Although China has recorded what were likely hantavirus infections in ancient literature, dating back to the 12th century (Song, 1999), HFRS was first clinically recognized in 1931 in northeast China (Zhang WY et al., 2014). HFRS first came to the attention of western physicians when 3, 200 United Nations troops fell ill in Korea between 1951 and 1954 (Schmaljohn and Hjelle, 1997). The first pathogenic hantavirus was isolated along the Hantaan River, in South Korea in 1976 by Lee et al., who named it the hantaan virus (HTNV) (1978). Hantaan, Seoul, Dobrava, and Puumala viruses are prevalent mainly in Europe and Asia, and are referred to as Old World hantaviruses. Five clinical phases are manifested in typical HFRS patients, including fever, hypotensive shock, and oliguric, polyuric, and convalescent phases. Furthermore, some of these phases overlap in severe cases, but might not be evident in mild cases of the disease (Wang et al., 2014). The incidence of HFRS in males is over three times greater than that in females. HFRS outbreaks can vary depending on the season, with most cases in epidemic areas occurring in the winter to early spring. Farmers account for the largest number of cases (Huang et al., 2012; Zhang S et al., 2014), especially in China. In recent years, new foci of infection have been detected and the endemic areas have extended beyond rural areas. Several factors are thought to be related to the expanding endemic trend of hantavirus infection, including rapid economic development, urbanization, human migration, and the effects of climate change (Zuo et al., 2011). Several inactivated vaccines have been generated from hantavirus in cell cultures or the rodent brain, and a few of these have been licensed for use in humans in Korea and China (Kruger et al., 2011). Inactivated monovalent vaccines reportedly have a protective efficacy of 93.77%-97.61% and inactivated bivalent vaccines, a protective efficacy of nearly 100% (Kruger et al., 2011). DNA vaccines and attenuated live vaccines are currently under evaluation in clinical trials. To our knowledge, no licensed vaccines currently exist in other countries, probably because of the relatively low incidence of HFRS. The use of antiviral agents is seldom reported, but ribavirin has been tested and its therapeutic efficacy has been proven in HFRS patients in China (Huggins et al., 1991).
Nephropathia epidemica (NE) was first described in Sweden in the 1930s and thousands of hantavirus infection cases occur annually throughout Europe (Latus et al., 2015b). Although a number of various hantavirus species [e.g., Dobrava-Belgrade virus (DOBV) and Tula hantavirus (TULV)] are circulating in Europe, Puumala virus (PUUV) is by far the most prevalent pathogen (Manigold and Vial, 2014; Kruger et al., 2013). In central and northern Europe, PUUV is responsible for thousands of NE cases annually. NE is a mild form of HFRS that is characterized by acute kidney injury (AKI) and thrombocytopenia. The occurrence of thrombocytopenia in infected patients varies from 39% to 98% (Krautkramer et al., 2013). Severe thrombocytopenia is very common, however, bleeding complications are uncommon in acute NE (Latus et al., 2015a). Smokers reportedly exhibit more severe kidney injury than non-smokers in cases of PUUV infection (Tervo et al., 2015).
In 1993, a previously unrecognized syndrome (HCPS) was first described in the United States (Peters et al., 2002). Subsequently, Sin Nombre virus (SNV) was identified as the etiological agent (Ksiazek et al., 1995). SNV and ANDV are prevalent mainly in North and South America, and are referred to as New World hantaviruses. Approximately 43 strains have been reported in the Americas, and 20 of those strains are associated with human disease. In patients with HCPS, the primary target organ is the lungs (Table 1). Most cases occur during the late spring and early summer months, in contrast to hantavirus infections in Asia. The seroprevalence of hantavirus has been reported in healthy populations (Ferrer et al., 2003; Armien et al., 2004). In North America, SNV is the most prevalent hantavirus that causes HCPS (Knust and Rollin, 2013), whereas in South America, ANDV is the most significant pathogenic hantavirus, with ongoing discovery of new strains (Jonsson et al., 2010; Firth et al., 2012). Most of the South American hantavirus strains are divided into three monophyletic groups, referred to as the Andes, Laguna Negra, and Rio Mamore clades (Firth et al., 2012). ANDV is the only hantavirus with person-to-person transmission, a characteristic that places tremendous challenges to the healthcare systems of Argentina and Chile (Figueiredo et al., 2014; Martinez-Valdebenito et al., 2014). Recently, HCPS was reportedly induced by PUUV in Germany (Vollmar et al., 2016). Symptomatic and supportive treatment remain the most important treatment for the lack of specific therapeutics for HCPS.
