Hantavirus Infection: a Review and Global Update

Review Article

Hantavirus Infection: a review and global update

Zhenqiang Bi, Pierre B.H. Formenty, Cathy E. Roth

Biorisk Reduction for Dangerous Pathogens, Department of Epidemic and Pandemic Alert and Response, World Health Organization, Geneva, Switzerland.

Abstract Hantaviruses have the potential to cause two different types of diseases in human: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). HFRS, initially described clinically at the turn of the 20th century, occurs endemically in the Asian and European continents, while HPS, recognized as a clinical entity since 1993, represents the prototype of emerging diseases occurring in the Western hemisphere. Approximately 150,000 to 200,000 cases of HFRS are hospitalized each year world wide, with most of the cases occurring in the developing countries. The case fatality rate of HFRS varies from <1% to 12% depending on the viruses. Although HPS is much smaller in number than HFRS, with approximately 200 HPS cases per year in the Americas, the average case fatality rate is 40%. The reported cases of hantaviral infection is increasing in many countries and new hantavirus strains have been increasingly identified worldwide, which constitutes a public health problem of increasing global concern. Hantaviral infection might be underestimated due to its asymptomatic and non- specific mild infection, and the lack of simple standardized laboratory diagnostics in hospitals, especially in the developing countries. This review summarizes the current knowledge on virology, epidemiology, clinical manifestation, laboratory diagnostics, treatment and prevention of hantaviruses and hantaviral infections. Key Words: hantavirus, hemorrhagic fever with renal syndrome, HFRS, hantavirus pulmonary syndrome, HPS, rodent control, vaccine.

J Infect Developing Countries 2008; 2(1):3-23.

Received 19 September 2007 - Accepted 7 December 2007.

Copyright © 2007 Bi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction HPS deaths are caused by myocardial dysfunction Since the first hantavirus, Hantaan virus and hypoperfusion rather than hypoxia, some (HTNV), was isolated in 1976 [1], many other investigators have recently begun to use the term hantaviruses have been identified [2], with at least hantavirus cardiopulmonary syndrome (HCPS) [7]. 22 being pathogenic to humans. Hantaviruses We will use HPS instead of HCPS in the context of have the potential to cause two different types of the review. Herein, we provide a global update of diseases in humans: hemorrhagic fever with renal hantaviral infections focusing on virology, global syndrome (HFRS) and hantavirus pulmonary prevalence, the hantaviruses causing human syndrome (HPS). HFRS, which includes diseases infections, clinical features and treatment, formerly known as Korean hemorrhagic fever laboratory diagnostics and control and prevention. (KHF), epidemic hemorrhagic fever (EHF) and nephropathia epidemica (NE), denotes a group of Virology clinically similar illnesses that occur throughout the Hantaviruses, negative-sense single-strained Eurasian landmass and adjoining areas [3]. After RNA viruses, represent a separate genus in the about 30 years of its first modern description in the Bunyaviridae family. However, in contrast to other Russia Federation [4], HFRS came to the attention genera of the Bunyaviridae, hantavirus is of the world when approximately 3,200 cases were transmitted to human not by arthropod but from reported from 1951 to 1954 among American contact with persistently infected rodents and their soldiers deployed in the Republic of Korea [5]. excreta [2]. The genus consists of different Hantavirus once again attracted the attention of species, which are also called "serotype", the world in 1993, when it was identified to be the "genotype" or simply "hantavirus". Hantavirus etiologic agent of HPS outbreak in the Four generally grows slowly even inoculated in the most Corners region of the United States [6]. Since most susceptible vero cell E6 clone, and usually results

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23. in little or no cytopathic effect (CPE). Electron [16,17], there is considerable evidence that microscopic studies of thin sections of postmortem immunopathology, especially T-cell responses tissue samples show the hantaviral particles to rather than direct viral cytopathology, is have a morphology fairly typical of members of the responsible for its pathogenesis [18,19]. Cytokines Bunyaviridae family, forming predominantly such as tumor necrosis factor-α (TNF-α), spherical or irregular particles 80 to 120 nm in interleukin (IL)-6, IL-10, and γ-interferon may also diameter. Elongated particles averaging about 170 play some roles in pathogenesis of hantaviral nm in length have also been observed, which is infection [20,21]. atypical of viruses of the Bunyaviridae family [2,3]. The Virions have surface structures in an unusual Global Prevalence of Hantavirus Infections square grid-like pattern with each morphologic unit Hantavirus causes a significant number of being about 8 nm in diameter when viewed by human illnesses, making it a global public health negative staining. Like other enveloped viruses, threat (Figure 1). Approximately 150,000 to hantaviruses are readily inactivated by heat, 200,000 patients with HFRS are hospitalized each detergents, UV irradiation, organic solvents and year throughout the world [22]. On average, hypochlorite solutions [8]. approximately 200 cases of HPS per year are As all members of the Bunyaviridae family, the reported in the Americas, and although the number consensus terminal nucleotide sequences of the L, of cases is much smaller in number than that of M and S genome segments of Hantavirus are HFRS, its average case fatality is about 40% [2]. AUCAUCAUCUG… at the 3'-end [9, 10] and UAGUAGUA… at the 5'-end Figure 1. Global geographic distribution of hantavirus (http://www.ncbi.nlm.nih.gov/ICTVdb/Ictv/ pulmonary syndrome and hemorrhagic fever with renal index.htm). The Hantavirus coding strategy is the syndrome. simplest of the five genera of the Bunyaviridae, with all the three segments encoding only one protein in the virus complementary sense. The genome consists of a large [6530-6550 nucleotide (nt)] segment (L) encoding for the protein or viral RNA-dependent RNA polymerase; a medium (3613-3707 nt) segment (M) encoding for a polyprotein cleaved by co-translational cleavage to form two viral glycoproteins, Gn and Gc; and a small (1696-2083 nt) segment (S) encoding for the nucleocapsid (N) protein. Hantavirus produces chronic persistent Asia infection in the host rodent [11,12]. Transmission In Asia, clinical cases of HFRS caused by of these viruses across a species barrier results in HTNV and Seoul Virus (SEOV) have been human infections. Virus type correlates closely identified mainly in China, the Republic of Korea, with disease severity. The pathogenicity of and the Far East Region of the Russia Federation Hantavirus remains incompletely understood. It (Table 1). In China, more than 1,400,000 clinical has been demonstrated that some pathogenic cases, with about 45,000 deaths, were reported Hantavirus enters cells via beta-3 integrins, which over the period 1950 to 2001 [23], which makes are present on the surfaces of endothelial cells, China the most endemic country of HFRS with macrophages and platelets [13,14]; however, a 40,000 to 60,000 cases annually reported in recent recent study showed that beta-3 integrins did not years, accounting for 70% to 90% of the total play a critical role for respiratory epithelial cell HFRS cases reported in the world [24]. In the monolayer integrity [15]. The hallmark feature of Republic of Korea, a total of 14,309 HFRS patients hantaviral infections is capillary leak. Although were hospitalized from 1951 to 1986, with one Hantavirus has been shown to replicate in cultured third being soldiers [25]. In a recent study [26], it human endothelial cells and is present in was noted that the yearly number of HFRS endothelial cells in HFRS and HPS patients patients has decreased from 1,234 cases in 1991

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23. to 750 cases in 1998 since a vaccination campaign Europe began in 1991. The number of hospitalized HFRS NE, a mild form of HFRS described in Sweden patients has declined to 100 to 300 per year in since 1934, remains the most prevalent hantaviral recent years in the Republic of Korea [27]. In the disease in Western and Central Europe (Table 2). Asian region of the Russia Federation, The causative agent of NE, Puumala virus approximately 100 to 200 HFRS cases are (PUUV), was first isolated in bank voles reported each year in recent years [28], which only (Clethrionomys glareolus) in Puumala, Finland, in account for 3% of the total number of HFRS cases the early 1980s [44]. Nowadays, more than 9,000 in the country [29]. In Japan, although there have cases per year are reported in Europe (Table 2), been no HFRS cases reported since 1985, HFRS with an increasing tendency [45-48]. outbreaks were reported from the 1960s to the In Finland, a total of 8,184 laboratory 1970s, and seropositive R. norvegicus have been confirmed cases were reported from March 1995 identified in ports and reclaimed areas in different to February 2002 [45]. Recently, peak years have locations through the country [30]. been at 3-year intervals, with 2,300 cases, 2,603 cases and 2526 cases recorded in the years1999, Table 1. Hantavirus infection (HFRS) in selected 2002 and 2005 respectively (Markus Brummer- countries in Asia. Korvenkontio, Anti Vaheri and Olli Vapalahti, Countries/districts Reported Cases Seroprevalence personal communication). With an average PUUV China 40000-60000/year 1%-12% seroprevalence of 5% in humans, it was estimated Hong Kong SAR 1 in 1987 4% that about 5,000 infections occurred in Finland on 6.2% (2.5%- Province of Taiwan 14 as of 2005 a yearly basis [49]. In Sweden, it has been 1.6%) estimated that at least 4,500 human infections Republic of Korea 300-400/year 2.7%-12.5%** occurred there in 1998, but only one eighth were Far East Russia 100-300/year Federation diagnosed and reported [50]. In Norway, about 100 Japan None since 1985 0.48% cases of HFRS are reported each year [3]. India 2 fatal in 2000 5.50% In Belgium, two major HFRS outbreaks were Indonesia 11 cases in 2002 reported in 1995-1996 and 1999, with 217 and 124 Malaysia 3 as of 2001 2.52% cases respectively [51], and an increase was Singapore 3 as of 1996 2%-8% observed in recent years [48]. In France, 320 Thailand 1 in 2005 5.3%-33.3% cases were diagnosed from the first recognition of Sri Lanka 14 in1988 5.60% HFRS in 1982 to the end of 1992. A sharp Cambodia 8.20%# increase has been observed since 2003, with 128 Israel 2%-12.3%* cases reported in that year, and 115 cases were Kuwait 7% (6%-11%) reported in 2005 [46,47]. In Germany, an annual Laos 10% number of about 200 clinical hantavirus infections Philippines 6.1%(5.1%-7.6) were reported from 2001 to 2003 [52], and an Viet Nam 5.40% increase in hantavirus infections was observed in *The seroprevalence among hemodialysis patients, mild to moderate renal 2005, with at least 258 cases reported in the first failure patients, and health population were 12.3%, 9% and 2%, respectively half of the year [47]. **Seroprevalence among civilians in endemic areas. The seroprevalence rate in Korea military personnel is 2.1 to 16.4 In Austria, approximately 15 HFRS cases have # seroprevalence in rodents. been diagnosed per year, with a maximum of 72 cases in 2004 [53]. In Hungary, 235 clinical cases Clinical cases of HFRS have also been of hantaviral infection were confirmed between reported in other countries and districts in Asia [31- 1992 and 2000, and the overall seroprevalence 36] (Table 1). Serological investigation indicated was 10% in the general population [54]. In that there were strong evidences of hantaviral Bulgaria, 399 HFRS cases were diagnosed infections in humans in Israeli, Kuwait, Laos, between 1954 and 1988 with a fatality of 15.8%, Malaysia, Philippines, Viet Nam and the China and a significant rise in the incidence and mortality Hong Kong Special Administrative Region [37-42]. was observed in 1987-1988 when 36.7% of the Hantaviral infection was also demonstrated in patients died [55]. However, the etiology of HFRS rodents in Cambodia, though there has been no in Bulgaria still needs to be further characterized. report of human infections [43] (Table 1).

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

In Czech Republic, HFRS cases including a fatal Table 2. Human hantavirus infections in Europe.

