|Year : 2017 | Volume
| Issue : 2 | Page : 165-175
Globally emerging hantaviruses: An overview
Sara Chandy1, Dilip Mathai2
1 International Clinical Epidemiology Network (INCLEN), INCLEN Trust International, New Delhi, India
2 Apollo Medical College and Research Center, Hyderabad, Telangana, India
|Date of Web Publication||5-Jul-2017|
BASIS INCLEN Project Office, No. 42, New Tank Street, Nungambakkam, Chennai - - 600 034, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Hantaviruses are known to cause haemorrhagic fever with renal syndrome in Eurasia and hantavirus cardiopulmonary syndrome in the Americas. They are globally emerging pathogens as newer serotypes are routinely being reported. This review discusses hantavirus biology, clinical features and pathogenesis of hantavirus disease, its diagnostics, distribution and mammalian hosts. Hantavirus research in India is also summarised.
Keywords: Emerging, hantaviruses, rodent-borne
|How to cite this article:|
Chandy S, Mathai D. Globally emerging hantaviruses: An overview. Indian J Med Microbiol 2017;35:165-75
| ~ Introduction|| |
Globally, emerging zoonotic pathogens remain a serious public health problem. In this regard, hantaviruses have attracted a lot of attention as novel pathogenic serotypes are frequently being reported. Hantaviruses belong to family Bunyaviridae and are hosted by small mammals. Humans get infected by either inhaling virus-contaminated aerosols or through contact with the animal droppings. Haemorrhagic fever with renal syndrome (HFRS) in Asia and Europe and hantavirus cardiopulmonary syndrome (HCPS) in the Americas are two important clinical syndromes associated with hantavirus infections. 'Hantavirus disease/fever' may be an inclusive terminology since pathogenesis and clinical features of these syndromes overlap.
| ~ History|| |
The first hantavirus isolate, Thottapalayam virus (TPMV), was from the spleen of an insectivore, Suncus murinus, captured in Vellore (India) in 1964. The Asian hantavirus prototype, Hantaan virus (HTNV) was isolated in 1978 from an infected rodent and was named after the Han river basin where the rodent was caught. The name 'hantavirus' was proposed in 1985, by Schmaljohn, a pioneer in hantavirus research.
In 1993, there was an outbreak of a cardiopulmonary disease among young heathy individuals in the Four Corners region of Southwestern US (Mexico, Utah, Arizona and Colorado). Mortality was about 40%; the aetiological agent was a novel pathogenic hantavirus, Sin Nombre virus (SNV). This outbreak changed the history of hantaviruses, which till then were known to cause renal disease in Europe and Asia. Andes virus (ANDV), a South American serotype an isolate from human serum reportedly caused human-to-human transmission of HCPS in Peru at the turn of the 20th century. It was isolated from the serum of a patient.
In 2012, an outbreak of hantavirus infections occurred among visitors to the Yosemite National Park in California, USA. Investigations identified ten cases. Eight were HCPS cases, five required intensive care with ventilator support, and three died. An overnight stay in a signature tent cabin (nine case-patients) was significantly associated with hantavirus infection (P < 0.001).
The only known indigenous hantavirus species, TPMV, was isolated in Vellore, South India, from the spleen of an insectivore, S. murinus in 1964. Initially believed to be an arbovirus, TPMV joined the genus Hantavirus when it was found to have bunyavirus morphology and the signature 3' nucleotide sequence.
| ~ General Properties of Hantaviruses|| |
Hantaviruses are enveloped RNA viruses with a negative-sense, tri-segmented genome. The large (L), medium (M) and small (S) segments code for viral RNA-dependent-RNA polymerase, glycoprotein precursor (GPC) which is processed into the two envelope glycoproteins (Gn and Gc) and the nucleocapsid (N) protein, respectively.
Hantavirus N protein
Hantavirus N protein is the most abundant viral protein in the virion and infected cells. There is a strong and rapid immune response to this protein. The amino-terminus of the N protein comprising 100 amino acids is highly antigenic hence used in diagnostic assays. B-cell epitopes are located in the N-terminal region while T-cell epitopes are distributed randomly throughout the protein. Between different strains of given hantavirus serotype, the amino acid sequence of the N protein is generally conserved. Recombinant N protein can be commercially produced in Escherichia More Details coli, baculovirus and yeast expression systems. These recombinant proteins are increasingly being used in diagnostic assays in place of native proteins.,,
Surface glycoproteins G1 and G2 are expressed as a polyprotein precursor, GPC which are degraded by cellular proteases. These glycoproteins interact with surface receptors, β3 integrins and facilitate entry of hantaviruses.
| ~ Classification of Hantaviruses|| |
Hantaviruses are hosted by persistently infected rodents, insectivores and bats. Each hantavirus serotype appears to have a predominant natural mammal reservoir suggesting long-term co-evolution of the host and microbe.
Genus Hantavirus is roughly classified into two main groups based on the reservoir mammals.
While Old World hantaviruses circulate in Asia and Europe, New World hantaviruses are found in the Americas [Table 1]. They are hosted by mammals of families, Muridae (subfamily Murinae including Old World rats and mice) and Crecetidae (subfamilies Arvicolinae, Neotominae and Sigmodontinae including voles, lemmings and New World rats and Mice, respectively).
Old World hantaviruses are hosted by four rodent genera: Myodes, Microtus, Apodemus and Rattus and two insectivore families: Soridae and Talpidae [Figure 1].,
Phylogenetic analysis of the N protein classifies hantaviruses into four main groups:
- Group A: Murinae-borne species, HTNV, Seoul virus (SEOV), Thailand virus (THAIV) and Dobrava/Belgrade virus (DOBV) causing HFRS in Asia
- Group B: Arvicolinae-borne species such as Puumala virus (PUUV), aetiological agent of nephropathia epidemica (NE), a mild form of HFRS in Europe
- Group C: Sigmodontinae and Neotominae-borne species such as SNV, ANDV and others causing HCPS in the Americas
- Group D and E comprising shrew, mole and bat-borne species.
In the history of hantavirus research, TPMV holds a special place. It was the first-ever hantavirus to be isolated from a shrew (insectivore) captured in Vellore, South India in 1964. Initially believed to be an arbovirus, its identification belied the long-held view that hantaviruses are hosted only by rodents.
Little is known about hantavirus infections of shrew, mole and bat and their impact on human health.
| ~ Hantavirus-related Clinical Syndromes|| |
Haemorrhagic fever with renal syndrome
The clinical picture and severity of HFRS depend on the infecting species. Typically, the clinical course can be divided into five phases: febrile, hypotensive, oliguric, polyuric and convalescent.
