodent host of human-pathogenic hantaviruses is listed in Table 1Go.

Depending on the specific rodent reservoir, its specific behaviour, and the particular hantavirus type, three discrete modes of transmission can be differentiated.

(i) Sylvatic transmission: rodent host is a sylvatic species, only rarely linked to infestation of human settlements; transmission by exposition to forests prevails (example: Clethrionomys glareolus (red bank vole) and Puumala virus in central Europe).
(ii) Rural transmission: rodent host species harbors meadows and fields; transmission may occur by both, rodent contact outdoors in fields, and rodent contact in or around buildings (example: Apodemus flavicollis (yellow-necked mouse) and Dobrava virus in central and southeastern Europe).
(iii) Urban transmission: rodent species is living in peridomestic areas and regularly infest human settlements and buildings, spreading the causative agent by aerosolization of infectious urine or droppings in the human living environment (example: Rattus norwegicus (Norway rat) and Seoul virus in Asia, possibly in Europe).

Conclusion

Hantaviruses, especially HFRS and NE, must be considered in the ‘Old World theatre’ whenever fever of unknown origin associated with renal involvement may occur. Nevertheless, the potential for importation of HPS cases from the Americas into Europe is present.

Epidemiological surveillance programmes tracking epidemic foci, incidence, mortality, and recovery rates of hantavirus infections are rudimentary or absent in Europe. Further studies must be conducted, to address the area-, hantavirus- and rodent species-specific modes of transmission, pathogenic potential of newly defined hantavirus species, as well as mapping of endemic and hyperendemic foci. Results obtained from these studies may directly lead to improved methods of treatment and prevention through vaccination, rodent reservoir monitoring and control, exposition prophylaxis, and disinfection techniques for treatment of rodent-infested human settlements.

Notes

Correspondence and offprint requests to: M. Faulde, Zentrales Institut des Sanitätsdienstes der Bundeswehr Koblenz, Laborabteilung I-Medizin, Labrp Med. Zoologie, BW442, Postfach 7340, D-56065 Koblenz, Germany. Back

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