2 3 case have been reported since 1992, and Dobrava 1 Cases/ Seroprevalence virus (DOBV), PUUV and Tula virus (TULV) have Region

year (%)

PUUV SAAV been co-circulating, with seroprevalence of DOBV antibodies against HTNV and PUUV being 1% and Europe + + 7000 6 1.4% respectively [56]. In Estonia, only a few Russia HFRS cases are officially reported each year; Finland + 2000 5 however, the overall hantaviral seroprevalence 8.0 in Northern rate is as high as 9.1%, with those for PUUV, Sweden + 300 part Saaremaa/Dobrava virus (SAAV/DOBV) and un- Germany + + 100 1-3 typed viruses being 5.1%, 3.4% and 0.6% France + 100 2.5 respectively [57]. Belgium + 100 1.5 In the Russia Federation, around 123,000 Norway + 100 24** HFRS cases were reported from 1990 to 2006, Serbia/ with an average yearly incidence of around 7,200 + + 30 Montenegro cases [58]. In 1997, a large-scale outbreak of HFRS Hungary + + 30 10 caused by PUUV occurred in the Republic of Austria + 15 1.2 (0.02-1.8) Bashkortostan, resulting in 10,057 reported cases Croatia + + 15 1.6 including 503 children, with an attack rate of 2.87% Slovenia + + + 15 1.7 [59]. The highest prevalence of 58/100,000 was Netherlands + 10 0.7 in blood donor reported in Bashkortostan [3], where 2,723 cases Bulgaria 10 were recorded in 2006, with a 40% increase over Denmark + + 10 1 in some areas the previous year (http://depts.washington.edu/ Slovakia + + 10 Bosnia- einet/newsbrief230.html? article=2848#2848). + + 10 5 In the Balkans, and particularly the Federal Herzegovina Republic of Yugoslavia, HFRS outbreaks have Greece + + 10 4 been recorded since the early 1950s with a case Luxembourg + 5 fatality rate of 5% to 10%, with Dobrava virus Switzerland 1▲ 0-1.9▲▲ (DOBV) being the predominant pathogenic virus Poland 1▲▲▲ [60]. An epidemic with more than 2,000 severe Estonia + + 9.1 cases was reported in the Federal Republic of Latvia + + 4 Yugoslavia from 1995 to 1996 [61]. In Croatia, 235 0.7 in blood Lithuania + + HFRS cases, of which 62.6% were soldiers, were donors reported from 1987 to 2001 [62], whereas 317 Czech + + 1-2 HFRS cases were diagnosed during an epidemic Republic in 2002 [63]. In Serbia and Montenegro, a large Portugal 1 0-10.7 in high- epidemic with 128 laboratory-confirmed cases Italy # occurred in 2002, and since then, more than 30 risks cases have been serologically confirmed each Albania + year [64]. In Greece, most human infections are Moldova + 7.8 sporadic, but outbreaks were also reported. From Spain 0.06-4.54 1 PUUV=Puumala virus; 2 DOBV=Dobrava virus; 3 SAAV= Saaremaa virus 1982, when the first case of HFRS was described, *In foresters in Ile-de-France; **In patients without symptoms of NE in Hattfjelldal, an endemic area to May 2001, there were 210 cases diagnosed in ▲Only one HFRS case possibly related to Tula virus was reported in the country with a case fatality of 9% [65,66]. Switzerland. ▲▲ 0% in forestry workers, 0.5% in blood donors, 0.8% in farmers, 1.1% in There have been reports of clinical hantaviral hunters and 1.9% in soldiers. infections in Albania [67], Denmark [68], ▲▲▲only one serologically confirmed case reported. #Hantaan-like virus infection, with a rate of 2.3% in "healthy" population. Luxembourg [48], Poland [69], Romania [70], Slovakia [71], Switzerland [72], the Netherlands Sero-epidemiological surveys have [73] and the United Kingdom [74] (Table 2). demonstrated human hantaviral infections in Italy [75], Latvia [76], Lithuania [77], Portugal [3], the

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

Republic of Moldova [78], and Spain [79], though overall seroprevalence of hantaviral infections in no clinical cases have been reported in these the Chaco area of Panama was 43% [95]. countries (Table 2). Recently, Puumala virus In the Caribbean region, a single case of HPS infection was serologically demonstrated for the was serologically confirmed in eastern Venezuela first time by using immunofluorescence assays in recently, and a low prevalence (1.7%) but wide Turkish Microtus voles [80]. distribution of hantaviral infections was demonstrated in the country [96]. Human Americas infections in Colombia [90] and rodent infection HPS constitutes a public health problem, with Sin Nombre-like hantaviruses in Costa Rica, especially in South America, where an increasing Mexico and Peru have been reported [98-100]. number of HPS cases are reported each year. In Canada, cases of HPS are rare, fewer than Since HPS was first recognized as a hantaviral 8 being reported per year, with the first Canadian disease in the Four Corner areas of the United case of HPS identified retrospectively back to 1989 States in 1993 [6], clinical cases have also been [83]. A 26% case fatality of HPS was reported in confirmed in the Americas in Argentina, Bolivia, Northern Alberta, Canada [101]. In the United Brazil, Canada, Chile, Panama, Paraguay, United States of America, HPS was retrospectively traced States and Uruguay [81-83], with more than 2,000 back to as early as 1975 [102], but HPS was first cases of HPS recorded in the Region of Americas recognized in May 1993 [6]. As of 10 May 2006, from 1993 to 2004. CDC-USA has confirmed 438 cases of HPS In Argentina, the first case of HPS was reported from 30 states; 35% of these cases were confirmed by virus detection in 1995 [84]. Three fatal [103]. clusters involving 29 cases and a severe outbreak The HFRS-causing Old World hantaviruses are with 18 HPS cases were later reported in 1995 and widely distributed in Asian and European 1996 respectively [85]. By the end of 2006, a total countries. However, the Old World hantaviruses, of 841 cases were reported in the country [86]. In especially the SEOV, have also been detected in Bolivia, through 2002, at least 10 HPS cases were the United States, Canada, and South American reported with 6 deaths [87]. By the end of 2004, 36 countries, although few clinical HFRS cases have cases had been reported in the country been reported on the American continent (http://www.paho.org). In Brazil, The first case of [104,105]. Recently, Seoul- or Puumala-like HPS was reported in a family cluster in 1993 [88], hantavirus infections were reported in humans and and 855 HPS cases were reported between 1993 rodents in the Caribbean country, Barbados [106]. and 2006 with a 39.3% case fatality [89]. In Chile, since the first identification of HPS in 1995 [90], Africa 352 cases of HPS had been reported by August 4, There had been no data available on 2006, with a case fatality rate of 33% hantavirus infections in Africa until 1984 when (http://epi.minsal.cl/epi/html/bolets/reportes/Hantav Gonzalez et al. demonstrated serological evidence irus/Hantavirus.pdf). In Uruguay, the first evidence of hantaviral infections in human and rodents in of the circulation of these viruses came from a Benin, Burkino Faso, the Central African Republic study of serum specimens collected from blood and Gabon [107]. Since then, human hantavirus donors between 1985 and 1987 [91]. Since then, infections have also been demonstrated in more than 60 cases of HPS have been confirmed Senegal, Nigeria, Djibouti, and Egypt through [92] serological survey [108-111]. Recently, the first The first cluster of HPS in Central America African hantavirus, Sangassou virus (SANGV), occurred from late December 1999 to February was identified in Guinea [112]. To our best 2000 in Los Santos Province in Panama. Through knowledge, only one case of HFRS has been 2006, there were 85 cases of HPS reported in reported in Africa [113]; however, the potential Panama with a CFR of 17.6% [93] In Paraguay, pathogenicity of SANGV or other African the first outbreak of HPS occurred in 1995 [87], hantaviruses cannot be ignored. HFRS may be and through 2004, there had been 99 cases of confused with other severe diseases HPS in that country (http://www.paho.org). The (leptospirosis, rickettsiosis, other viral hemorrhagic fevers, plague, severe pneumonia, sepsis) or may

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23. be unrecognized because it is difficult to access Table 3. Hantaviruses associated with human laboratories for diagnosis in African countries. infections. Geographical Rodent reservoir Associated Reservoir distribution subfamily, virus diseases species Hantaviruses causing Human Infections of virus HFRS-associated Hantaviruses Murinae Presently, there are seven hantaviruses Apodemus China, Korea, Hantaan HFRS associated with HFRS (Table 3). The most severe agrarius Russia Apodemus form of HFRS is caused by HTNV in Asia and Dobrava HFRS Balkans flavicollis DOBV in the Federal Republic of Yugoslavia Apodemus Saaremaa HFRS Europe region and other parts of Europe [2,3], with a agrarius Rattus Seoul HFRS World wide mortality rate from 3% to12%. Saaremaa virus norvegicus (SAAV), with Apodemus agrarius as the rodent Apodemus Amur HFRS Far East Russia reservoir in Europe, was recently separated from peninsulae DOBV and recognized as a distinct causative Arvicolinae Clethrionomys agent of a mild form of HFRS [114]. PUUV, the Puumala HFRS Europe glareolus most variable hantavirus, causes the mild form of HFR through central and northern Europe, the Sigmodontinae Peromyscus Sin Nombre HPS USA, Canada Russia Federation and the Balkans with a mortality maniculatus of 0.1-0.4%. Peromyscus New York HPS USA SEOV infections are responsible for the leucopus Peromyscus moderate form of HFRS, with a CFR of 1-2% [25]. Monongahela HPS maniculatus Eastern USA Though SEOV is distributed worldwide in Rattus nubiterrae Oryzomys Southeastern norvegicus and R. rattus, and SEOV antibody has Bayou HPS palustris USA been detected in rats and people in Asia, Europe, Sigmodon Black Creek Canal HPS USA (Florida) the Americas and Africa, HFRS caused by SEOV hispidus Calomys Paraguay, Laguna Negra HPS is confined mainly to Asia. The few human HFRS laucha Bolivia cases in Africa [113] and America [115] were not Oligoryzomys Argentina, Chile, Andes HPS demonstrated to be associated with SEOV, and no longicaudatus Uruguay Oligoryzomys Northern Orán HPS clear evidence of SEOV-related HFRS is available longicaudatus Argentina Oligoryzomys in Europe except from laboratory infections [116]. Choclo HPS Panama fulvescens Amur and Far East viruses were recently identified Neacomys Río Mamoré HPS Bolivia in severe HFRS cases in the far eastern region of spinosus Oligoryzomys the Russia Federation [117,118], and need to be Lechiguanas HPS Argentina flavescens further characterized. Bolomys Araraquara HPS Brazil lasiurus Oligoryzomys Juquitiba HPS Brazil HPS-associated Hantaviruses nigripes Since Sin Nombre virus (SNV) was first Unknown identified as the causative agent of HPS in the US Far East HFRS - Far East Russia [6], at least 15 hantaviruses have been associated Castelo dos Sonhos HPS - Brazil with HPS (Table 3). The HPS-related New World hantaviruses are Hu39694 HPS - Argentina mainly confined to the Americas (Figure 1). SNV is the most common cause of HPS in Canada and Andes virus (ANDV), characterized in United States, while New York virus (NYV), Argentina in 1995 on the basis of specimens from Monongahela (MONV), Bayou (BAYV) and Black a patient who died of HPS [81], has been Creek Canal (BCCV) cause HPS only in the United responsible for most HPS cases recorded in States [83,119]. This reflects the geographical Argentina, Chile, and Uruguay. Languna Negra distribution of Peromyscus in contrast to the virus (LNV) causes HPS in Bolivia and Paraguay. reservoirs for these other viruses. Oran, Lechiguanas and Hu39694 were found only in Argentina, while Araaquara, Castelo dos Sonhos and Juquitiba are all Brazilian isolates

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

[81]. Recently, Andes and Juquitiba were detected (Suncus murinus) [2]. Murinae comprise the in Northeastern Argentina and Eastern Paraguay largest number of Old World rodents and are the [120]. Choclo virus, identified in Panama, was the reservoirs for HNTV, DOBV, SAAV, SEOV and first isolate of hantavirus causing HPS in Central Amur virus, which cause HFRS and other America [121]. hantaviruses that are not associated with human disease. Arvicolinae are voles and the reservoirs Hantaviruses with Disease Potentials for PUUV, which has been associated with mild Tula virus (TULV) is widely spread in rodents from HFRS in Europe, and for Prospect Hill virus and central and eastern European, in Austria, Belgium, related viruses in the United States, which have Croatia, Poland, the Russia Federation, Serbia, not been demonstrated to cause human infection. and Slovakia [122-128]. TULV has been linked to Sigmodontinae are the largest group of New World human infections in the Czech Republic, rats and mice that are the hosts of SNV and Switzerland and Germany [129-131]. However, numerous other New World viruses. Each rodent association of TULV with human diseases has not subfamily carries phyelogenetically distinct viruses, been unequivocally demonstrated. The discovery some of which are human pathogens but some of Topografov virus (TOPV) in Siberian lemming others are not human pathogens. suggested that the historic disease "Lemming Each hantavirus appears to have a single fever" may be hantavirus-mediated and may predominant natural reservoir (Table 3). With rare account for an outbreak of disease in German exception, the phylogenetic interrelationships troops in 1942 [132]. Nevertheless, there is no among the viruses and those of their predominant current evidence linking TOPV with human host show remarkable concordance [2,3]. All diseases [133]. The Thottapalayam virus (TPMV) known hantaviruses, except TPMV [5] and the was isolated from an insectivore, Suncus murinus, several newly identified viruses including in India in 1964 [134], and hantaan-like virus Tangganya virus (TGNV) [138], Seewis virus infections were reported in the country [31]. (SWSV) [139], Ripley virus (RPLV) [140] and the However, the fundamental biology of TMPV, Cao Bang virus (CBNV) [141], have their own including its true natural host and pathogenicity to murid rodents host. However, hantaviruses other humans, is unclear [135]. The Thailand virus than these viruses have been detected in (THAIV) was originally isolated from greater insectivores such as Suncus murinus, in bats, cats bandicoot rats (Bandicota indica) in 1985 [136]. and birds [142-145]. Serological evidence of Recently, the first clinical case of infection with hantavirus infection was also demonstrated in THAIV (or at least a hantavirus closely related dogs and pigs [146-147]. It is not clear whether antigentically to THAIV), with symptoms consistent these species are persistently infected or just with HFRS, was reported in Thailand, suggesting spillover hosts, i.e., a secondary host infected that THAIV may represent an additional causative through contact with the primary host [5]. agent of HFRS [137]. The newly identified SOOV from Apodemus peninsulae was believed to be Transmissions responsible for part of the remaining HFRS cases Transmission of Hantavirus is thought to occur unrelated to HTN and SEOV viruses in Korea [27], mainly through contact with infected animal but the confirmed HFRS cases caused by SOOV excreta, i.e. saliva, urine and feces. Though the need to be further investigated. Recently, the aerosol route of infection is undoubtedly the most presence of the hantavirus SANGV was common means of transmission among rodents convincingly demonstrated in African wood mouse and to humans [2,3,5], virus transmission by bite [112], but its association with human infections occurs among rodents [148,149] and may also remains unclear. result in human infection. Mites (gamasid mites and chigger mites) have been found PCR positive Epidemiology and Transmission for HTNV in China [150] and for Bayou virus in Reservoir hosts USA [151], indicating that they may also play some Hantaviruses have been identified in rodents of roles in transmission of both the Old World and the subfamilies Murinae, Arvicolinae, New World hantaviruses. There are no cases Sigmodontinae and at least one Insectivore suggesting transmission of SNV from infected