An incubation period of 2–4 weeks is followed by a febrile phase lasting about 3–7 days, characterised by fever, headache, vomiting, abdominal pain, back and visual disturbances. Petechiae on the palate and conjunctival suffusion may be seen towards the end of this phase. The hypotensive (shock) phase can last from a few hours to 2 days. In severe cases, one-third of the deaths are associated with fulminant irreversible shock. Thrombocytopenia, leucocytosis and pronounced haemorrhagic manifestations are characteristic of this phase. Acute kidney injury (AKI) may cause death in the oliguric phase which lasts about 3–7 days. Patients with AKI usually need dialysis. Half of the fatalities occur during this phase. Serum creatinine and urea levels are elevated. Renal function recovery occurs during the polyuric phase. The onset of the diuretic phase is a positive prognostic sign. Convalescence can last up to 6 months. The clinical picture of HFRS in children may mimic that in adult but is less severe. Abdominal manifestations are reportedly common.,
Hantavirus cardiopulmonary syndrome
This is more severe than HFRS. A typical course of HCPS comprises three phases: prodromal, cardiopulmonary and convalescent. The prodromal stage is characterised by non-specific flu-like symptoms such as fever, chills, malaise, headache, vomiting, abdominal pain and diarrhoea. The clinical picture in the early stages of HCPS may be confused with other viral infections. The symptoms of the cardiopulmonary phase includes progressive cough, shortness of breath and tachycardia. Non-cardiac pulmonary oedema and hypotension are frequently seen in patients. Severe disease causes respiratory failure warranting mechanical ventilation. Complications of cardiogenic shock, lactic acidosis and haemoconcentration can cause death within hours of hospitalisation. Survivors enter the polyuric phase followed by resolution of the pulmonary oedema. Recovery is complete and sequelae, uncommon.,,
The traditional belief that HFRS affects the kidneys and HCPS the lungs is partially correct as recent studies indicate that these syndromes greatly overlap in their clinical presentation. HFRS with lung involvement and HCPS with renal and haemorrhagic manifestations have been reported.,
| ~ Laboratory Diagnosis|| |
Thrombocytopenia, leucocytosis, increased haematocrit, haematuria, proteinuria and serum creatinine are important laboratory findings in both HFRS and HCPS. Early signs being non-specific, clinical findings are not enough to diagnose hantavirus infections.
Serology is the mainstay of laboratory diagnosis of hantavirus infections. On onset of symptoms, almost all patients have detectable anti-hantavirus IgM and/or IgG levels. Indirect immunofluorescence assay (IFA) was the earliest diagnostic tests employing hantavirus-infected cells fixed on glass slides, as antigens. However, use of virus-infected cells as antigens is limited as the yield of hantaviruses in cell lines is low and can be performed only in biosafety level 3 laboratories.
Currently, serological assays employ recombinant hantavirus antigens. Indirect IgM and IgG enzyme-linked immunosorbent assays (ELISA) and IgM capture ELISA are commonly used for laboratory diagnosis., A high level of anti-N IgM is detectable at the onset of symptoms. N protein has been expressed and purified from bacterial, baculovirus, Saccharomyces spp. and insect cells. Apart from homologous assays, simultaneous detection of different clinically relevant hantaviruses can be done using a cocktail of antigens.,,, Antibody response against Gn and Gc protein are not of diagnostic significance as they arise later and are not conserved among different hantaviruses.
Immunochromatographic devices for rapid diagnosis of PUUV infection have been developed with baculovirus expressed N protein immobilised on nitrocellulose membrane. Immunoblot assays with superior specificity and sensitivity to ELISA have also been explored. Conventionally, focus reduction neutralisation test is employed for serological serotyping of infecting species.
HCPS is a rapidly progressing illness. Within 12–24 h, a patient can progress from the acute febrile phase to severe pneumonia, respiratory failure and cardiogenic shock. Severe HCPS and HFRS cases are associated with a high viral load. Hence, sensitive molecular techniques can be used for the diagnosis of severe cases before use of serological tools. Hantavirus genome can be detected by reverse transcriptase-polymerase chain reaction (PCR) on whole blood and/or serum samples collected during the acute phase. Primers from the high homologous regions in the N protein are used. A pan-hantavirus PCR targeting the conserved region of the L segment can detect known and novel hantaviruses., Real-time PCR is rapid and sensitive and can quantitate the viral load. However, PCR is useful only in the acute viremic phase. In particular cases, the viremic stage may be very short, and the genome may be missed by the most sensitive technique.,
Prospective evaluation of contacts of HCPS index cases has proved that quantitative PCR on whole blood samples was positive at least 10 days before onset of clinical symptoms. In cases with high pre-test probability (i.e., contacts of an index case), molecular tools are more sensitive than serological testing.
Isolation of hantaviruses is difficult as the yield is low and can be performed only in biosafety level three laboratories. Vero E6 clone is used for isolation.
In summary, a combination of molecular and serological testing is the prudent approach for laboratory diagnosis of hantavirus infections.
| ~ Pathogenesis|| |
Hantaviruses primarily infect macrophages and endothelial cells of capillaries of the lungs and kidneys., The disease process begins with inhalation of an aerosolised particle containing the pathogen. The hantaviral Gn and Gc surface proteins interact with the beta-3-integrin, the main receptor molecule present on the endothelial cells., Immature dendritic cells express β3 integrins and may have a role in the dissemination of hantaviruses.In vitro studies have shown that hantavirus replication in infected cells does not induce any cytopathic damage.,, A strong association between increased hantavirus load and disease severity has been established in HTNV, ANDV and DOBV infections.,, Hantaviruses upregulate production of vascular endothelial growth factor (VEGF), a vascular permeability agent. VGEF exerts its effects after binding to its receptor, VEGF-R2. VEGF-R2 interacts with VE-cadherin and together they maintain the endothelial cell barrier. When VEGF binds to VEGF-R2, it initiates the degradation of VE-cadherin expression and subsequent disruption of the endothelial barrier function.,
Toll-like receptors (TLRs) mediate innate immune response by triggering the release of inflammatory cytokines and type 1 interferon (IFN)., TLR2, TLR3, TLR4, TLR7 and TLR9 have been detected in HTNV-infected vascular endothelial cells. Upregulation of TLR4 may increase expression of tumor necrosis factor (TNF)-α, IFN-β and interleukin-6 (IL-6) in HFRS.
The pathogenesis of hantavirus disease is largely attributed to the overproduction of inflammatory cytokines or the 'cytokine storm.' Studies have reported copious production of molecules by macrophages, monocytes and lymphocytes in response to pro-inflammatory signals. Type I IFN- α /β regulate viral replication. Serum concentrations of TNF-α, IL-6, IFN-β, IL-8, IP-10 and RANTS were higher in HFRS patients than in controls., Highest concentrations were seen during the febrile, hypotensive and oliguric phases in severe HFRS. Investigators have suggested that TNF-α and IL-6 induce fever and septic shock and with IFN-β were responsible for increased permeability of endothelial cells.,,
Animal hantavirus studies have shown T-cell-related organ damage, but data from human infections on the role of T-cell-mediated immunopathogenesis is contradictory and unclear. In HCPS, hantavirus-specific T-cell response correlated with disease severity. In HFRS-related studies, different results have been reported. Few studies correlate increased innate and adaptive immunity to more severe disease. It is not clear whether a severe infection induces a severe immune response or the strong immune response by itself causes pathogenesis. It is also speculated that CD8+ T cells may be involved in the pathogenesis of hantavirus infections.,
HLA alleles can contribute to susceptibility to infection. Patients with HLA types B8 and DRB1 * 0301 had greater virus loads and greater chances of going into shock and requiring dialysis.,,
| ~ Reassortment of Hantaviruses|| |
Reassortment is an important strategy employed by segmented viruses to enhance survival and improve propagation. Reassortment can occur between genetically different strains of similar serotypes between related hantaviruses circulating among closely related rodent host species and rarely among distantly related species. When different animals share an ecological niche, spill-over infections may occur from natural reservoirs to non-specific animal hosts. Dual infections of reservoir host with different hantavirus species may result in reassortment. In vitro generated genetic reassortants between ANDV and SNV exhibited novel infectivity characteristics different from that seen in the parental strains.