HFRS NE HCPS Common features sudden fever, prostration, myalgia and abdominal discomfort Symptoms hemorrhage, petechiae, inflammatory symptoms of the eye, acute myopia, varying degrees of acute renal failure dry cough, rapidly increasing dyspnea On chest radiography, rapidly evolving bilateral interstitial edema Clinical phases five phases (febrile, hypotensive, oliguric, polyuric, convalescent) five phases (febrile, hypotensive, oliguric, polyuric, convalescent) three phases (prodromal, cardiopulmonary, convalescent) Main target organ kidneys kidneys lungs Morbidity rate 1%-12% 0.1%-1.0% 40%-50% Complications acute encephalomyelitis, bleeding, multiorgan dysfunction, pituitary hemorrhage, glomerulonephritis, pulmonary edema, shock, acute respiratory distress syndrome, disseminated intravascular coagulation, lethal outcome acute encephalomyelitis, bleeding, multiorgan dysfunction, need of dialysis, perimyocarditis, pituitary hemorrhage, pulmonary edema, shock, lethal outcome renal insufficiency, thrombocytopenia, bleeding, myalgia, headache, nausea, vomiting, diarrhea, shock, lethal outcome Note:HFRS, hemorrhagic fever with renal syndrome; NE, nephropathia epidemica; HCPS, hantavirus cardiopulmonary syndrome. NE is a mild form of HFRS.(Maes et al., 2009; Papa, 2012; Mustonen et al., 2013; Jiang et al., 2016)
Table 1. General features of HFRS, NE and HCPS
Rodents, shrews, moles, and bats are all reservoir hosts for hantaviruses. Although persistent infection can become established and high titers of neutralizing antibodies can accumulate, these reservoirs remain asymptomatic following infection (Vaheri et al., 2013; Yu et al., 2014). Each hantavirus is associated with a distinct rodent host species, and spillover to other rodent species seems to induce the production of specific antibodies and clearance of the virus (Spengler et al., 2013). Hantaviruses apparently co-evolve with their hosts (Vaheri et al., 2013).
Apodemus agrarius (host species for HTNV) and Rattus norvegicus[host species for Seoul virus (SEOV)] are the predominant reservoirs in the wild and in residential areas, respectively (Zhang S et al., 2014). Phylogenetic analysis shows that at least nine clades of HTNV and five clades of SEOV are prevalent in China (Huang et al., 2012; Zou et al., 2016), including the Xinyi and Fugong viruses that have been recently reported in specific epidemic foci (Ge et al., 2016; Gu et al., 2016). Rodent-borne hantaviruses have also been detected in Lao PDR, Thailand (Thailand hantavirus, THAIV) and Cambodia (THAIV-like virus) (Blasdell et al., 2011; Pattamadilok et al., 2006). Among those viruses, THAIV can cause disease in humans (Pattamadilok et al., 2006; Gamage et al., 2011). Epizootiology studies have reported the presence of rats in Vietnam and Singapore with antibodies against SEOV (Truong et al., 2009; Johansson et al., 2010). SEOV has also been detected in rodents from Indonesia (Ibrahim et al., 1996). In the Mekong Delta of Vietnam, rodents can be infected with DOBV and SEOV with a positive rate of 6.9% (Van Cuong et al., 2015). There have also been studies claiming that selenium deficiency is correlated with increased prevalence of hantavirus infections in both humans and rodents (Fang LQ et al., 2015).
The distribution of pathogenic hantaviruses is expanding, and the differences between the “Old World” and “New World” viruses are gradually becoming less obvious. Technological advancements in molecular biology make it possible for investigators to rapidly search and characterize newly discovered hantaviruses. So far, more than 50 hantavirus strains have been identified, and 24 of those strains are of pathogenic relevance to humans (Table 2). Other hantaviruses may remain undetected, as infections are likely to go unreported in many areas, particularly in Africa, the Middle East, Central America, the Indian subcontinent, and Mongolia.