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23. mother to infants in uterus or via breast feeding different areas), leaving at least 70% of the PUUV [152-153], and no vertical SNV infection was infection undiagnosed because they were sub- shown in deer mouse [154]. However, it was clinical or showed only minimal or atypical demonstrated in cotton rats that BCCV, an HPS symptoms [49]. A study in China showed a ratio of associated virus, could be vertically transmitted clinical to sub-clinical infection of 1:5.4 in some [155]. Recent studies showed that HFRS virus rural areas [167]. Previously published studies could cause intrauterine infection and lead to fetal found no antibodies against SNV, the first HPS- death [156], but no post natal deformity in babies causing hantavirus identified in the US, in a high- naturally born from infected mothers was observed risk population [168,169]. However, recent studies [157]. Hantaviral infection associated with animal found 0.5% to 40.4% seroprevalence rates of manipulation was well recognized through the antibody SNV [170,171], and a serological survey world [2,3,5]. In a recent study, prolonged survival in Brazil demonstrated 14.3% seroprevalence rate of PUUV was observed and indirect transmission for antibody against ANDV [172], another HPS- of PUUV among rodents was demonstrated, causing hantavirus in the southern Americas. High providing evidence for hantavirus transmission via prevalence of antibodies against other HPS- environment [158]. causing hantavirus were also reported by different Person-to-person transmission of hantaviruses investigators despite rare clinical cases of HSP in had not been documented until 1996, when the populations [95,173]. It is therefore suggested possible inter-human transmission was that these viruses, like HFRS-causing viruses, may demonstrated in an Andes-virus-associated HPS cause unrecognized infections, either outbreak in Argentina [159]. The evidence asymptomatic or subclinical infection, in addition to supporting inter-human transmission of ANDV is HPS. increasing, although there are also contrary Occupation is a dominant factor, with animal reports [160,161]. Pinna et al. reported inter- trappers, forestry workers, farmers and military human transmission in a cluster of three HPS personnel at highest risk [174]. Epidemiological cases caused by AND South lineage [162]. investigations have linked viral exposure to Person-to-person transmission was demonstrated activities such as heavy farm work, threshing, for HPS caused by AND Cent BsAs, another sleeping on the ground, military exercises, and lineage of the virus [163]. Biological evidence for lower socioeconomic status [5]. For both HFRS person-to-person transmission of Andes virus was and HPS, infection is more common in males than demonstrated in an HPS outbreak [164]. Recently, in females, with a M:F ratio of 2:1 to 3:1, with most the analyses of the clusters of hantavirus infection of the cases occurring within the 20-40 age group in Southern Argentina [165] and a prospective [5], although infections can occasionally occur in study in Chile [166] provided further evidence of children [152]. The time- and space-distribution of interpersonal transmission. However, it seems that hantavirus infection mirrors the distribution and inter-human transmission is confined to ANDV, fluctuation of their rodent hosts [5,175]. In Finland, and further investigation is needed to explore the bank vole population follows a 3 to 4 year whether such a transmission mechanism exists cycle, often with two consecutive high density among other hantaviruses. years, which is believed to have led to the patterns of PUU infection in human in the country [49]. In Epidemiological features Sweden, the years of highest incidence of HFRS Hantaviral infections are predominant in rural show a period pattern coincident with that of bank areas, though HFRS caused by SEOV occurs in vole population dynamics with approximately a 3- urban areas [2]. Asymptomatic or non-specific mild year interval between peaks [50]. Such human infections result in underestimation of the number infection-rodent relationships have been observed of hantavirus infections. The ratio of sub-clinical to in China [19]. clinical infection is 5:1 to 10:1 in Europe, and the ratio could be as high as 14:1 to 20:1 for some Clinical Features and Management hantaviruses [5]. An eight-year study in Finland Hemorrhagic Fever with Renal Syndrome demonstrated that the estimated ratio of diagnosed Hemorrhagic Fever with Renal Syndrome HFRS cases was only 13% (4% to 30% for (HFRS) manifests as mild, moderate, or severe

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23. disease, depending in part on the causative virus symptoms include gastrointestinal disturbance, [3,165]. In general, after infection with HTNV or headache and chills. DOBV , there is a 2- to 3-week incubation period followed by a typical five-period clinical course, Figure 2. Clinical course and symptoms of hemorrhagic namely, febrile period, hypotensive period, oliguric fever with renal syndrome. period, diuretic period and convalescent period (Figure 2). HFRS due to HTNV and SEOV presents clinical features involving multiple organs in the neurological, gastrointestinal, and cardiovascular systems, giving rise to a wide range of symptoms and signs [2]. It was recently observed that DOBV infection could cause unusually extended pulmonary involvement [176].Though HFRS caused by HTNV and DOBV has a relatively high case fatality from 3% to12%, it did not increase mortality rate among survivors in later life, as demonstrated in a case control study in Korean War veterans [177]. However, there is still some impact on selected morbidity outcomes, such as hypertension and renal dysfunctions. NE is a mild form of HFRS caused by PUUV with a CFR of 0.1% to 0.4% [178]. NE patients, after 1 to 8 weeks of incubation period, typically have an acute onset of disease, with hallmarks of fever, abdominal pain and/or back pain and/or headache, and signs of renal involvement, but they do not necessarily have the five distinct clinical phases of HFRS caused by HTNV and DOBV. NE usually have a favorable prognosis. However, PUUV infection could lead to a severe disease, including disseminated encephalomyelitis, and hypopituitarism [179,180]. Respiratory manifestations and chest X-ray abnormalities were shown in 30% and 50% of PUUV patients respectively [181]. HPS-like severe pulmonary impairment has also been observed in HFRS The febrile phase of SNV-induced HPS is patients caused by PUUV [182]. In addition, PUUV followed by a cardiopulmonary phase infection might cause long-term mild to moderate characterized by acute onset of pulmonary edema impairment of renal functions [183]. [184]. At this stage, cough is generally present, and gastrointestinal manifestations may dominate Hantavirus Pulmonary Syndrome the clinical presentations. HPS is a more severe disease than HFRS, with a Tachypnea, tachycardia, and postural mortality rate of about 40% [2]. The clinical course hypotension are typical, whereas chest of HPS is divided into three periods: the febrile examination is not impressive. Like HFRS, the prodrome, cardiopulmonary stage and most common hematologic abnormalities at the convalescence (Figure 3). There is a 14- to 17-day late phase of HPS are thrombocytopenia and incubation period after exposure followed by the leukocytosis [185]. prodrome phase typically lasting 3-6 days with myalgia, malaise, and fever of abrupt onset in the absence of cough and coryza. Other early

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

Figure 3. Clinical course of hantavirus pulmonary monitored [165]. Maintaining fluids balance is very syndrome. important; it must be carefully monitored according to the patient's fluid status, amount of diuresis, and kidney function. Usually one or two haemodialysis sessions are needed for HFRS treatment, while mechanical ventilation when indicated and appropriate use of pressures are crucial to HPS patients [3]. Extracorporeal membrane oxygenation has been found useful as a rescue therapy in patients with severe HPS [189]. Although corticosteroids are not standard of care in the treatment of hantaviral infection, steroid was used to treat severe HFRS and HPS cases. Recently, two HPS cases caused by PUU virus were successfully treated with corticosteroids combined with continuous veno-venous hemodiafiltration [182]. However, the utility of steroids in treatment of hantavirus infections needs further systematic evaluation. High levels of neutralizing antibodies was detected in people long after recovery from SNV infection [7], and the protective capacity of immune serum against HPS caused by ANDV has been demonstrated in animal experiments [190,191], suggesting the possibility of passive immunotherapy at the early stage of HPS, as it is with other hemorrhagic fever [192]. In severe cases, significant myocardial Ribavirin was demonstrated to have anti- depression occurs, resulting in low cardiac output hantaviral effect both in vitro and in vivo by and hypotension [185]. Pulmonary evaluation will causing error catastrophe during hantavirus be distinctly abnormal, with low PAO2 level or low replication [194]. Ribavirin is often used in pulse oximetry findings [2]. Like HFRS, symptoms treatment of HFRS in China and clinical trials there of HPS vary somewhat depending on the have shown that Ribavirin therapy can significantly causative agents. Renal disease and myositis reduce the mortality and the risk of entering the appear to be more common in cases with Bayou oliguric phase and experiencing hemorrhage [194]. virus and Black Creek virus infection in the United Ribavirin is included in the WHO Model List of States [186]. Neuropsychological impairments Essential Medicines for HFRS treatment in 2007 were also observed in some survivors of HPS (http://mednet3.who.int/EML/expcom/expcom15/ex [187]. There have been confirmed cases of SNV pertcomm15.htm). However, an open-label trial of infections without cardiopulmonary involvement Ribavirin failed to demonstrate a significant [188], indicating the diversity of HPS clinical improvement in outcome in HPS patients [195], presentations. and the subsequent placebo-controlled, double- blind trial suggested that Ribavirin was probably Clinical Management not effective in the treatment of HPS in the Currently, there is no specific therapy available cardiopulmonary stage [196]. It seems that for both HFRS and HPS; therefore, the Ribavirin should not be recommended for routine cornerstone of treatment remains supportive therapy of HPS until further evidence is measures. The management must include early documented. Recently, synergistic antiviral admission to an intensive care unit where blood effectiveness of the combined use of amixine, an and tissue oxygenation, cardiac output, central interferon inducer, and Ribavirin was blood pressure and cerebral pressure can be demonstrated in experimental HFRS in suckling

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23. albino mice [197], and the evidence that hantaviruses [203], indicating that ELISA or other hantaviruses are prone to error catastrophe opens serological tests such as IFA or immunoblotting the door to the development of new therapeutic cannot be used for serotyping. The plaque strategies. reduction neutralization test (PRNT) is considered to be the gold standard serological test and, it can Laboratory Diagnostics be used to discriminate between different species The diagnosis of hantaviral infections is based of Hantavirus [204]. However, the PRNT test with on clinical and epidemiological information and infectious hantavirus should be done in a biosafety laboratory tests. However, it is almost impossible level-three laboratory, which is a serious limitation in the individual case with moderate to mild clinical for many investigators. For post-mortem symptoms to diagnose hantavirus infection on confirmations, detection of hantavirus antigens can clinical grounds only. Laboratory diagnosis of be done by immunohistochemistry testing of acute hantavirus infection has to be primarily formalin-fixed tissues with appropriately specific based on serology, since the viraemia of human monoclonal or polyclonal antibodies [205]. Nucleic hantavirus infections is short-termed and viral RNA acid tests and reverse transcriptional-polymerase cannot be regularly detected in the blood or urine chain reaction (RT-PCR) can detect hantaviral of patients in hospitals [198], although the virus is RNA in fresh-frozen lung tissues, blood clots or readily detectable by rt-PCR during acute illness in nucleated blood cells, and can be used for research laboratories [199]. However, high levels hantavirus confirmation and genotyping [206]. of virus-specific antibody are usually detected at Recently, one-step assays for detecting the onset of hantavirus diseases (Figure 4), and hantaviruses based on real-time RT-PCR were the serological assay is readily accessible to most developed and proved to be of high levels of hospitals. sensitivity, specificity and reproducibility [207]. A wide array of technologies have been used Virus isolation is extremely rare from human to detect antibodies to hantaviruses, using cultured sources and thus is not considered an option for and/or purified native-virus preparations or diagnostic purpose of hantavirus infections. recombinant proteins expressed in bacteria, yeast or insect cells. Both indirect fluorescent assay Control and Prevention (IFA) and enzyme immunoassay (EIA) are widely The most effective way of controlling hantaviral used for detection of specific IgM or low-avidity diseases is to reduce human exposure to infected IgG antibodies [200]. IgM detecting methods are rodents and their excrement. Monitoring of important tools for diagnosis of acute infections, hantavirus prevalence in rodent populations may especially in endemic areas with a high prevalence give some warning of expected increase in the of virus-specific IgG due to previous infections. numbers of human cases [208]. CDC The μ-captured ELISA to detect IgM antibodies, recommendations call for rodent-proofing of using viral native or recombinant N antigens, homes, reduction of rodent cover around houses, should be preferred because it is superior to IFA minimization of food available for rodents, trapping and solid phase ELISA in terms of sensitivity [201]. in and around dwellings, and the careful disposal Western blot assays can be used, which are of dead rodents [209]. Removal of rodents from a generally in agreement with those of the IgM- non-rodent-proofed ranch building did not reduce capture format for acute infections. In addition, the rodent infestation, while the application of simple immunochromatographic 5-min IgM-antibody test rodent-proofing measures to dwellings can has been developed for rapid diagnosis [202]. decrease the frequency and intensity of rodent The IFA test remains popular in Europe and intrusion, thereby reducing the risk of HPS among Asia, perhaps in part because it is so easily rural residents [210,211]. Similarly, workplaces performed, but such tests are intrinsically limited and conditions in agriculture, forestry and military by problems with specificity, especially with activities should be modified when possible to inexperienced users. Although ELISA is optimal for reduce human-rodent exposure. In China, a a highly specific serological confirmation of comprehensive preventive strategy against hantaviral infections, the antibody responses hantavirus infection, including health education usually cross-react strongly between different and promotion, rodent control, surveillance, and