| ~ Epidemiology of Hantavirus Infections|| |
Currently, about forty hantavirus species are known, of which 22 are considered pathogenic. Each of the species is hosted by an unique mammal and its geographical distribution closely reflects that of its host. Pathogenic species are hosted by rodents; those hosted by moles, shrews and bats are of doubtful pathogenicity [Figure 2]. Hosts get chronically infected, and despite the presence of neutralising antibodies, there is active replication of the virus. The host does not show any signs of illness, but the infection affects the lifespan of the host. High-reservoir host populations lead to increased hantavirus infection and transmission among the hosts. This inadvertently leads to increased human infections. Transmission among rodents and other hosts are horizontally through infighting and aggressive behaviour.,,,
Humans are considered dead-end hosts, they get accidentally infected by inhalation of aerosols generated from infected host excretions such as urine, faeces and saliva and occasionally through bites or scratches. The lethal outcome of intragastric administration of ANDV into Syrian hamsters may indicate possible transmission of hantaviruses through ingestion of contaminated food. ANDV is the only species for which person-to-person transmission has been documented. The outbreak of HCPS in the Four Corners Region in the United States in 1993 raised many rumors that the aetiological agent was a deadly virus that had escaped from a military laboratory involved in bioweapons research. The victims of HCPS were healthy young adults who succumbed to the viral infection. However, detailed scientific studies have proved that hantaviruses have a low potential as bioterrorist weapon.
| ~ Hantaviruses in Africa|| |
Seroepidemiological evidence of hantaviruses in Africa was first reported in 1984. Since then, the presence of hantavirus antibodies in humans, rodents, shrews and bats has been demonstrated from serosurveys in Egypt, Guinea, Djibouti, Nigeria and Senegal. The first African species, Sangassou virus was identified from the African wood mouse, Hylomyscus simus and has been isolated by cell culture. Retrospective studies on patients with fever of unknown origin from Sangoussou village in Guinea have indicated a seropositivity of 4.4% (3 patients of 68). The first bat-borne hantavirus was also identified in Africa.
| ~ Hantaviruses in the Americas|| |
The history of hantaviruses in the Americas began with the outbreak of an unknown acute respiratory disease in the Four Corners Region of the USA in 1993. A new clinical syndrome, HCPS, with a high fatality rate was recognised. Since then, more than 4000 cases have been reported from Canada, Panama and Brazil, Argentina, Bolivia, Chile, Paraguay and Uruguay in South America.,,, About thirty hantavirus species, of which fifteen are pathogenic, are recognised as circulating in the Americas. SNV, the primary aetiologic agent of hantavirus pulmonary syndrome in North America, is hosted by deer mice, Peromyscus maniculatus. About 500 human hantavirus cases have been reported from the United States up to late 2009, most of them from Arizona, Colorado and New Mexico. 63% of the cases were male.
Human hantavirus infections occur following contact with secretions or excretions from infected rodents. They occur more frequently in men; the male-female ratio is variable in different geographical locations., Hantavirus survival in the environment is crucial for its transmission. Factors which affect its survival are temperature, humidity, UV exposure, sunlight and organic material from the infected host. HCPS was initially described as a rural disease, very few infections occur in the suburban habitat where humans encounter P. maniculatus. Most HCPS infections are acquired around peridomestic settings, 10% at the workplace, 5% at recreational spots and few are unknown encounters. Rodents enter uninhabited human dwellings and contaminated droppings; urine and nesting material can be a source of infection. Attempts to clean such dwellings without personal protective equipment lead to inhalation of aerosolised particulates and thereby infection. Rodent bites infrequently transmit infection.,
In Central America, the first outbreak of hantavirus infections occurred in Panama in 1999–2000.
By 2010, there were over 100 human infections with mortality rate of 26%. The male to female ratio was 1.2:1. In South America, ANDV is the primary aetiologic agent. In Chile, over 600 cases of ANDV-related hantaviruses have been reported between 2001 and 2009 with a case fatality rate of 36%. All ethnic and racial groups are equally susceptible to hantavirus infections. In Central and South America, rural communities were at the highest risk of acquiring hantavirus infections. Person-to-person transmission has been documented during a ANDV outbreak in Argentina in 1998.,
| ~ Hantaviruses in Eurasia|| |
History of HFRS began with an outbreak during the Korean War (1951–1954) which affected almost 3000 soldiers. Two decades later, the aetiological agent, HTNV, was isolated. Most hantavirus infections occur in Asia specifically China and South Korea. In 2010, China reported more than 11,000 HFRS cases, Russia reported 89,000 cases from 1996 to 2006 and about 500 cases get reported from Korea Serological evidence of hantavirus disease has been documented in Singapore, Vietnam, Thailand, Sri Lanka and India, but the burden of disease in these countries remains unknown.
HTNV, Amur virus (AMRV), Soochong virus (SOOV) and SEOV viruses are circulating in Asia. Severe HFRS with mortality rate of 15% is caused by HTNV, SOOV and AMRV. Rat-borne SEOV virus is global in circulation and causes mild HFRS with a low case fatality rate of 1%–2%. Bandicoot-borne THAIV and Rattus-borne Serang virus (SERV) virus have been circulate in Thailand and Indonesia and have been detected in the animal hosts by molecular techniques. However, there exists only serological evidence of human disease caused by these Asian species.