Virus isolate or strain Abbreviation Associated disease Rodent host Geographic distribution Amur virus (Zhang et al., 2013) AMRV HFRS Apodemus peninsulae Russia, China, Korea Dobrava-Belgrade virus (Papa, 2012) DOBV HFRS Apodemus flavicollis Europe (Balkans) Hantaan Virus (Jiang et al., 2016) HTNV HFRS Apodemus agrarius China, South Korea, Russia Puumala virus (Maes et al., 2004) PUUV HFRS/NE/HCPS Clethrionomys glareolus Myodes glareolus Europe (Finland) Saaremaa virus (Plyusnina et al., 2009a) SAAV HFRS/NE Apodemus agrarius Europe Seoul virus (Yao et al., 2012) SEOV HFRS Rattus norvegicus Worldwide Thailand hantavirus (Pattamadilok et al., 2006; Gamage et al., 2011) THAIV HFRS Bandicota indica Thailand Tula virus (Nikolic et al., 2014) TULV HFRS Microtus arvalis Europe Andes virus (Torres-Perez et al., 2016) ANDV HCPS Oligoryzomys longicaudatus Argentina, Chile Araraquara virus (de Araujo et al., 2015) ARAV HCPS Necromys lasiurus Brazil Bayou virus (Holsomback et al., 2013) BAYV HCPS Oryzomys palustris North America Bermejo virus (Padula et al., 2002) BMJV HCPS Oligoryzomys chacoensis Oligoryzomys flavescens Argentina, Bolivia Black Creek Canal virus (Knust and Rollin, 2013) BCCV HCPS Sigmodon hispidus North America Castelo Dos Sonhos virus (Firth et al., 2012) CASV HCPS Oligoryzomys spp.? Brazil Choclo virus (Nelson et al., 2010) CHOV HCPS Oligoryzomys fulvescens Panama Juquitiba virus (Figueiredo et al., 2014) JUQV HCPS Oligoryzomys nigripes Argentina, Brazil Laguna Negra Virus (Figueiredo et al., 2014) LANV HCPS Calomys callosus Argentina, Paraguay, Bolivia Lechiguanas virus (Guterres et al., 2015) LECV HCPS Oligoryzomys flavescens Argentina Maciel virus (Guterres et al., 2015) MCLV HCPS Bolomys obscurus Argentina Monongahela virus (Rhodes et al., 2000) MGLV HCPS Peromyscus leucopus North America Muleshoe virus (Rawlings et al., 1996) MULEV HCPS Sigmodon hispidus North America New York virus (Knust and Rollin, 2013) NYV HCPS Peromyscus leucopus North America Oran virus (Figueiredo et al., 2014) ORNV HCPS Oligoryzomys chacoensis Argentina Sin Nombre virus (Brocato et al., 2014) SNV HCPS Peromyscus maniculatus North America
Table 2. Geographic distribution of pathogenic hantaviruses
Many new strains of hantavirus have been identified with the discovery of the respective host species. Recent studies report that mites can transmit hantaviruses both by biting laboratory mice and vertically through the eggs to their offspring. However, transmission from mites to humans has not been reported (Yu and Tesh, 2014). Hantaviruses have also been found in novel hosts, such as bats (Zhang YZ, 2014), Cricetulus griseus (Fang LZ et al., 2015), the stripe-backed shrew (Zuo et al., 2014), brown rat (Guo et al., 2016), and other small mammals, including Asian house shrews and house mice. Some of these hosts are closely associated with humans and inhabit areas in and around homes in China. The epidemiological significance of these unconventional hosts has not yet been defined. However, the threat of hantaviruses is of major concern, as it has been detected in pet rats in the United Kingdom and in Sweden (McElhinney et al., 2016).
Some recently discovered hantaviruses, such as the Muju virus (MUJV) detected in the royal vole (also known as the Korean red-backed vole; Myodes regulus), and the Imjin (MJNV) and Jeju viruses (JJUV) in the shrew and bat, have been reported in Korea (Lee et al., 2014). The hantavirus genome referred to as the Asama virus (ASAV) has been detected in the Japanese shrew mole (Urotrichus talpoides) (Arai et al., 2008). Hantavirus sequences have also been recovered from an Asian house rat (Rattus tanezumi) captured in Indonesia (Plyusnina et al., 2009b). A bat-borne hantavirus (Xuan Son virus, XSV) has been reported in Vietnam (Arai et al., 2013). Since 2007, non-rodent hosts of hantaviruses (mainly shrews and moles) have been reported in Europe. Three distinct hantaviruses have also been discovered in wild rodents in Mexico. However, whether these viruses cause human disease remains unclear.
Hantavirus was first detected in Africa following PCR analysis in 2006. The virus was called the Sangassou virus (SANGV) and although the positive rate was relatively low, it was detected in the African wood mouse (Hylomyscus simus) in a forested habitat in Guinea, (Klempa et al., 2006). Since then, several other shrew-borne hantaviruses have been identified in Africa. For example, Tanganya virus (TGNV) was detected in Therese's shrew (Crocidura theresae); Azagny virus (AZGV), in the West African pygmy shrew (Crocidura obscurior) in C te d'Ivoire; and Bowé virus (BOWV), in Doucet's musk shrew (Crocidura douceti) in southwestern Guinea. Tigray virus (TIGV), the first hantavirus reported in Eastern Africa, was discovered in Ethiopia (Witkowski et al., 2014). With the exception of SANGV, which was first isolated in cell culture in 2012 (Klempa et al., 2012), the aforementioned species were all detected by PCR, and are not yet approved as new viral species (Witkowski et al., 2014).
New types of hantavirus are still being discovered in Africa. The host diversity of hantaviruses on the African continent has challenged the view that hantaviruses are predominantly rodent-borne viruses. Several shrew-borne, and the first bat-borne hantaviruses (Magboi virus, MGBV) have been reported in Africa. Kilimanjaro (KILV) and Uluguru viruses (ULUV) have been reported in shrews of the genus Myosorex (M. zinki and M. geata) in Tanzania. As natural reservoirs of hantaviruses, surveillance and monitoring of the bat population might facilitate efficient pathogen maintenance and spread, as bats can travel over comparatively longer distances (Weiss et al., 2012). The serological and ecological aspects, as well as the clinical significance of many viruses still need to be considered. However, evidence has emerged of human infections with shrew-borne hantaviruses in C te d'Ivoire and Gabon (Heinemann et al., 2016).