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23. vaccination, has been implemented in the most case-control study demonstrated dose-dependent endemic areas [24]; however, the contributions of protective effectiveness of the vaccine [214]. More these measures to control and prevent hantavirus recently, a cell culture-derived inactivated vaccine disease remains to be evaluated. against Hantaan virus was developed in Korea, and was demonstrated to be more protective than Figure 4. Viremia and antibody response in human Hantavax [215]. hantavirus infection. Table 4. Inactivated hantavirus vaccines used in China and Korea. Virus Generated Vaccination Protection Country strains in Programme

+ 3 basic doses HTNV MGKC >90% China + 1 booster ++ 2 basic doses SEOV GHKC >95% China + 1 booster +++ 3 basic doses HTNV SMB >90% China + 1 booster 2 basic doses HTN/SEO MGKC 100% China + 1 booster 2 basic doses HTNV SMB 75-100% Korea + 1 booster + MGKC: Mongolian gerbil kidney cell; ++ GHKC: Gold hamster kidney cell; +++SMB: suckling mouse brain.

Recombinant candidate hantavirus vaccines have been generated on the basis of replication- competent vaccinia viruses (VACV) or recombinant bacteria encoding single or various viral proteins [216]. A VACV recombinant HTNV vaccine carrying the S and M segment was demonstrated to be immunogenic and safe in human volunteers. A recent double-blinded, placebo controlled clinical trial revealed the induction of neutralizing antibodies in 72% of VACV-naive volunteers after two immunizations In laboratory animal facilities, all laboratory [217]. A virus-like particle (VPLs) vaccine against work involving the propagation of hantaviruses in PUUV was developed in Europe [218]. VLPs, such cell culture or animals should be conducted in as hepatitis B virus (HBV) core antigen, are highly- biosafety level-four conditions. Even in work with structured, repetitive protein complexes that have animals of unknown hantaviral infection status, many desirable properties as immunogens. The protocols should minimize potential contact with 120 aa region of PUUV N-protein presented on the secretions [209]. HBV core particle provided complete protection in Vaccines against hantaviral infections have the bank vole [219]. The VLP approach, while still been used for years in China and the Republic of at an early stage, shows some promise because of Korea (Table 4). Four kinds of hantavirus vaccines the unusually intense immune responses that based on inactivated HTN and SEO viruses have VLPs often provoke against foreign antigens. been widely used and have been demonstrated DNA vaccine is based on the introduction of an safe and effective in China [212]. A new purified antigen-encoding plasmid into the organism bivalent vaccine for HTNV and SEOV is also under directing the de novo synthesis in vivo. DNA development [213]. In the Republic of Korea, an vaccination with SEOV M segment elicits inactivated vaccine purified from suckling mouse neutralizing antibodies and protects against SEOV brain (Hantavax) against HTNV was approved in infection in Hamsters [220], and vaccination with 1990 and started to be used in 1991 [26]. A recent HTNV M segment protects against several HFRS- causing hantaviruses and elicits a high-titer

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23. neutralizing antibody response in Rhesus monkey Acknowledgements [221]. DNA vaccines against SNV and ANDV have The author is a staff member of the World Health Organization. The author alone is responsible for the views expresses in this also been shown to be effective in mice models publication and they do not necessarily represent the decisions or the [222,223]. Recently, a bivalent HTN/AND viral stated policy of the World Health Organization. DNA vaccine was constructed and has been shown to elicit a potent memory response, and to References elicit antibody responses that neutralize viruses 1. Lee HW, Lee PW, Johnson KM (1978) Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect Dis causing both HFRS and HPS [224]. 137: 298-308. The high yield of stable and highly pure 2. Lednicky JA (2003) Hantavirus: a short review. Arch nucleocapsid proteins of HTNV, PUUV and DOBV Pathol Lab Med 127: 30-35. in yeast Saccharomyces cerevisiae represents a 3. Vapalahti O, Mustonen J Lundkvist A, Henttonen H, useful tool for vaccine development against Plyusnin A, Vaheri A (2003) Hantavirus infections in Europe. The Lancet Infect Dis 3: 653-752. hantavirus infection [225]. Hantaviral recombinant 4. Sirotin BZ, Keiser NP (2001) On the history of the study proteins, which could also be obtained from of hemorrhagic fever with renal syndrome in eastern transgenic plants, were able to elicit specific Russia. Nephrol Dial Transplant 16: 1288-90. immune responses [226]. In addition, through the 5. Hart CA, Bennett M (1999) Hantavirus infections: epidemiology and pathogenesis. Microbes and Infections development of reverse genetics for negative- 1:1229-1237. stranded RNA viruses [227], it should be possible 6. Nichol ST, Spiropoulou CF, Morzunov S, Rollin PE, in the future to generate attenuated hantavirus Ksiazek TG, Feldmann H, Sanchez A, Childs J, Zaki S, vaccine with defined alterations/deletions in Peters CJ (1993) Genetic identification of a hantavirus pathogenicity-related regions. associated with an outbreak of acute respiratory illness. Science 262: 914-917. 7. Ye C, Prescott J, Nofchissey R, Goade D, Hjelle B (2004) Concluding Remarks Neutralizing antibodies and Sin Nombre virus RNA after Over the past few decades, the understanding recovery from hantavirus cardiopulmonary syndrome. and recognition of hantaviral infections through the Emerg Infect Dis 10: 478-482. 8. Kraus AA, Priemer C, Heider H, Kruger DH, Ulrich R world has greatly improved. The number of (2005) Inactivation of Hantaan virus-containing samples recognized viruses continues to increase, as does for subsequent investigations outside biosafety level 3 the spectrum of hantaviral infections. Though facilities. Intervirology 48: 255-261. newly detected, Hantavirus is an old disease. 9. McCaughey C, Hart CA (2000) Hantavirus. J Med Environmental changes may affect the geographic Microbiol 49: 587-599. 10. Schmaljohn CS, Dalrymple JM. (1983) Analysis of distribution, abundance, and dynamics of the Hantaan virus RNA: evidence for a new genus of rodent carrier, and hence the epidemiology of bunyaviridae. Virology. 131:482-91. hantavirus infections. It is generally accepted that 11. Easterbrook JD, Zink MC, Klein SL (2007) Regulatory T hantaviruses are distributed worldwide, but the cells enhance persistence of the zoonotic pathogen Seoul virus in its reservoir host. Proc Natl Acad Sci U S A. 104: distribution of specific virus remains to be further 15502-7. investigated. With the development of more rapid 12. Schountz T, Prescott J, Cogswell AC, Oko L, Mirowsky- and sensitive tests, and increased clinician Garcia K, Galvez AP, Hjelle B (2007) Regulatory T cell- awareness, human hantaviral infections will like responses in deer mice persistently infected with Sin presumably be detected in new areas, and new Nombre virus. Proc Natl Acad Sci U S A. 104:15496-501. 13. Larson RS, Brown DC, Ye C, Hjelle B (2005) Peptide rodent species might be found to carry yet antagonists that inhibit Sin Nombre virus and hantaan unknown viruses. There is still a long way to go to virus entry through the beta3-integrin receptor. J Virol 79: find an effective treatment for hantavirus 7319-7326. infections, and the long-term prognosis of 14. Song JW, Song KJ, Baek LJ, Frost B, Poncz M, Park K (2005) In vivo characterization of the integrin beta3 as a hantaviral infections and the pathogenicity of receptor for Hantaan virus cellular entry. Exp Mol Med. certain virus species remain to be established. 37:121-7. Prevention can be partially achieved by rodent 15. Rowe RK, Pekosz A (2006) Bidirectional virus secretion avoidance, but real protection will require a safe and nonciliated cell tropism following Andes virus and effective multivalent vaccine or a vaccine infection of primary airway epithelial cell cultures. J Virol. 80: 1087-97. adapted to local conditions. 16. Cosgriff TM (1991) Mechanisms of disease in Hantavirus infection: pathophysiology of hemorrhagic fever with renal syndrome. Rev Infect Dis 13: 97-107.