Vole-borne Muju virus identified in the Korean red-backed vole may cause HFRS. Antibodies to TPMV from a patient with fever of unknown aetiology in Thailand may indicate pathogenic potential. The pathogenicity of newly discovered shrew and bat-borne hantaviruses, Imjin virus and Jeju virus in Korea, needs to be established.,
In Europe, PUUV causes majority of infections. PUUV is hosted by, Myodes glareolus which habitats throughout Europe. It causes a mild form of HFRS, NE. PUUV infections have been reported from Finland, Sweden, Norway, France, Hungary, Austria, the Balkan countries and European Russia. DOBV hosted by Apodemus flavicollis, causes HFRS in the Balkans, Russia and Denmark. SAAV identified in field mice, Apodemus agrarius, causes human disease in Russia, Germany and Slovakia.,,,,,,,,,,
| ~ Epizootiology of Old World and New World Hantaviruses|| |
Hantaviruses are transmitted to humans by small mammals that act as natural reservoir hosts. Rodents were considered primary reservoir of hantaviruses. However, at the turn of the century research on hantavirus hosts have added insectivores and even bats to the list of reservoir hosts. The ecology and geographical distribution of hantaviruses closely resembles that of its host. Hantaviruses are usually associated with a single-host reservoir and they coevolve together. Hantaviruses detected in larger animals such as moose, red fox, dog and the domestic cat are spillover infections without any risk of human infection. Spillover infections favor natural reassortment and origin of novel hantavirus species. Man is a dead-end host in the hantavirus life cycle. In the host, the pathogen establishes an inapparent, persistent infection without any clinical disease. However, poorer host survival, lower growth of infected animals and presence of histopathological evidence of infection in the hosts indicate the impact of infection.,
History of hantaviruses begin in Asia. Hantaviruses circulating in Europe and Asia are designated as 'Old World hantaviruses.' HFRS is the most common hantavirus disease in Asia. The isolation of the prototype, HTNV from the striped field mouse, A. agrarius in 1976 set the stage for discovery of HFRS causing hantaviruses and their reservoir hosts. Old World hantaviruses are hosted by four rodent genera: Myodes (voles), Microtus, Apodemus (mice) and Rattus (rats and bandicoots) and two insectivore families: Soridae and Talpidae. Hantavirus species hosted by Old World Apodemus species include HTNV, AMRV, SOOV cause severe HFRS in Far East Russia, China and South Korea. The European Apodemus mice host a range of hantavirus species. Severe HFRS in Slovenia and the Balkan regions is caused by Dobrava virus hosted by Apodemus flavicollis. Tula virus, a DOBV-like virus, was recovered from. Rat-borne hantaviruses include Rattus norvegicus harbours SEOV, R. rattus hosts Gou virus in China and R. tanezumi carries SERV in Southeast Asia. The bandicoot rats, Bandicota indica and Bandicota saveili are known to harbor THAIV. Bank voles, M. glareolus are distributed throughout most of Europe and are the common rodent reservoirs for hantaviruses. PUUV causing NE is carried by these rodents.,,
The recognition of HCPS in Northwestern US IN 1993 and identification of its aetiological agent, SNV from (P. maniculatus) was a landmark event in the history of New World hantaviruses. New York virus, Monongahela virus, Black Creek Canal virus and Bayou virus are Sigmodontinae (New World rats and mice) - associated, pathogenic North American New World hantaviruses from harbored by Peromyscus leucopus (white-footed mouse), P. maniculatus (deer mice), Oryzomys palustris (the marsh rice rat) and Sigmodon hispidus (cotton rat), respectively.,,,,
In Central America, Choclo virus causes HCPS in Panama. In South America, the diversity and distribution of pathogenic hantavirus is complex. The pathogenic serotypes are Lechiguanas hosted by Oligoryzomys flavescens (rice rat), ANDV and Oran virus hosted by Oligoryzomys longicaudatus (long-tailed mouse) and Laguna Negra virus hosted by Calomys laucha (vesper mouse).,
HFRS epidemics and HCPS outbreaks correlate with increased rodent populations. There are many reasons for rodent population increase. In temperate regions of Europe, rodent populations peak during mast years. A mast year indicates time periods of abundant availability of forest nuts for rodents. Rodent peaks can be predicted by high summer temperatures of 2 years previous and high autumn temperatures 1 year before the mast year. In the non-mast years, there is modest variations of rodent populations which may not guarantee efficient transmission of the pathogen. Studies from China have proved that a good harvest, low rainfall and flooding favor indiscriminate breeding of field mice. Studies from North America suggest that precipitation can increase rodent populations and thereby hantavirus infections. The complex dynamics of the environment-reservoir-virus is maintained not only by climate but also by the reservoir microhabitat and host macrohabitat.
| ~ Treatment of Hantavirus Infections|| |
There are no specific antiviral drugs for treatment of hantavirus infections. Ribavirin (1-β-D-ribofuranosyl-1, 2, 4-triazole-3-carboxamide) has exhibited some in vivo and in vitro effects against replication of hantaviruses. However, it remains ineffective for the treatment of HCPS. Supportive therapy is the best method to control progression towards life-threatening symptoms. Careful fluid management, electrolyte balance and haemodynamic monitoring are the best options for supportive therapy of HFRS and HCPS patients.,,,
| ~ Hantavirus Research in India|| |
Almost four decades later, in 2005, the first hospital-based study on hantavirus infections in India was reported and suggested that hantaviruses may cause symptomatic and asymptomatic infections. Commercial laboratory assays, ELISA and IFA were employed for diagnosis. Nausea, vomiting, myalgia, headache and hepatomegaly were the prominent clinical signs and symptoms seen among the seropositive patients. Thrombocytopenia was seen in about three-fourths of the seropositive patients while only half of those had leucocytosis and elevated liver enzymes. The second hospital-based study on hantavirus infections defined serological evidence of hantavirus infections as seropositivity for IgM (by ELISA and IFA) and IgG (by ELISA and IFA) in acute samples or significant difference in IgG titre between acute phase and convalescent-phase samples or demonstration of hantavirus RNA in patients' sample. Of 347 samples tested for anti-hantavirus IgM, Of the 78, only 18 (5.2%) of the patients showed serological evidence of hantavirus infection according to the study criteria. Hantavirus-specific IgM was detected as early as 3 days after onset of illness. Mean age of patients with evidence of hantavirus infections was 39 ± 15.8. The partial S sequences was obtained from 6 (2.3%) of 266 patients and had a homology of 84%–98.5% with HTNV. The cases were distributed in the early part of the year and in autumn coinciding with the cooler and rainy months of the year.,,,
Close on the heels of this report, SEOV-like and PUUV-like infections were reported from patients presenting with leptospirosis-like illness from Chennai and Kochi.
A seroprevalence study conducted on risk groups (Irulas, chronic renal patients and godown workers) and blood donors indicated a low prevalence of hantavirus infections in India (4%). Among the risk groups, Irulas displayed a high hantavirus specific-IgG seropositivity (11%) when compared to the blood donor control group (4%, P < 0.05). The renal disease patient group had a higher seropositivity (7%) compared to the blood donor control group. Eighty percent of the seropositives were from Eastern and Northeastern India. Warehouse workers showed a low seropositivity in this study (2%).
The reactivity pattern of serotyping suggests the presence of more than a single novel hantavirus species in India: Thailand-like virus and one or more HTNV-like unknown serotype.