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

17. Zaki SR, Greer PW, Coffield LM, Zaki SR, Greer PW, Mizutani T, Osawa K, Sato H, Takashima I (2004) Coffield LM, Goldsmith CS, Nolte KB, Foucar K, Epizootiological and epidemiological study of hantavirus Feddersen RM, Zumwalt RE, Miller GL, Khan AS (1995) infection in Japan. Microbiol Immunol 48 :843-851. Hantavirus pulmonary syndrome: pathogenesis of an 31. Clement J, Maes P, Muthusethupathi M, Nainan G, van emerging infectious disease. Am J Pathol 146: 552-579. Ranst M. (2006) First evidence of fatal hantavirus 18. Terajima M, Vapalahti O, Van Epps HL, Vaheri A, Ennis nephropathy in India, mimicking leptospirosis. Nephrol FA (2004) Immune responses to Puumala virus infection Dial Transplant 21: 826-827. and the pathogenesis of nephropathia epidemica. 32. Groen J, Suharti C, Koraka P van Gorp EC, Sutaryo J, Microbes Infect 6: 238-245. Lundkvist A, Osterhaus AD (2002) Serological evidence 19. Borges AA, Campos GM, Moreli ML, Souza RL, Aquino of human hantavirus infections in Indonesia. Infection 30: VH, Saggioro FP, Figueiredo LT (2006) Hantavirus 326-327. cardiopulmonary syndrome: immune response and 33. Chan KP, Chan YC, Doraisingham S (1996) A severe pathogenesis. Microbes Infect 8: 2324-2330. case of hemorrhagic fever with renal syndrome in 20. Mori M, Rothman AL, Kurane I, Montoya JM, Nolte KB, Singapore. Southeast Asian J Trop Med Public Health 27: Norman JE, Waite DC, Koster FT, Ennis FA (1999) High 408-10. levels of cytokine-producing cells in the lung tissues of 34. Vitarana T, Colombage G, Bandaranayake V, Lee HW.( patients with fatal hantavirus pulmonary syndrome. J 1988) Hantavirus diseases in Sri Lanka. The Lancet 2: Infect Dis 179: 295-302. 1263. 21. Makela S, Mustonen J, Ala-Houhala I, Hurme M, 35. Tai PW, Chen LC, Huang CH. Hanta hemorrhagic fever Partanen J, Vapalahti O, Vaheri A, Pasternack A. (2002) with renal syndrome: a case report and review. J Human leukocyte antigen-B8-DR3 is a more important Microbiol Immunol Infect. 2005;38(3):221-223. risk factor for severe Puumala hantavirus infection than 36. Suputthamongkol Y, Nitatpattana N, Chayakullkeeree M, the tumor necrosis factor-alpha(-308) G/A polymorphism. Palabodeewat S, Yoksan S, Gonzalez JP (2005) J Infect Dis 86: 843-846. Hantavirus infection in Thailand: first clinical case report. 22. Lee HW (1996). Epidemiology and pathogenesis of Southeast Asian J Trop Med Public Health 36: 700-703 haemorrhagic fever with renal syndrome. In: Elliot RM, 37. George J, Patnaik M, Bakshi E, Levy Y, Ben-David A, ,editor, The Bunyaviridae. New York: Plenum Press. 253- Ahmed A, Peter JB, Shoenfeld Y (1998) Hantavirus 267. seropositive in Israeli patients with renal failure. Viral 23. Wu GH (2003) Progress of epidemiological studies on Immunol 11:103-108. hemorrhagic fever with renal syndrome in China. Chin J 38. Pacsa AS, Elbishbishi EA, Chaturvedi, Chu KY, Mustafa Epidemiol 24: 413-415. AS (2002) Hantavirus-specific antibodies in rodents and 24. Zhang YZ, Xiao DL, Wang Y, Wang HX, Sun L, Tao XX, human living in Kuwait. FEMS Immunol Med Microbiol 33: Qu YG. (2004) The epidemic characteristics and 139-42. preventive measures of hemorrhagic fever with renal 39. Rollin PE, Nawrocka E, Rodhain F (1986) Serological syndrome in China. Chin J Epidemiol 25: 466-469. data on hemorrhagic fever with renal syndrome in 25. Lee HW (1989). Hemorrhagic fever with renal syndrome Southeast Asia. Bull Soc Pathol Exot Filiales 79: 473- in Korea. Rev Infect Dis 11 Suppl 4: 864-876. 475. 26. Cho HW, Howard CR, Lee HW (2002) Review of an 40. Lam SK, Chua KB, Myshrall T, Devi S, Zainal D, Afifi SA, inactivated vaccine against hantaviruses. Intervirology 45: Nerome K, Chu YK, Lee HW (2001) Serological evidence 328-333. of hantavirus infections in Malaysia. Southeast Asian J 27. Baek LJ, Kariwa H, Lokugamage K Yoshimatsu K, Trop Med Public Health 32: 809-813. Arikawa J, Takashima I, Kang JI, Moon SS, Chung SY, 41. Quelapio ID, Villa L, Clarin M, Bacosa M, Tupasi TE Kim EJ, Kang HJ, Song KJ, Klein TA, Yanagihara R, (2000) Seroepidemiology of Hantavirus in the Philippines. Song JW (2006) Soochong virus: an antigenically and Int J Infect Dis 4: 104-107. genetically distinct Hantavirus isolated from Apodemus 42. Shortridge KF, Lee HW, LeDuc JW, Wong TW, Chau peninusulae in Korea. J Med Virol 78: 290-297. GW, Rosen L (1987) Serological evidence of Hantaan- 28. Yashina LN, Patrushev NA, Ivanov LI Slonova RA, Mishin related viruses in Hong Kong. Trans R Soc Trop Med Hyg VP, Kompanez GG, Zdanovskaya NI, Kuzina II, Safronov 81: 400-2. PF, Chizhikov VE, Schmaljohn C, Netesov SV (2000) 43. Reynes JM, Soares JL, Hue T, Bouloy M, Sun S, Kruy Genetic diversity of Hantavirus associated with SL, Flye Sainte Marie F, Zeller H (2003) Evidence of the hemorrhagic fever with renal syndrome in the Far East of presence of Seoul virus in Cambodia. Microbes Infect 5: Russia. Virus Res 70: 31-44. 769-773. 29. Tkachenko E, Dzagurova T, Bashkirtsev V, Bernshtein A, 44. Brummer-Korevakontio M, Vaheri A, Hove T, von Apekina N, Sedova N, Okulova N, Korotina N, Bonsdorff CH, Vuorimies J, Manni T, Penttinen K, N. Nabatnikov P, Malkin A, Smirnov A, Morozov V, Oker-Blom, Lähdevirta (1980) Nephropathia epidemica: Yunicheva Y, Klempa B, Kruger D ( 2007 ) Epidemiology detection of antigen in bank voles and serologic diagnosis of hemorrhagic fever with renal syndrome in european of human infections. J Infect Dis 141: 131-134. Russia. The 7th International Conference on HFRS, HPS 45. Rose AM, Vapalahti O, Lyytikäinen, Nuorti P (2003) and Hantaviruses, Buenos Aires, Argentina. June 13-15, Patterns of puumala virus infections in Finland. Euro Abstract book, Page 17. Surveillance 8: 9-13. 30. Lokugamage N, Kariwa H, Lokugamage K, Iwasa MA, 46. Mailles A, Vaillant V, Haeghbaert S, Fradet MR, Capek I, Hagiya T, Yoshii K, Tachi A, Ando S, Fukushima H, Zeller H (2005). Increase of Hantavirus infections in Tsuchiya K, Iwasaki T, Araki K, Yoshimatsu K, Arikawa J, France, 2003. Med Mal Infect 35: 68-72.

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

47. Mailles A, Sin MA, Ducoffre G, Heyman P, Koch J, Zeller 63. Mulic R, Ropac D, Gizdic Z, Sikic N (2003) What is new H (2005) Larger than usual increase in cases of in the epidemiologic characteristics of hemorrhagic fever hantavirus infections in Belgium, France and Germany, with renal syndrome in Croatia? Acta Med Croatica June 2005. Euro Surveillance 10: E050721.4. 57:399-405. 48. Schneider F and Mossong J (2005) Increased hantavirus 64. Papa A, Bojovic B, Antoniadis A (2006) Hantaviruses in infections in Luxembourg, August 2005. Euro Serbia and Montenegro. Emerg Infect Dis 12: 1015-1018 Surveillance 10: E050825.1. 65. Papa A, Antoniadis A (2001) Hantavirus infections in 49. Brummer-Korvenkontio M, Vapalahti O, Henttonen H, Greece--an update. Eur J Epidemiol 17:189-94. Koskela P, Kuusisto P, Vaheri A (1999) Epidemiological 66. Papa A, Nemirov K, Henttonen H, Niemimaa J, study of nephropathia epidemica in Finland 1989-96. Antoniadis A, Vaheri A, Plyusnin A, Vapalahti O (2001) Scand J Infect Dis 31: 427-435. Isolation of Dobrava virus from Apodemus flavicollis in 50. Olsson GE, Dalerum F, Hörnfeldt B, Elgh F, Palo TR, Greece. J Clin Microbiol 39: 2291-2293. Juto P, Ahlm (2003) Human hantavirus infections, 67. Eltari E, Nuti M, Hasko I, Gina A (1978) Hemorrhagic Sweden. Emerg Infect Dis 9: 1395-1401. fever with renal syndrome in a case in northern Albania. 51. Heyman P, Vervoort T, Colson P, Chu YK, Avsic-Zupanc Lancet 2:1211. T, Lundkvist A (1999) A major outbreak of hantavirus 68. Nemirov K, Andersen HK, Leirs H, Henttonen H, Vaheri infection in Belgium in 1995 and 1996. Epidemiol Infect A, Lundkvist A, Plyusnin A (2004) Saaremaa hantavirus 122: 447-453. in Denmark. J Clin Virol 30: 254-257. 52. Ulrich R, Meisel H, Schutt M, Schmidt J, Kunz A, Klempa 69. Knap JP, Brzostek T, Raczka A, Burzynski W, Litarska U B, Niedrig M, Pauli G, Kruger DH, Koch J. Prevalence of (2006) A case of haemorrhagic fever with renal hantavirus infections in Germany (2004) syndrome. Pol Merkur Lekarski 21: 474-476. Bundesgesundheitsblatt Gesundheitsforschung 70. Manasia M, Olinic O, Zagreanu I, Serban A (1977) Gesundheitsschutz 47: 661-670. Hemorrhagic fever with renal syndrome. Report of 11 53. Plyusnina A, Aberle SW, Aberle JH, Plyusnin A (2006) observations. Int Urol Nephrol 9: 177-84. Genetic analysis of Puumala hantavirus strains from 71. Sibold C, Ulrich R, Labuda M, Lundkvist A, Martens H, Austria. Scand J Infect Dis 38: 512-519. Schutt M, Gerke P, Leitmeyer K, Meisel H, Kruger DH 54. Ferenczi E, Racz G, Szekeres J, Balog K, Toth E, (2001) Dobrava hantavirus causes hemorrhagic fever Takacs M, Csire M, Mezey I, Berencsi G, Faludi G (2003) with renal syndrome in central Europe and is carried by New data for the public health importance of hantaviruses two different Apodemus mice species. J Med Virol 63: in Hungary. Orv Hetil 144: 467-474. 158-167. 55. Vasilenko S, Brodvarova I, Topov Y, Shindaro L , 72. Schultze D, Fierz W, Matter H, Bankoul S, Niedrig M, Kebedzhiev G (1990) Hemorrhagic fever with renal Schmiedl A (2007) Cross-sectional survey on hantavirus syndrome in Bulgaria: isolation of hantaviruses and seroprevalence in Canton St. Gallen, Switzerland. Swiss epidemiologic considerations. Arv Virol. 33 Suppl 1: 63- Med Wkly 137: 21-26. 67. 73. Dillingh SJ, Jira P, Morroy G, Wolters B, Beutler J, 56. Pejcoch M, Kriz B (2003). Hantavirus in the Czech Schneeberger PM (2006) Two patients with Hantavirus Republic. Emerg Infect Dis 9: 756-7. infection in The Netherlands; substantial increase in 57. Golovljova I, Sjolander KB, Lindegren G, Vene S, incidence in neighbouring countries Ned Tijdschr Vasilenko V, Plyusnin A, Lundkvist A (2002) Hantaviruses Geneeskd 10; 150: 1303-1306. in Estonia. J Med Virol 68: 589-598. 74. Pether JV, Lloyd G (1993) The clinical spectrum of 58. Maksyoma I (2007) Hemorrhagic fever with renal human hantavirus infection in Somerset, UK. Epidemiol syndrome in Russia. The 7th International Conference on Infect 111: 171-5. HFRS, HPS and Hantaviruses, Buenos Aires, Argentina. 75. Kallio-Kokko H, Laakkonen J, Rizzoli A, Tagliapietra V, June 13-15 Cattadori I, Perkins SE, Hudson PJ, Cristofolini A, Versini 59. Nurgaleeva RG, Tkachenko EA, Stepanenko AG, W, Vapalahti O, Vaheri A, Henttonen H (2006) Hantavirus Mustafin IM, Kireev SG, Dzagurova TK, Dekonenko AE, and arenavirus antibody prevalence in rodents and Klimchuk LA (1999) An epidemiological analysis of humans in Trentino, Northern Italy. Epidemiol Infect 134: hemorrhagic fever with renal syndrome morbidity in the 830-836. Republic of Bashkortostan in 1997. Zh Mikrobiol 76. Lundkvist A, Lindegren G, Brus Sjolander K, Mavtchoutko Epidemiol Immunobiol 6: 45-49. V, Vene S, Plyusnin A, Kalnina V (2002) Hantavirus 60. Lukac V, Obradovic M, Gligic A, Stojanovic R, Rakovic- infections in Latvia. Eur J Clin Microbiol Infect Dis 21:626- Savcic L, Diglisic G, Drndarevic D, Dordevic D (1990) 629. Hemorrhagic fever with renal syndrome in Yugoslavia 77. Sandmann S, Meisel H, Razanskiene A, Wolbert A, Pohl 1951-1988. Vojnosanit Pregl 47: 242-248. B, Krüger DH, Sasnauskas K, Ulrich R (2005) Detection 61. Skataric V, Dimitrijevic J, Jovanovoc D, Marie M, of human hantavirus infections in Lithuania. Infection 33: Kovacevic Z, Glogic A. (1998) Clinical features of 66-72. hemorrhagic fever with renal syndrome in Yugoslavia 78. Mikhailenko AG, Tkachenko EA, Smirnov IIa, Malkin AE, 1996. The Fourth International Conference of HFRS and Chebotar' IF (1994) Results of serologic screening for hantaviruses, Atlanta, USA, March 5-7 hemorrhagic fever with kidney syndrome in Moldova. 62. Mulić R, Ropac D (2002) Epidemiologic characteristics Vopr Virusol 39: 260-262. and military implications of hemorrhagic fever with renal 79. Lledo L, Klingstrom J, Gegundez MI, Plyusnina A, syndrome in Croatia. Croat Med J. 43:581-6. Vapalahti O, Saz JV, Beltran M, Sjolander KB, Vaheri A, Plyusnin A, Lundkvist A (2003) Hantavirus infections in