Wild indigenous small mammals (n = 83, bandicoot and black rats, house mice and a shrew) captured from multiple sites in Vellore, South India, were tested. HTNV IFA followed by THAIV-WB confirmed hantavirus-reactive antibodies in nine rodents (rats and bandicoots). This study documented the first laboratory evidence for rodent-associated hantaviruses in South India.
| ~ Hantaviruses Causing Acute Undifferentiated Fever in India (Unpublished Data)|| |
An acute undifferentiated fever (AUF) study was conducted from April 2011 to November 2012 on patients aged >5 years admitted with AUF for 2–14 days from five secondary hospitals located at Ambur and Oddanchatram in Tamil Nadu, Anantapur in Andhra Pradesh, Ratnagiri in Maharashtra and Tezpur in Assam. Blood samples were tested for hantavirus aetiology using two in-house ELISA systems employing N antigen. A commercial ELISA using a cocktail of hantavirus antigens was used as a confirmatory assay. Seropositivity in Tamil Nadu, Assam, Maharashtra and Andhra Pradesh, was 2.5%, 3.9%, 5.5% and 6.5%, respectively.
| ~ Thottapalayam Virus: the Only Known Hantavirus from India|| |
TPMV was believed to be an arbovirus till it was characterised as a hantavirus by its ultrastructural features. Antigenic and genetic characteristics of TPMV have been compared to that of other known hantaviruses., However, very little is known about the biology, pathogenicity and natural host of TPMV though its isolation predates that of the prototype HTNV.
Antigenic analysis has shown that antisera prepared against HTNV, SEOV, THAIV and PUUV have a 16-fold or lower titre to TPMV antigen than to the homologous antigens. Among the hantaviruses, TPMV is the only one that does not show cross-neutralisation with other serotypes. Heterologous antisera do not neutralise TPMV and anti-TPMV sera do not neutralise any of the other hantaviruses. Nucleotide analysis of the whole S and L segment of TPMV reveals the genetic divergence of TPMV from other hantavirus members.,
Anti-TPMV was detected in a patient with acute febrile illness in Thailand and in two shrews captured in Indonesia. The presence of TPMV IgG antibodies in the patient gives the impression that TPMV may be a human pathogen and S. murinus its natural rodent host.
The analysis of the TPMV S (1530 nucleotides long) genome segment sequence and the newly derived M (3621 nt) and L (6581 nt) segment sequences also proves that the entire TPMV genome is very unique. TPMV S, M and L RNA segments differ from other hantaviruses by 44.2%–47.1%, 46.8%–49.2% and 37.0%–38.0%, respectively. Amino acid divergence for the N, glycoproteins and L proteins between TPMV and other hantaviruses range from 50.8% to 54.5%, 54.9%–57.2% and 37.6%–38.9%, respectively.
| ~ Conclusion|| |
Hantaviruses have a widespread geographical distribution. However, no hantavirus case has been reported from India which is the place of origin of one of the most divergent hantaviruses, the TPMV. The absence of detailed studies on hantaviruses in India is due to many reasons, such as the absence of diagnostic kits which even if available, are exorbitantly priced and the lack of awareness among clinicians. New World hantaviruses are often described as a bioterror weapons; this obstructs productive intercountry collaborations between laboratories willing to pursue hantavirus research. Some of the serotypes such as DOBV in Asia and SNV in America cause serious infections while others such as the SEOV and PUUV cause mild infections which often go unnoticed. The protean clinical manifestations of hantavirus infections could result in cases either being misdiagnosed or ignored in case of mild disease with non-specific symptoms. Zoonotic diseases often go unnoticed unless there is an outbreak as in the Four Corners Region in 1993. Future research based on the present work includes characterisation of the circulating species, extensive study of possible rodent reservoirs in India and development of more cost-effective and user-friendly diagnostic tools (serological and molecular) for rapid diagnosis of hantavirus infections in humans.
Sara Chandy carried out this review as part of the postdoctoral fellowship (2012–2015) provided by the University Grants Commission.
Financial support and sponsorship
This study was supported by the University Grants Commission postdoctoral fellowship (2012–2015).
Conflicts of interest
There are no conflicts of interest.
| ~ References|| |
Clement J, Maes P, Lagrou K, Van Ranst M, Lameire N. A unifying hypothesis and a single name for a complex globally emerging infection: Hantavirus disease. Eur J Clin Microbiol Infect Dis 2012;31:1-5.
Carey DE, Reuben R, Panicker KN, Shope RE, Myers RM. Thottapalayam virus: A presumptive arbovirus isolated from a shrew in India. Indian J Med Res 1971;59:1758-60.
Lee HW, Lee PW, Johnson KM. Isolation of the etiologic agent of Korean hemorrhagic fever 1978. J Infect Dis 2004;190:1711-21.
Nichol ST, Spiropoulou CF, Morzunov S, Rollin PE, Ksiazek TG, Feldmann H, et al.
Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science 1993;262:914-7.
Núñez JJ, Fritz CL, Knust B, Buttke D, Enge B, Novak MG, et al.
Hantavirus infections among overnight visitors to Yosemite National Park, California, USA, 2012. Emerg Infect Dis 2014;20:386-93.
Kaukinen P, Vaheri A, Plyusnin A. Hantavirus nucleocapsid protein: A multifunctional molecule with both housekeeping and ambassadorial duties. Arch Virol 2005;150:1693-713.
Lundkvist A, Björsten S, Niklasson B, Ahlborg N. Mapping of B-cell determinants in the nucleocapsid protein of Puumala virus: Definition of epitopes specific for acute immunoglobulin G recognition in humans. Clin Diagn Lab Immunol 1995;2:82-6.
Plyusnin A. Genetics of hantaviruses: Implications to taxonomy. Arch Virol 2002;147:665-82.
Yoshimatsu K, Arikawa J. Antigenic properties of N protein of hantavirus. Viruses 2014;6:3097-109.
Yoshimatsu K, Arikawa J. Serological diagnosis with recombinant N antigen for hantavirus infection. Virus Res 2014;187:77-83.
McCaughey C, Hart CA. Hantaviruses. J Med Microbiol 2000;49:587-99.
Krüger DH, Ulrich R, Lundkvist AA. Hantavirus infections and their prevention. Microbes Infect 2001;3:1129-44.
Jonsson CB, Hooper J, Mertz G. Treatment of hantavirus pulmonary syndrome. Antiviral Res 2008;78:162-9.
Enria DA, Briggiler AM, Pini N, Levis S. Clinical manifestations of new world hantaviruses. Curr Top Microbiol Immunol 2001;256:117-34.
Hjelle B, Goade D, Torrez-Martinez N, Lang-Williams M, Kim J, Harris RL, et al.
Hantavirus pulmonary syndrome, renal insufficiency, and myositis associated with infection by Bayou hantavirus. Clin Infect Dis 1996;23:495-500.
Kanerva M, Paakkala A, Mustonen J, Paakkala T, Lahtela J, Pasternack A. Pulmonary involvement in nephropathia epidemica: Radiological findings and their clinical correlations. Clin Nephrol 1996;46:369-78.
Bi Z, Formenty PB, Roth CE. Hantavirus infection: A review and global update. J Infect Dev Ctries 2008;2:3-23.
Brummer-Korvenkontio M, Vaheri A, Hovi T, von Bonsdorff CH, Vuorimies J, Manni T, et al.
Nephropathia epidemica: Detection of antigen in bank voles and serologic diagnosis of human infection. J Infect Dis 1980;141:131-4.
Elgh F, Lundkvist A, Alexeyev OA, Stenlund H, Avsic-Zupanc T, Hjelle B, et al.
Serological diagnosis of hantavirus infections by an enzyme-linked immunosorbent assay based on detection of immunoglobulin G and M responses to recombinant nucleocapsid proteins of five viral serotypes. J Clin Microbiol 1997;35:1122-30.
Kallio-Kokko H, Lundkvist A, Plyusnin A, Avsic-Zupanc T, Vaheri A, Vapalahti O. Antigenic properties and diagnostic potential of recombinant Dobrava virus nucleocapsid protein. J Med Virol 2000;61:266-74.
Jonsson CB, Gallegos J, Ferro P, Severson W, Xu X, Schmaljohn CS. Purification and characterization of the Sin Nombre virus nucleocapsid protein expressed in Escherichia coli
. Protein Expr Purif 2001;23:134-41.
Vapalahti O, Lundkvist A, Kallio-Kokko H, Paukku K, Julkunen I, Lankinen H, et al.
Antigenic properties and diagnostic potential of Puumala virus nucleocapsid protein expressed in insect cells. J Clin Microbiol 1996;34:119-25.
Manigold T, Vial P. Human hantavirus infections: Epidemiology, clinical features, pathogenesis and immunology. Swiss Med Wkly 2014;144:w13937.
Hujakka H, Koistinen V, Eerikäinen P, Kuronen I, Mononen I, Parviainen M, et al.
New immunochromatographic rapid test for diagnosis of acute Puumala virus infection. J Clin Microbiol 2001;39:2146-50.
Ferres M, Vial P, Marco C, Yanez L, Godoy P, Castillo C, et al.
Prospective evaluation of household contacts of persons with hantavirus cardiopulmonary syndrome in chile. J Infect Dis 2007;195:1563-71.
Peters CJ, Simpson GL, Levy H. Spectrum of hantavirus infection: Hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Annu Rev Med 1999;50:531-45.
Saksida A, Duh D, Korva M, Avsic-Zupanc T. Dobrava virus RNA load in patients who have hemorrhagic fever with renal syndrome. J Infect Dis 2008;197:681-5.
Krüger DH, Schönrich G, Klempa B. Human pathogenic hantaviruses and prevention of infection. Hum Vaccin 2011;7:685-93.
Kramski M, Meisel H, Klempa B, Krüger DH, Pauli G, Nitsche A. Detection and typing of human pathogenic hantaviruses by real-time reverse transcription-PCR and pyrosequencing. Clin Chem 2007;53:1899-905.
Kruger DH, Figueiredo LT, Song JW, Klempa B. Hantaviruses – Globally emerging pathogens. J Clin Virol 2015;64:128-36.
Hughes JM, Peters CJ, Cohen ML, Mahy BW. Hantavirus pulmonary syndrome: An emerging infectious disease. Science 1993;262:850-1.
Gavrilovskaya IN, Brown EJ, Ginsberg MH, Mackow ER. Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by beta3 integrins. J Virol 1999;73:3951-9.
Gavrilovskaya IN, Peresleni T, Geimonen E, Mackow ER. Pathogenic hantaviruses selectively inhibit beta3 integrin directed endothelial cell migration. Arch Virol 2002;147:1913-31.
Peebles RS Jr., Graham BS. Viruses, dendritic cells and the lung. Respir Res 2001;2:245-9.
Kim S, Kang ET, Kim YG, Han JS, Lee JS, Kim YI, et al.
Localization of Hantaan viral envelope glycoproteins by monoclonal antibodies in renal tissues from patients with Korean hemorrhagic fever H. Am J Clin Pathol 1993;100:398-403.
Zaki SR, Greer PW, Coffield LM, Goldsmith CS, Nolte KB, Foucar K, et al.
Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. Am J Pathol 1995;146:552-79.
Terajima M, Hayasaka D, Maeda K, Ennis FA. Immunopathogenesis of hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome: Do CD8+T cells trigger capillary leakage in viral hemorrhagic fevers? Immunol Lett 2007;113:117-20.
Xiao R, Yang S, Koster F, Ye C, Stidley C, Hjelle B. Sin Nombre viral RNA load in patients with hantavirus cardiopulmonary syndrome. J Infect Dis 2006;194:1403-9.
Yi J, Xu Z, Zhuang R, Wang J, Zhang Y, Ma Y, et al.
Hantaan virus RNA load in patients having hemorrhagic fever with renal syndrome: Correlation with disease severity. J Infect Dis 2013;207:1457-61.
Wang W, Zhang Y, Li Y, Pan L, Bai L, Zhuang Y, et al.
Dysregulation of the ğ3 integrin-VEGFR2 complex in Hantaan virus-directed hyperpermeability upon treatment with VEGF. Arch Virol 2012;157:1051-61.
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783-801.
Beutler BA. TLRs and innate immunity. Blood 2009;113:1399-407.
Jiang H, Wang PZ, Zhang Y, Xu Z, Sun L, Wang LM, et al.
Hantaan virus induces toll-like receptor 4 expression, leading to enhanced production of beta interferon, interleukin-6 and tumor necrosis factor-alpha. Virology 2008;380:52-9.
Vaheri A, Strandin T, Hepojoki J, Sironen T, Henttonen H, Mäkelä S, et al.
Uncovering the mysteries of hantavirus infections. Nat Rev Microbiol 2013;11:539-50.
Wang PZ, Li ZD, Yu HT, Zhang Y, Wang W, Jiang W, et al.
Elevated serum concentrations of inflammatory cytokines and chemokines in patients with haemorrhagic fever with renal syndrome. J Int Med Res 2012;40:648-56.
Linderholm M, Ahlm C, Settergren B, Waage A, Tärnvik A. Elevated plasma levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptors, interleukin (IL)-6, and IL-10 in patients with hemorrhagic fever with renal syndrome. J Infect Dis 1996;173:38-43.
Hayasaka D, Maeda K, Ennis FA, Terajima M. Increased permeability of human endothelial cell line EA.hy926 induced by hantavirus-specific cytotoxic T lymphocytes. Virus Res 2007;123:120-7.
Gavrilovskaya IN, Gorbunova EE, Mackow NA, Mackow ER. Hantaviruses direct endothelial cell permeability by sensitizing cells to the vascular permeability factor VEGF, while angiopoietin 1 and sphingosine 1-phosphate inhibit hantavirus-directed permeability. J Virol 2008;82:5797-806.
Terajima M, Ennis FA. T cells and pathogenesis of hantavirus cardiopulmonary syndrome and hemorrhagic fever with renal syndrome. Viruses 2011;3:1059-73.
Temonen M, Mustonen J, Helin H, Pasternack A, Vaheri A, Holthöfer H. Cytokines, adhesion molecules, and cellular infiltration in nephropathia epidemica kidneys: An immunohistochemical study. Clin Immunol Immunopathol 1996;78:47-55.
Mäkelä S, Mustonen J, Ala-Houhala I, Hurme M, Partanen J, Vapalahti O, et al.
Human leukocyte antigen-B8-DR3 is a more important risk factor for severe Puumala hantavirus infection than the tumor necrosis factor-alpha(–308) G/A polymorphism. J Infect Dis 2002;186:843-6.