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

Spain: analysis of sera from the general population and Human and rodent epidemiology of hantavirus in Panama from patients with pneumonia, renal disease and 2000-2006. The 7th International Conference on HFRS, hepatitis. J Clin Virol 27: 296-307. HPS and Hantaviruses, Buenos Aires, Argentina. June 80. Laakkonen J, Kallio-Kokko H, Oktem MA, Blasdell K, 13-15, Abstract book, Page 97). Plyusnina A, Niemimaa J, Karataş A, Plyusnin A, Vaheri 94. Williams RJ, Bryan RT, Mills JN, Palma RE, Vera I, De A, Henttonen H (2006) Serological survey for viral Velasquez F, Baez E, Schmidt WE, Figueroa RE, Peters pathogens in Turkish rodents. J Wildl Dis 42: 672-676. CJ, Zaki SR, Khan AS, Ksiazek TG (1997) An outbreak of 81. Padula PJ, Colavecchia SB, Martinez VP, Gonzalez Della hantavirus pulmonary syndrome in western Paraguay. Valle MO, Edelstein A, Miguel SD, Russi J, Riquelme JM, Am J Trop Med Hyg 57: 274-282. Colucci N, Almiron M, Rabinovich RD (2000) Genetic 95. Ferrer JF, Galligan D, Esteban E, Rey V, Murua A, diversity, distribution, and serological features of Gutierrez S, Gonzalez L, Thakuri M, Feldman L, Poiesz hantavirus infection in five countries in South America. J B, Jonsson C (2003) Hantavirus infection in people Clin Microbiol 38: 3029-3035. inhabiting a highly endemic region of the Gran Chaco 82. Johnson AM, de Souza LT, Ferreira IB, Pereira LE, territory, Paraguay: association with Trypanosoma cruzi Ksiazek TG, Rollin PE, Peters CJ, Nichol ST (1999) infection, epidemiological features and haematological Genetic investigation of novel hantaviruses causing fatal characteristics. Ann Trop Med Parasitol 97:269-280. HPS in Brazil. J Med Virol 59: 527-535. 96. Rivas YJ, Moros Z, Moron D, Uzcátegui MG, Durán Z, 83. Weir E. Hantavirus: 'tis the season. CMAJ 2005; 17:147. Pujol FH, Liprandi F, Ludert JE (2003) The 84. Lopez N, Padula P, Rossi C, Lazaro ME, Franze- seroprevalences of anti-hantavirus IgG antibodies among Fernandez MT (1996) Genetic identification of a new selected Venezuelan populations. Ann Trop Med hantavirus causing severe pulmonary syndrome in Parasitol 97: 61-67. Argentina. Virology 220: 223-226. 97. Mattar S, Parra M (2004) Serologic evidence of 85. Levis S, Morzunov SP, Rowe JE, Enria D, Pini N, hantavirus infection in humans, Colombia. Emerg Infect Calderon G, Sabattini M, St Jeor SC (1998) Genetic Dis 10: 2263-2264. diversity and epidemiology of hantaviruses in Argentina. I 98. Hjelle B, Anderson B, Torrez-Martinez N, Song W, Infect Dis 177: 529-538. Gannon WL, Yates TL (1995) Prevalence and geographic 86. Capria SG, Elder M, Cacace ML, Cortes J, Bruno MR, genetic variation of hantaviruses of New World harvest Farace MI, Padula PJ (2007) Hantavirus pulmonary mice (Reithrodontomys): identification of a divergent syndrome in Argentina, 1995-2006. The 7th International genotype from a Costa Rican Reithrodontomys Conference on HFRS, HPS and Hantaviruses, Buenos mexicanus. Virology 207: 452-459. Aires, Argentina. June 13-15, Abstract book, Page 22 99. Suzan G, Ceballos G, Mills J, Ksiazek TG, Yates T 87. Carroll DS, Mills JN, Montgomery JM, Bausch DG, Blair (2001) Serologic evidence of hantavirus infection in PJ, Burans JP, Felices V, Gianella A, Iihoshi N, Nichol sigmodontine rodents in Mexico. J Wildl Dis 37:391-393. ST, Olson JG, Rogers DS, Salazar M, Ksiazek TG (2005) 100. Powers AM, Mercer DR, Watts DM, Guzman H, Fulhorst Hantavirus pulmonary syndrome in Central Bolivia: CF, Popov VL, Tesh RB (1999) Isolation and genetic relationships between reservoir hosts, habitats, and viral characterization of a hantavirus (Bunyaviridae: genotypes. Am J Trop Med Hyg 72: 42-46. Hantavirus) from a rodent, Oligoryzomys microtis 88. Moreli ML, Sousa RL, Figueiredo LT (2004). Detection of (Muridae), collected in northeastern Peru. Am J Trop Med Brazilian hantavirus by reverse transcription polymerase Hyg 61: 92-98. chain reaction amplification of N gene in patients with 101. Verity R, Prasad E, Grimsrud K, Artsob H, Drebot M, hantavirus cardiopulmonary syndrome. Mem Inst Miedzinski L, Preiksaitis J (2000) Hantavirus pulmonary Oswaldo Cruz 99: 633-638. syndrome in northern Alberta, Canada: clinical and 89. Da Silva MV (2007) Brazilian hantavirus: clinical laboratory findings for 19 cases. Clin Infect Dis 31: 942- manifestions and case-fatality rate. The 7th International 946. Conference on HFRS, HPS and Hantaviruses, Buenos 102. Wilson C, Hjelle B, Jenison S (1994) Probable hantavirus Aires, Argentina. June 13-15, Abstract book, Page 43). pulmonary syndrome that occurred in New Mexico in 90. Espinoza R, Vial P, Noriega LM, Johnson A, Nichol ST, 1975. Ann Intern Med 120: 813. Rollin PE, Wells R, Zaki S, Reynolds E, Ksiazek TG 103. Engelthaler D, Levy C, Ettestad P, Kruger K, (1998) Hantavirus pulmonary syndrome in a Chilean Schuermann J, Leslie M (2006) Hantavirus Pulmonary patient with recent travel in Bolivia. Emerg Infect Dis 4: Syndrome --- Five States, 2006. MMWR 55:627-629. 93-95. 104. Diglisic G, Rossi CA, Doti A, Walshe DK. (1999) 91. Weissenbacher MC, Cura E, Segura EL, Hortal M, Baek Seroprevalence study of Hantavirus infection in the LJ, Chu YK, Lee HW (1996). Serological evidence of community based population. Md Med J 48: 303-306. human Hantavirus infection in Argentina, Bolivia and 105. LeDuc JW, Smith GA, Pinheiro FP, Vasconcelos PF, Uruguay. Medicina (B Aires) 56: 17-22. Rosa ES, Maiztegui JI. (1985) Isolation of a Hantaan- 92. Delfraro A, Tome L, Elia GD, Glara M, Rego N, Achaval related virus from Brazilian rats and serologic evidence of F, Arbiza J (2007) Hantavirus reservoir hosts and its widespread distribution in South America. Am J Trop genotypies circulating in uruguay. The 7th International Med Hyg 34: 810-815. Conference on HFRS, HPS and Hantaviruses, Buenos 106. Groen J, Koraka P, Edwards CN, Branch SL, Douglas Aires, Argentina. June 13-15, Abstract book, Page 118. KO, Osterhaus AD, Levett PN (2002) Serological 93. Armien B, Armien A, Pascale JM, Avila M, Gonzalez P, evidence of hantavirus in humans and rodents in Munoz C, Mendoza O, Guevara Y, Koster F, Salazer J, Barbados. J Infect 45: 109-110. Hjelle B, Yates T, Mertz G, Gracia F, Glass G (2007)

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

107. Gonzalez JP, McCormick JB, Baudon D, Gautun JP, identification of novel hantaviruses and their likely Meunier DY, Dournon E, Georges AJ. (1984) Serological reservoirs. Virology 277: 14-19. evidence for Hantaan-related virus in Africa. Lancet 2: 122. Bowen MD, Gelbmann W, Ksiazek TG, Nichol ST, 1036-1037. Nowotny N (1997) Puumala virus and two genetic 108. Saluzzo JF, Digoutte JP, Adam F, Bauer SP, McCormick variants of Tula virus are present in Austrian rodents. J JB (1985) Serological evidence for Hantaan-related virus Med Virol 53: 174-181. infection in rodents and man in Senegal. Trans R Soc 123. Heyman P, Klingstrom J, de Jaegere F, Klingstrom J, Trop Med Hyg 79: 874-875 Vandenvelde C, Lundkvist A, Rozenfeld F, Zizi M. 109. Tomori O, Morikawa S, Matsuura Y, Kitamura T (1986) (2002)Tula hantavirus in Belgium. Epidemiol Infect 128: Antibody to Japanese strains of haemorrhagic fever with 251-256. renal syndrome (HFRS) virus in Nigerian sera. Trans R 124. Scharninghausen JJ, Pfeffer M, Meyer H, (2002) Genetic Soc Trop Med Hyg; 80: 1008-1009. evidence for tula virus in Microtus arvalis and Microtus 110. Rodier G, Soliman AK, Bouloumie J, Kremer D. agrestis populations in Croatia. Vector Borne Zoonotic (1993)Presence of antibodies to hantavirus in rat plus Dis 2: 19-27. human populations of Djibouti. Trans R Soc Trop Med 125. Song JW, Baek LJ, Song KJ, Skrok A, Markowski J, Hyg 87: 160-161. Bratosiewicz-Wasik J, Kordek R, Liberski PP, Yanagihara 111. Botros BA, Sobh M, Wierzba T, Arthur RR, Mohareb EW, R. (2004) Characterization of Tula virus from common Frenck R, El Refaie A, Mahmoud I, Chapman GD, voles (microtus arvalis) in Poland: evidence for Graham RR (2004) Prevalence of hantavirus antibody in geographic-specific phylogenetic clustering. Virus Genes patients with chronic renal disease in Egypt. Trans R Soc 29: 239-247. Trop Med Hyg 98: 331-336. 126. Plyusnin A, Vapalahti O, Lankinen H, Lehväslaiho H, 112. Klempa B, Fichet-Calvet E, Lecompte E, Auste B, Aniskin Apekina N, Myasnikov Y, Kallio-Kokko H, Henttonen H, V, Meisel H, Denys C, Koivogui L, ter Meulen J, Kruger Lundkvist A, Brummer-Korvenkontio M (1994) Tula virus: DH. (2006) Hantavirus in African Wood Mouse, Guinea. a newly detected hantavirus carried by European Emerg Infect Dis 12: 838-840. common voles. J Virol 68: 7833-7839. 113. Coulaud X, Chouaib E, Georges AJ, Rollin P, Gonzalez 127. Song JW, Gligic A, Yanagihara R (2002) Identification of JP. (1987) First human case of haemorrhagic fever with Tula hantavirus in Pitymys subterraneus captured in the renal syndrome in the Central African Republic. Trans R Cacak region of Serbia-Yugoslavia. Int J Infect Dis 6: 31- Soc Trop Med Hyg 81: 686. 36. 114. Sironen T, Vaheri A, Plyusnin A (2005) Phylogenetic 128. Sibold C, Meisel H, Kruger DH, Schulz A, Cifire F, Ulrich evidence for the distinction of Saaremaa and Dobrava R, Kozuch O, Labuda M, Kruger DH (1999) hantaviruses. Virol J 2: 90-95. Recombination in Tula hantavirus evolution: analysis of 115. Glass GE, Watson AJ, LeDuc JW, Childs JE. (1994) genetic lineages from Slovakia. J Virol 73: 667-675. Domestic cases of hemorrhagic fever with renal 129. Vapalahti O, Lundkvist A, Kukkonen SK, Cheng Y, syndrome in the United States. Nephron 68: 48-51. Gilljam M, Kanerva M, Manni T, Pejcoch M, Niemimaa J, 116. Heyman P, Plyusnina A, Berny P, Cochez C, Artois M, Kaikusalo A, Henttonen H, Vaheri A, Plyusnin A. (1996) Zizi M, Pirnay JP, Plyusnin A. (2004) Seoul hantavirus in Isolation and characterization of Tula virus, a distinct Europe: first demonstration of the virus genome in wild serotype in the genus Hantavirus, family Bunyaviridae. J Rattus norvegicus captured in France. Eur J Clin Gen Virol 77: 3063-3067. Microbiol Infect Dis 23: 711-717. 130. Schultze D, Lundkvist A, Blauenstein U, Heyman P. 117. Yashina L, Mishin V, Zdanovskaya N, Schmaljohn C, (2002) Tula virus infection associated with fever and Ivanov L. (2001) A newly discovered variant of a exanthema after a wild rodent bite. Eur J Clin Microbiol hantavirus in Apodemus peninsulae, far Eastern Russia. Infect Dis 21: 304-306. Emerg Infect Dis 7: 912-913. 131. Klempa B, Meisel H, Rath S, Bartel J, Ulrich R, Kruger 118. Lokugamage K, Kariwa H, Lokugamage N, Miyamoto H, DH. (2003) Occurrence of renal and pulmonary syndrome Iwasa M, Hagiya T, Araki K, Tachi A, Mizutani T, in a region of northeast Germany where Tula hantavirus Yoshimatsu K, Arikawa J, Takashima I. (2004) Genetic circulates. J Clin Microbiol 41: 4894-4897. and antigenic characterization of the Amur virus 132. Clement J, Heyman P, McKenna P, Colson P, Avsic- associated with hemorrhagic fever with renal syndrome. Zupanc T. (1997) The hantavirue of Europe: from the Virus Res 101: 127-134. bedside to the beach. Emerg Infect Dis 3: 205-211. 119. McIntyre NE, Chu YK, Owen RD, Abuzeineh A, De la 133. McMaughey C and Hart CA. Hantavirus (2000) J Med Sancha N, Dick CW, Holsomback T, Nisbett RA, Jonsson Microbiol 49: 587-599. C (2005) A Longitudinal study of Bayou virus, hosts, and 134. Carey, D. E., R. Reuben, K. N. Panicker, R. E. Shope, habitat. Am J Trop Med Hyg 73: 1043-1049. and R. M. Myers (1971) Thottapalayam virus: a 120. Padula P, Martinez VP, Bellomo C, Maidana S, San presumptive arbovirus isolated from a shrew in India. Juan J, Tagliaferri P, Bargardi S, Vazquez C, Colucci N, Indian J. Med. Res. 59:1758-1760. Estévez J, Almiron M (2007) Pathogenic hantaviruses, 135. Okumura M, Yoshimatsu K, Kumperasart S, Nakamura I, northeastern Argentina and eastern Paraguay. Emerg Ogino M, Taruishi M, Sungdee A, Pattamadilok S, Infect Dis. 13:1211-4. Ibrahim IN, Erlina S, Agui T, Yanagihara R, Arikawa J 121. Vincent MJ, Quiroz E, Gracia F, Sanchez AJ, Ksiazek (2007) Development of serological assays for TG, Kitsutani PT, Ruedas LA, Tinnin DS, Caceres L, Thottapalayam virus, an insectivore-borne Hantavirus. Garcia A, Rollin PE, Mills JN, Peters CJ, Nichol ST Clin Vaccine Immunol. 14:173-81. (2000) Hantavirus pulmonary syndrome in Panama:

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

136. Elwell MR, Ward GS, Tingpalapong M, LeDuc JW, 1985. 151. Houck MA, Qin H, Roberts HR (2001) Hantavirus Serologic evidence of Hantaan-like virus in rodents and transmission: potential role of ectoparasites. Vector man in Thailand. Southeast Asian J Trop Med Public Borne Zoonotic Dis 1: 75-79. Health 16: 349– 354. 152. Overturf GD (2005) Clinical sin nombre hantaviral 137. Pattamadilok S, Lee BH, Kumperasart S, Yoshimatsu K, infections in children. Pediatr Infect Dis J 24: 373-374 Okumura M, Nakamura I, Araki K, Khoprasert Y, 153. Howard MJ, Doyle TJ, Koster FT, Zaki SR, Khan AS, Dangsupa P, Panlar P, Jandrig B, Krüger DH, Klempa B, Petersen EA, Peters CJ, Bryan RT (1999) Hantavirus Jäkel T, Schmidt J, Ulrich R, Kariwa H, Arikawa J (2006) pulmonary syndrome in pregnancy. Clin Infect Dis 29: Geographical distribution of hantaviruses in Thailand and 1538-1544. potential human health significance of Thailand virus. Am 154. Botten J, Mirowsky K, Ye C, Gottlieb K, Saavedra M, J Trop Med Hyg. 75:994-1002. Ponce L, Hjelle B (2002) Shedding and intracage 138. Klempa B, Fichet-Calvet E, Lecompte E, Auste B, transmission of Sin Nombre hantavirus in the deer mouse Aniskin V, Meisel H, Barrière P, Koivogui L, ter Meulen J, (Peromyscus maniculatus) model. J Virol 76: 7587-7594 Krüger DH (2007) Novel Hantavirus Sequences in Shrew, 155. Hutchinson KL, Rollin PE, Shieh WJ, Zaki S, Greer PW, Guinea. Emerg Infect Dis. 13:520-2. Peters CJ (2000) Transmission of Black Creek Canal 139. Song JW, Gu SH, Bennett SN, Arai S, Puorger M, Hilbe virus between cotton rats. J Med Virol 60: 70-76. M, Yanagihara R (2007) Seewis virus, a genetically 156. Ma RM, Xiao H, Jing XT, Lao TT (2003) Hemorrhagic distinct hantavirus in the Eurasian common shrew (Sorex fever with renal syndrome presenting with intrauterine araneus). Virol J. 4(1):114. fetal death. A case report. J Reprod Med 48: 661-664. 140. Arai S, Song JW, Sumibcay L, Bennett SN, Nerurkar VR, 157. Peng H, Tang S and Qi X (2002) Clinical study on Parmenter C, Cook JA, Yates TL, and Yanagihara R intrauterine hemorrhagic fever with renal syndrome virus (2007) Hantavirus in Northern Short-tailed Shrew, United infection. Chin J Exp Clin Virol. 16:281-2. States. Emerg Infect Dis. 13:1420-23. 158. Kallio ER, Klingstrom J, Gustafsson E, Manni T, Vaheri A, 141. Song JW, Kang HJ, Song KJ, Truong TT, Bennett SN, Henttonen H, Vapalahti O, Lundkvist A (2006) Prolonged Arai S, Truong NU, and Yanagihara R (2007) Newfound survival of Puumala hantavirus outside the host: evidence Hantavirus in Chinese Mole Shrew, Vietnam. Emerg for indirect transmission via the environment. J Gen Virol Infect Dis. 13:1784-87. 87: 2127-2134. 142. Tang YW, Xu ZY, Zhu ZY Tsai TF (1985) Isolation of 159. Enria D, Padula P, Segura EL, Pini N, Edelstein A, Posse haemorrhagic fever with renal syndrome virus from CR, Weissenbacher MC (1996) Hantavirus pulmonary Suncus murinus, an insectivore. The Lancet 1: 513-514 syndrome in Argentina. Possibility of person to person 143. Jung YT, Kim GR (1995) Genomic characterization of M transmission. Medicina (B Aires) 56: 709-711. and S RNA segments of hantaviruses isolated from bats. 160. Chaparro J, Vega J, Terry W, Vera JL, Barra B, Meyer R, Acta Virol 39: 231-233. Peters CJ, Khan AS, Ksiazek TG (1998) Assessment of 144. Luo ZZ, Li SQ, Peng DS, Wang YY, He H, Li YZ, Zhou N, person-to-person transmission of hantavirus pulmonary Ni DS, Li YX, Xue ZY (1985) Isolation and syndrome in a Chilean hospital setting. J Hosp Infect 40: characterization of epidemic haemorrhagic fever virus 281-285. from domestic cats. Chin J Microbiol Immunol 5: 79-81. 161. Vitek CR, Breiman RF, Ksiazek TG, Rollin PE, 145. Slonova RA, Tkachenko EA, Kushnarev EL, Dzagurova McLaughlin JC, Umland ET, Nolte KB, Loera A, Sewell TK, Astakova TI (1992) Hantavirus isolation from birds. CM, Peters CJ (1996) Evidence against person-to-person Acta Virol 36: 493. transmission of hantavirus to health care workers. Clin 146. Malecki TM, Jillson GP, Thilsted JP, Elrod J, Torrez- Infect Dis 22: 824-826. Martinez N, Hjelle B (1998) Serologic survey for 162. Pinna DM, Martinez VP, Bellomo CM, López C, Padula P. hantavirus infection in domestic animals and coyotes (2004) New epidemiologic and molecular evidence of from New Mexico and northeastern Arizona. J Am Vet person to person transmission of hantavirus Andes Sout. Med Assoc 212: 970-973. Medicina (B Aires) 64: 43-46. 147. Yang Z, Liu Y, Peng Z (1998) Epidemiologic and 163. Martinez VP, Bellomo C, San Juan J, Pinna D, Forlenza experimental studies on epidemic haemorrhagic fever R, Elder M, Padula PJ (2005) Person-to-person virus in pigs. Chin J Epidemol 19: 218-220. transmission of Andes virus. Emerg Infect Dis 11: 1848- 148. Glass G, Childs J, Korch G, LeDuc JW (1988) 1853. Association of intraspecific wounding with hantaviral 164. Padula PJ, Edelstein A, Miguel SD, Lopez NM, Rossi infection in wild rats (Rattus norvegicus). Epidemiol Infect CM, Rabinovich RD (1998) Hantavirus pulmonary 101: 459-472. syndrome outbreak in Argentina: molecular evidence of 149. Hinson ER, Shone SM, Zink MC, Glass GE, Klein SL person to person transmission of Andes virus. Viology (2004) Wounding: the primary mode of Seoul virus 241: 323-330. transmission among male Norway rats. Am J Trop Med 165. Lázaro ME, Cantoni GE, Calanni LM, Resa AJ, Herrero Hyg 70: 310-317. ER, Iacono MA, Enria DA, González Cappa SM (2007) 150. Zhang Y, Zhu J, Deng XZ, Wu GH, Wang JJ, Zhang JJ, Clusters of hantavirus infection, southern Argentina. Xing AH, Wu JW (2003) Detection of hantaan virus from Emerg Infect Dis 13: 104-110. gamasid mite and chigger mite by molecular biological 166. Ferres M, Vial P, Marco C, Yanez L, Godoy P, Castillo C, methods. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Hjelle B, Delgado I, Lee SJ, Mertz GJ; Andes Virus Za Zh 17: 107-111. Household Contacts Study Group (2007) Prospective evaluation of household contacts of persons with

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

hantavirus cardiopulmonary syndrome in Chile. J Infect and detection of viral antigen in the hypophysis. Clin Dis. 195:1563-71. Infect Dis 35: 96-101. 167. Ruo SL, Li YL, Tong Z, Ma QR, Liu ZL, Tang YW, Ye KL, 181. Nguyen AT, Penalba C, Bernadac P, Jaafar S, Kessler M, McCormick JB, Fisher-Hoch SP, Xu ZY (1994) Canton P, Hoen B (2001) Respiratory manifestations of Retrospective and prospective studies of hemorrhagic hemorrhagic fever with renal syndrome. Retrospective fever with renal syndrome in rural China. J Infect Dis 170: study of 129 cases in Champagne-Ardenne and Lorraine. 527-534. Presse Med 30: 55-58. 168. Vitek CR, Ksiazek TG, Peters CJ, Breiman RF (1996) 182. Seitsonen E, Hynninen M, Kolho E, Kallio-Kokko H, Evidence against infection with hantaviruses among Pettilä V (2006) Corticosteroids combined with forest and park workers in the southwestern United continuous veno-venous hemodiafiltration for treatment of States. Clin Infect Dis. 23:283-5. hantavirus pulmonary syndrome caused by Puumala 169. Zeitz PS, Graber JM, Voorhees RA, Kioski C, Shands LA, virus infection. Eur J Clin Microbiol Infect Dis 25: 261- Ksiazek TG, Jenison S, Khabbaz RF (1997) Assessment 266. of occupational risk for hantavirus infection in Arizona and 183. Novo R, Gagnadoux MF, Le Guenno Y, Gubler MC, New Mexico. J Occup Environ Med. 39:463-7. Niaudet P, Guyot C, Broyer M (1999) Chronic renal 170. Fulhorst CF, Milazzo ML, Armstrong LR, Childs JE, Rollin failure after Puumala virus infection. Pediatr Nephrol 13: PE, Khabbaz R, Peters CJ, Ksiazek TG. (2007) 934-935. Hantavirus and arenavirus antibodies in persons with 184. Hallin GW, Simpson SQ, Crowell RE, James DS, Koster occupational rodent exposure. Emerg Infect Dis. 13:532- FT, Mertz GJ, Levy H. (1996) Cardiopulmonary 538. manifestations of hantavirus pulmonary syndrome. Crit 171. Ferrer JF, Jonsson CB, Esteban E, Galligan D, Care Med 24: 252-258. Basombrio MA, Peralta-Ramos M, Bharadwaj M, Torrez- 185. Raboni SM, Rubio G, DE Borba L, Zeferino A, Skraba I, Martinez N, Callahan J, Segovia A, Hjelle B. (1998) High Goldenberg S, Dos Santos CN (2005) Clinical survey of prevalence of hantavirus infection in Indian communities hantavirus in southern Brazil and the development of of the Paraguayan and Argentinean Gran Chaco. Am J specific molecular diagnosis tools. Am J Trop Med Hyg Trop Med Hyg. 59:438-44. 72: 800-804. 172. Campos GM, Moro de Sousa RL, Badra SJ, Pane C, 186. Hjelle B, Goade D, Torrez-Martinez N, Lang-Williams M, Gomes UA, Figueiredo LT (2003) Serological survey of Kim J, Harris RL, Rawlings JA (1996) Hantavirus hantavirus in Jardinopolis County, Brazil. J Med Virol. 71: pulmonary syndrome, renal insufficiency, and myositis 417-22. associated with infection by Bayou hantavirus. Clin Infect 173. Armien B, Pascale JM, Bayard V, Munoz C, Mosca I, Dis 23: 495-500. Guerrero G, Armien A, Quiroz E, Castillo Z, Zaldivar Y, 187. Hopkins RO, Larson-Lohr V, Weaver LK, Bigler ED Gracia F, Hjelle B, Koster F. (2004) High seroprevalence (1998) Neuropsychological impairments following of hantavirus infection on the Azuero peninsula of hantavirus pulmonary syndrome. J Int Neuropsychol Soc Panama. Am J Trop Med Hyg. 70:682-7. 4: 190-196. 174. Zeitz PS, Graber JM, Voorhees RA, Kioski C, Shands LA, 188. Kitsutani PT, Denton RW, Fritz CL, Murray RA, Todd RL, Ksiazek TG, Jenison S, Khabbaz RF (1997) Assessment Pape WJ, Wyatt Frampton J, Young JC, Khan AS, Peters of occupational risk for hantavirus infection in Arizona and CJ, Ksiazek TG (1999) Acute Sin Nombre hantavirus New Mexico. J Occup Environ Med 39: 463-467. infection without pulmonary syndrome, United States. 175. Suzán G, Giermakowski JT, Marcé E, Suzán-Azpiri H, Emerg Infect Dis 5: 701-705. Armién B, Yates TL. (2006) Modeling hantavirus reservoir 189. Crowley MR, Katz RW, Kessler R, Simpson SQ, Levy H, species dominance in high seroprevalence areas on the Hallin GW, Cappon J, Krahling JB, Wernly J (1998) Azuero Peninsula of Panama. Am J Trop Med Hyg. Successful treatment of adults with severe Hantavirus 74:1103-10. pulmonary syndrome with extracorporeal membrane 176. Schutt M, Meisel H, Kruger DH, Ulrich R, Dalhoff K, Dodt oxygenation. Crit Care Med 26: 409-414. C (2004) Life-threatening Dobrava hantavirus infection 190. Custer DM, Thompson E, Schmaljohn CS, Ksiazek TG, with unusually extended pulmonary involvement. Clin Hooper JW (2003) Active and passive vaccination against Nephrol 62: 54-57. hantavirus pulmonary syndrome with Andes virus M 177. Mathes RW, Page WF, Crawford HM, McBean AM, Miller genome segment-based DNA vaccine. J Virol. 77:9894- RN (2005) Long-term sequelae of hemorrhagic fever with 905. renal syndrome attributable to Hantaan virus in Korean 191. Hooper JW, Ferro AM, Wahl-Jensen V. (2007) Immune War veterans. Mil Med 170: 315-319. Serum Produced by DNA Vaccination Protects Hamsters 178. Settergren B (2000) Clinical aspects of nephropathia Against Lethal Respiratory Challenge with Andes Virus. J epidemica (Puumala virus infection) in Europe: a review. Virol. Nov 21 [Epub ahead of print]. Scand J Infect Dis 32: 125-132. 192. Enria D, Maiztegui JI (1994) Antiviral treatment of 179. Krause R, Aberle S, Haberl R, Daxbock F, Wenisch C Argentine hemorrhagic fever. Antiviral Res 23: 23-31. (2003) Puumala virus infection with acute disseminated 193. Severson WE, Schmaljohn CS, Javadian A, Jonsson CB encephalomyelitis and multiorgan failure. Emerg Infect (2003) Ribavirin causes error catastrophe during Hantaan Dis 9: 603-605. virus replication. J Virol 77: 481-488. 180. Hautala T, Sironen T, Vapalahti O, Pääkkö E, Särkioja T, 194. Huggins JW, Hsiang CM, Cosgriff TM, Guang MY, Smith Salmela PI, Vaheri A, Plyusnin A, Kauma H (2002) JI, Wu ZO, LeDuc JW, Zheng ZM, Meegan JM, Wang QN Hypophyseal hemorrhage and panhypopituitarism during (1991) Prospective, double-blind, concurrent, placebo- Puumala Virus Infection: Magnetic Resonance Imaging controlled clinical trial of intravenous Ribavirin therapy of