Mustonen J, Partanen J, Kanerva M, Pietilä K, Vapalahti O, Pasternack A, et al.
Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus. Kidney Int 1996;49:217-21.
Plyusnin A, Hörling J, Kanerva M, Mustonen J, Cheng Y, Partanen J, et al.
Puumala hantavirus genome in patients with nephropathia epidemica: Correlation of PCR positivity with HLA haplotype and link to viral sequences in local rodents. J Clin Microbiol 1997;35:1090-6.
Guo WP, Lin XD, Wang W, Tian JH, Cong ML, Zhang HL, et al.
Phylogeny and origins of hantaviruses harbored by bats, insectivores, and rodents. PLoS Pathog 2013;9:e1003159.
Rizvanov AA, Khaiboullina SF, St. Jeor S. Development of reassortant viruses between pathogenic hantavirus strains. Virology 2004;327:225-32.
Kallio ER, Voutilainen L, Vapalahti O, Vaheri A, Henttonen H, Koskela E, et al.
Endemic hantavirus infection impairs the winter survival of its rodent host. Ecology 2007;88:1911-6.
Olsson GE, Dalerum F, Hörnfeldt B, Elgh F, Palo TR, Juto P, et al.
Human hantavirus infections, Sweden. Emerg Infect Dis 2003;9:1395-401.
Torres-Perez F, Wilson L, Collinge SK, Harmon H, Ray C, Medina RA, et al.
Sin Nombre virus infection in field workers, Colorado, USA. Emerg Infect Dis 2010;16:308-10.
Merino AC, Arias AA, Castillo HC. First case of hantavirus cardiopulmonary syndrome occurring after a rodent bite. Rev Chil Enferm Respir 2002;18:199-205.
Hooper JW, Ferro AM, Wahl-Jensen V. Immune serum produced by DNA vaccination protects hamsters against lethal respiratory challenge with Andes virus. J Virol 2008;82:1332-8.
Jonsson CB, Figueiredo LT, Vapalahti O. A global perspective on hantavirus ecology, epidemiology, and disease. Clin Microbiol Rev 2010;23:412-41.
Witkowski PT, Klempa B, Ithete NL, Auste B, Mfune JK, Hoveka J, et al.
Hantaviruses in Africa. Virus Res 2014;187:34-42.
Vincent MJ, Quiroz E, Gracia F, Sanchez AJ, Ksiazek TG, Kitsutani PT, et al.
Hantavirus pulmonary syndrome in Panama: Identification of novel hantaviruses and their likely reservoirs. Virology 2000;277:14-9.
Armién AG, Armién B, Koster F, Pascale JM, Avila M, Gonzalez P, et al.
Hantavirus infection and habitat associations among rodent populations in agroecosystems of Panama: Implications for human disease risk. Am J Trop Med Hyg 2009;81:59-66.
Bellomo C, Nudelman J, Kwaszka R, Vazquez G, Cantoni G, Weinzettel B, et al.
Geographic expansion of hantavirus pulmonary syndrome in Argentina. The southernest case report. Medicina (B Aires) 2009;69:647-50.
Figueiredo LT, Moreli ML, de-Sousa RL, Borges AA, de-Figueiredo GG, Machado AM, et al.
Hantavirus pulmonary syndrome, central plateau, southeastern, and Southern Brazil. Emerg Infect Dis 2009;15:561-7.
Sotomayor PV, Olea NA, Labraña AM, Castillo HC, Ortega RC, Riquelme OR, et al.
Diagnosis and treatment of cardiopulmonary hantavirus syndrome: Chile-2007. Rev Chilena Infectol 2009;26:68-86.
Ferrer JF, Galligan D, Esteban E, Rey V, Murua A, Gutierrez S, et al.
Hantavirus infection in people inhabiting a highly endemic region of the Gran Chaco territory, Paraguay: Association with Trypanosoma cruzi
infection, epidemiological features and haematological characteristics. Ann Trop Med Parasitol 2003;97:269-80.
Douglass RJ, Semmens WJ, Matlock-Cooley SJ, Kuenzi AJ. Deer mouse movements in peridomestic and sylvan settings in relation to Sin Nombre virus antibody prevalence. J Wildl Dis 2006;42:813-8.
Kuenzi AJ, Douglass RJ, White D Jr., Bond CW, Mills JN. Antibody to Sin Nombre virus in rodents associated with peridomestic habitats in west central Montana. Am J Trop Med Hyg 2001;64:137-46.
Gonzalez LM, Lindsey AE, Hjelle B, Dominguez D, Brown J, Goade D, et al.
Prevalence of antibodies to Sin Nombre virus in humans living in rural areas of Southern New Mexico and western Texas. Virus Res 2001;74:177-9.
Pini N, Levis S, Calderón G, Ramirez J, Bravo D, Lozano E, et al.
Hantavirus infection in humans and rodents, Northwestern Argentina. Emerg Infect Dis 2003;9:1070-6.
Zhang YZ, Zou Y, Fu ZF, Plyusnin A. Hantavirus infections in humans and animals, China. Emerg Infect Dis 2010;16:1195-203.
Pattamadilok S, Lee BH, Kumperasart S, Yoshimatsu K, Okumura M, Nakamura I, et al.
Geographical distribution of hantaviruses in Thailand and potential human health significance of Thailand virus. Am J Trop Med Hyg 2006;75:994-1002.
Plyusnina A, Ibrahim IN, Plyusnin A. A newly recognized hantavirus in the Asian house rat (Rattus tanezumi
) in Indonesia. J Gen Virol 2009;90(Pt 1):205-9.
Okumura M, Yoshimatsu K, Kumperasart S, Nakamura I, Ogino M, Taruishi M, et al.
Development of serological assays for Thottapalayam virus, an insectivore-borne Hantavirus. Clin Vaccine Immunol 2007;14:173-81.
Song KJ, Baek LJ, Moon S, Ha SJ, Kim SH, Park KS, et al.
Muju virus, a novel hantavirus harboured by the arvicolid rodent Myodes regulus
in Korea. J Gen Virol 2007;88(Pt 11):3121-9.
Song JW, Kang HJ, Song KJ, Truong TT, Bennett SN, Arai S, et al.
Newfound hantavirus in Chinese mole shrew, Vietnam. Emerg Infect Dis 2007;13:1784-7.
Vapalahti O, Mustonen J, Lundkvist A, Henttonen H, Plyusnin A, Vaheri A. Hantavirus infections in Europe. Lancet Infect Dis 2003;3:653-61.
Heyman P, Vaheri A, Lundkvist A, Avsic-Zupanc T. Hantavirus infections in Europe: From virus carriers to a major public-health problem. Expert Rev Anti Infect Ther 2009;7:205-17.
Vapalahti O, Lundkvist A, Kukkonen SK, Cheng Y, Gilljam M, Kanerva M, et al.
Isolation and characterization of Tula virus, a distinct serotype in the genus Hantavirus, family Bunyaviridae
. J Gen Virol 1996;77(Pt 12):3063-7.