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

hemorrhagic fever with renal syndrome. J Infect Dis 164: reverse transcriptase-polymerase chain reaction (RT- 1119-1127. PCR) and restriction fragment length polymorphism 195. Chapman LE, Mertz GJ, Peters CJ, Jolson HM, Khan AS, (RFLP) in renal syndrome patients with hemorrhagic Ksiazek TG, Koster FT, Baum KF, Rollin PE, Pavia AT, fever. Clin Nephrol 53: 79-89. Holman RC, Christenson JC, Rubin PJ, Behrman RE, 207. Aitichou M, Saleh SS, McElroy AK, Schmaljohn C, Bell LJ, Simpson GL, Sadek RF. (1999) Intravenous Ibrahim MS (2005) Identification of Dobrava, Hantaan, ribavirin for hantavirus pulmonary syndrome: safety and Seoul, and Puumala viruses by one-step real-time RT- tolerance during 1 year of open-label experience. Antivir PCR. J Virol Methods 124: 21-26. Ther 4: 211-219. 208. Mills JN (2005) Regulation of rodent-borne viruses in the 196. Mertz GJ, Miedzinski L, Goade D, Pavia AT, Hjelle B, natural host: implications for human disease. Arch Virol Hansbarger CO, Levy H, Koster FT, Baum K, Suppl 19:45-57. Lindemulder A, Wang W, Riser L, Fernandez H, Whitley 209. Centers for Disease Control and Prevention (1993) RJ, Collaborative Antiviral Study Group (2004) Placebo- Hantavirus infection--southwestern United States: interim controlled, double-blind trial of intravenous ribavirin for recommendations for risk reduction. MMWR Recomm the treatment of hantavirus cardiopulmonary syndrome in Rep 42: 1-13. North America. Clin Infect Dis 39: 1307-1313. 210. Douglass RJ, Kuenzi AJ, Williams CY, Douglass SJ, Mills 197. Loginova SIa, Koval'chuk AV, Borisevich SV, Kopylova JN (2003) Removing deer mice from buildings and the NK, Pashchenko IuI, Khamitov RA, Maksimov VA, risk for human exposure to Sin Nombre virus. Emerg Shuster AM (2005) Antiviral effectiveness of the Infect Dis 9: 390-392. combined use of amixine and virasole in experimental 211. Glass GE, Johnson JS, Hodenbach GA, Disalvo CL, hemorrhagic fever with renal syndrome in sucking albino Peters CJ, Childs JE, Mills JN (1997) Experimental mice. Vopr Virusol 50: 30-32. evaluation of rodent exclusion methods to reduce 198. Plyusnin A, Mustonen J, Asikainen K, Plyusnina A, hantavirus transmission to humans in rural housing. Am J Niemimaa J, Henttonen H, Vaheri A (1999) Analysis of Trop Med Hyg 56: 359-364. puumala hantavirus genome in patients with 212. Chen HX, Luo ZZ, Zhang JJ, Hantavirus Vaccine Efficacy nephropathia epidemica and rodent carriers from the Evaluation Working Group (2002) Large scale field sites of infection. J Med Virol 59: 397-405. evaluation on vaccines of hemorrhagic fever with renal 199. Kramski M, Meisel H, Klempa B, Krüger DH, Pauli G, syndrome in China. Chin J Epidemiol 23: 145-147. Nitsche A (2007) Detection and typing of human 213. Dong GM, Han L, An Q, Liu WX, Kong Y, Yang LH (2005) pathogenic hantaviruses by real-time reverse Immunization effect of purified bivalent vaccine to transcription-PCR and pyrosequencing. Clin Chem. haemorrhagic fever with renal syndrome manufactured 53:1899-905. from primary cultured hamster kidney cells. Chin Med J 200. Biel SS, Donoso Mantke O, Lemmer K, Vaheri A, (Engl) 118: 766-768. Lundkvist A, Emmerich P, Hukic M, Niedrig M (2003) 214. Park K, Kim CS, Moon KT (2004) Protective effectiveness Quality control measures for the serological diagnosis of of hantavirus vaccine. Emerg Infect Dis 10:2218-2220. hantavirus infections. J Clin Virol 28: 248-256. 215. Choi Y, Ahn CJ, Seong KM, Jung MY, Ahn BY (2003) 201. Kallio-Kokko H, Vapalahti O, Lundkvist A, Vaheri A Inactivated Hantaan virus vaccine derived from (1998) Evaluation of Puumala virus IgG and IgM enzyme suspension culture of Vero cells. Vaccine 21: 1867-1873 immunoassays based on recombinant baculovirus- 216. Schmaljohn CS, Hasty SE, Dalrymple JM (1992) expressed nucleocapsid protein for early nephropathia Preparation of candidate vaccinia-vectored vaccines for epidemica diagnosis. Clin Diagn Virol 10: 83-90. haemorrhagic fever with renal syndrome. Vaccine 10: 10- 202. Hujakka H, Koistinen V, Kuronen I, Eerikainen P, 13. Parviainen M, Lundkvist A, Vaheri A, Vapalahti O, 217. McClain DJ, Summers PL, Harrison SA, Schmaljohn AL, Narvanen A (2003) Diagnostic rapid tests for acute Schmaljohn CS (2000) Clinical evaluation of a vaccinia- hantavirus infections: specific tests for Hantaan, Dobrava vectored Hantaan virus vaccine. J Med Virol 60: 77-85. and Puumala viruses versus a hantavirus combination 218. Ulrich R, Koletzki D, Lachmann S, Lundkvist A, Zankl A, test. J Virol Methods 108: 117-122. Kazaks A, Kurth A, Gelderblom HR, Borisova G, Meisel 203. Lundkvist A, Hukic M, Horling J, Gilljam M, Nichol S, H, Kruger DH (1999) New chimaeric hepatitis B virus core Niklasson B (1997) Puumala and Dobrava viruses cause particles carrying hantavirus (serotype Puumala) hemorrhagic fever with renal syndrome in Bosnia- epitopes: immunogenicity and protection against virus Herzegovina: evidence of highly cross-neutralizing challenge. J Biotechnol 73: 141-153. antibody responses in early patient sera. J Med Virol 53: 219. Koletzki D, Lundkvist A, Sjolander KB, Gelderblom HR, 51-59. Niedrig M, Meisel H, Kruger DH, Ulrich R (2000) Puumala 204. Lee PW, Gibbs CJ Jr, Gajdusek DC, Yanagihara R (PUU) hantavirus strain differences and insertion (1985) Serotypic classification of hantaviruses by indirect positions in the hepatitis B virus core antigen influence B- immunofluorescent antibody and plaque reduction cell immunogenicity and protective potential of core- neutralization tests. J Clin Microbiol 22: 940-944. derived particles. Virology 276: 364-375. 205. Tennstedt C, Wunschmann S, Schmitz H, Schreiber M 220. Hooper JW, Kamrud KI, Elgh F, Custer D, Schmaljohn (1994) Pathological-anatomical findings after serologic CS (1999) DNA vaccination with hantavirus M segment and molecular biologic evidence of Hantaan virus elicits neutralizing antibodies and protects against Seoul infection. Zentralbl Pathol 140: 173-180. virus infection. Virology 255: 269-278. 206. Ahn C, Cho JT, Lee JG, Lim CS, Kim YY, Han JS, Kim S, 221. Hooper JW, Custer DM, Thompson E, Schmaljohn CS Lee JS (2000) Detection of Hantaan and Seoul viruses by (2001) DNA vaccination with the Hantaan virus M gene

Bi et al - Hantavirus infection review J Infect Developing Countries 2008; 2(1): 3-23.

protects Hamsters against three of four HFRS Corresponding Author: Zhenqiang Bi, Biorisk hantaviruses and elicits a high-titer neutralizing antibody Reduction for Dangerous Pathogens, Department of response in Rhesus monkeys. J Virol 75: 8469-8477. Epidemic and Pandemic Alert and Response, World 222. Custer DM, Thompson E, Schmaljohn CS, Ksiazek TG, Health Organization, 20 Avenue Appia, CH-1211 Hooper JW (2003) Active and passive vaccination against Geneva 27, Switzerland, Tel: +41 22 791 1085, Fax: hantavirus pulmonary syndrome with Andes virus M genome segment-based DNA vaccine. J Virol 77: 9894- +41 22 791 4198, e-mail: [email protected] or 9905. [email protected]. 223. Hooper JW, Custer DM, Smith J, Wahl-Jensen V (2006) Hantaan/Andes virus DNA vaccine elicits a broadly cross- Conflict of interest: No conflict of interest is declared. reactive neutralizing antibody response in nonhuman

primates. Virology 347: 208-216. 224. Bharadwaj M, Mirowsky K, Ye C, Masten B, Yee J, Lyons CR, Hjelle B (2002) Genetic vaccines protect against Sin Nombre hantavirus challenge in the deer mouse (Peromyscus maniculatus). J Gen Virol 83: 1745-1751. 225. Razanskiene A, Schmidt J, Geldmacher A, Ritzi A, Niedrig M, Lundkvist A, Krüger DH, Meisel H, Sasnauskas K, Ulrich R (2004) High yields of stable and highly pure nucleocapsid proteins of different hantaviruses can be generated in the yeast Saccharomyces cerevisiae. J Biotechnol 111:319-333. 226. Khattak S, Darai G, Sule S, Rosen-Wolff A (2002) Characterization of expression of Puumala virus nucleocapsid protein in transgenic plants. Intervirology 45: 334-339. 227. Palese P, Zheng H, Engelhardt OG, Garcia-Sastre A (1996) Negative-strand RNA viruses: genetic engineering and applications. Proc Natl Acad Sci USA 93: 11354- 11358.