Klempa B, Meisel H, Räth S, Bartel J, Ulrich R, Krüger DH. Occurrence of renal and pulmonary syndrome in a region of northeast Germany where Tula hantavirus circulates. J Clin Microbiol 2003;41:4894-7.
Heyman P, Ceianu CS, Christova I, Tordo N, Beersma M, João Alves M, et al.
A five-year perspective on the situation of haemorrhagic fever with renal syndrome and status of the hantavirus reservoirs in Europe, 2005-2010. Euro Surveill 2011;16. pii: 19961.
Antoniadis A, Stylianakis A, Papa A, Alexiou-Daniel S, Lampropoulos A, Nichol ST, et al.
Direct genetic detection of Dobrava virus in Greek and Albanian patients with hemorrhagic fever with renal syndrome. J Infect Dis 1996;174:407-10.
Avsic-Zupanc T, Petrovec M, Furlan P, Kaps R, Elgh F, Lundkvist A. Hemorrhagic fever with renal syndrome in the Dolenjska region of Slovenia – A 10-year survey. Clin Infect Dis 1999;28:860-5.
Lundkvist A, Hukic M, Hörling J, Gilljam M, Nichol S, Niklasson B. Puumala and Dobrava viruses cause hemorrhagic fever with renal syndrome in Bosnia-Herzegovina: Evidence of highly cross-neutralizing antibody responses in early patient sera. J Med Virol 1997;53:51-9.
Markotic A, Nichol ST, Kuzman I, Sanchez AJ, Ksiazek TG, Gagro A, et al.
Characteristics of Puumala and Dobrava infections in Croatia. J Med Virol 2002;66:542-51.
Papa A, Johnson AM, Stockton PC, Bowen MD, Spiropoulou CF, Alexiou-Daniel S, et al.
Retrospective serological and genetic study of the distribution of hantaviruses in Greece. J Med Virol 1998;55:321-7.
Sibold C, Meisel H, Lundkvist A, Schulz A, Cifire F, Ulrich R, et al.
Short report: Simultaneous occurrence of Dobrava, Puumala, and Tula Hantaviruses in Slovakia. Am J Trop Med Hyg 1999;61:409-11.
Childs JE, Ksiazek TG, Spiropoulou CF, Krebs JW, Morzunov S, Maupin GO, et al.
Serologic and genetic identification of Peromyscus maniculatus
as the primary rodent reservoir for a new hantavirus in the Southwestern United States. J Infect Dis 1994;169:1271-80.
Morzunov SP, Feldmann H, Spiropoulou CF, Semenova VA, Rollin PE, Ksiazek TG, et al.
A newly recognized virus associated with a fatal case of hantavirus pulmonary syndrome in Louisiana. J Virol 1995;69:1980-3.
Khan AS, Spiropoulou CF, Morzunov S, Zaki SR, Kohn MA, Nawas SR, et al.
Fatal illness associated with a new hantavirus in Louisiana. J Med Virol 1995;46:281-6.
Rollin PE, Ksiazek TG, Elliott LH, Ravkov EV, Martin ML, Morzunov S, et al.
Isolation of Black Creek Canal virus, a new hantavirus from Sigmodon hispidus
in Florida. J Med Virol 1995;46:35-9.
Williams RJ, Bryan RT, Mills JN, Palma RE, Vera I, De Velasquez F, et al.
An outbreak of hantavirus pulmonary syndrome in western Paraguay. Am J Trop Med Hyg 1997;57:274-82.
Levis S, Rowe JE, Morzunov S, Enria DA, St. Jeor S. New hantaviruses causing hantavirus pulmonary syndrome in central Argentina. Lancet 1997;349:998-9.
Chandy S, Mitra S, Sathish N, Vijayakumar TS, Abraham OC, Jesudason MV, et al.
A pilot study for serological evidence of hantavirus infection in human population in south India. Indian J Med Res 2005;122:211-5.
Chandy S, Yoshimatsu K, Boorugu HK, Chrispal A, Thomas K, Peedicayil A, et al.
Acute febrile illness caused by hantavirus: Serological and molecular evidence from India. Trans R Soc Trop Med Hyg 2009;103:407-12.
Basu G, Chrispal A, Boorugu H, Gopinath KG, Chandy S, Prakash JA, et al.
Acute kidney injury in tropical acute febrile illness in a tertiary care centre – RIFLE criteria validation. Nephrol Dial Transplant 2011;26:524-31.
Chrispal A, Boorugu H, Gopinath KG, Chandy S, Prakash JA, Thomas EM, et al.
Acute undifferentiated febrile illness in adult hospitalized patients: The disease spectrum and diagnostic predictors – An experience from a tertiary care hospital in South India. Trop Doct 2010;40:230-4.
Chandy S, Abraham S, Sridharan G. Hantaviruses: An emerging public health threat in India? A review. J Biosci 2008;33:495-504.
Chandy S, Boorugu H, Chrispal A, Thomas K, Abraham P, Sridharan G. Hantavirus infection: A case report from India. Indian J Med Microbiol 2009;27:267-70.
] [Full text]
Clement J, Maes P, Muthusethupathi M, Nainan G, van Ranst M. First evidence of fatal hantavirus nephropathy in India, mimicking leptospirosis. Nephrol Dial Transplant 2006;21:826-7.
Chandy S, Yoshimatsu K, Ulrich RG, Mertens M, Okumura M, Rajendran P, et al.
Seroepidemiological study on hantavirus infections in India. Trans R Soc Trop Med Hyg 2008;102:70-4.
Chandy S, Okumura M, Yoshimatsu K, Ulrich RG, John GT, Abraham P, et al.
Hantavirus species in India: A retrospective study. Indian J Med Microbiol 2009;27:348-50.
] [Full text]
Chandy S, Ulrich RG, Schlegel M, Petraityte R, Sasnauskas K, Prakash DJ, et al.
Hantavirus infection among wild small mammals in Vellore, South India. Zoonoses Public Health 2013;60:336-40.
Zeller HG, Karabatsos N, Calisher CH, Digoutte JP, Cropp CB, Murphy FA, et al.
Electron microscopic and antigenic studies of uncharacterized viruses. II. Evidence suggesting the placement of viruses in the family Bunyaviridae
. Arch Virol 1989;108:211-27.
Chu YK, Rossi C, Leduc JW, Lee HW, Schmaljohn CS, Dalrymple JM. Serological relationships among viruses in the Hantavirus genus, family Bunyaviridae
. Virology 1994;198:196-204.
Xiao SY, Leduc JW, Chu YK, Schmaljohn CS. Phylogenetic analyses of virus isolates in the genus Hantavirus, family Bunyaviridae
. Virology 1994;198:205-17.
Song JW, Baek LJ, Schmaljohn CS, Yanagihara R. Thottapalayam virus, a prototype shrewborne hantavirus. Emerg Infect Dis 2007;13:980-5.
Yadav PD, Vincent MJ, Nichol ST. Thottapalayam virus is genetically distant to the rodent-borne hantaviruses, consistent with its isolation from the Asian house shrew (Suncus murinus
). Virol J 2007;4:80.
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