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- Brief facts
- Genome organization
- Mechanisms of genetic diversity
- Virion morphology
- Life cycle
- Hosts and transmission, epidemiology
- Disease and pathogenesis
- Weather and climate change effects
A genus of the family BUNYAVIRIDAE causing HANTAVIRUS INFECTIONS, first identified during the Korean war. Infection is found primarily in rodents and humans. Transmission does not appear to involve arthropods. HANTAAN VIRUS is the type species. (MeSH, Year introduced: 1992)
Family Bunyaviridae and genus Hantavirus
Hantaviruses constitute a distinct genus (Hantavirus) in the family Bunyaviridae. They are enveloped, negative-strand RNA viruses with a tripartite genome.
The categorization of hantaviruses as belonging to the family Bunyaviridae is due in part to the consistent presence of three genomic RNA segments that are circularized in vivo as a result of the presence of terminal complementary nucleotides that help fold the genome into a “hairpin” morphology, first described for the Uukuniemi phlebovirus.
Other genera in the family include Bunyavirus, Nairovirus, Phlebovirus, and Tospovirus. Bunyaviruses, Nairoviruses, Phleboviruses, and Tospoviruses are classical arboviruses (ARthropode-BOrn viruses) in that they are all transmitted through obligate intermediate arthropode vectors such as mosquitoes, ticks, phlebotomine flies, other arthropods, or thrips. Hantaviruses, however, are transmitted directly from an infected rodent to a naïve rodent via aerosolized urinary, fecal, or salivary secretions without the aid of an intermediate vector.
There are currently about 20 well-described hantaviruses, each of which is closely associated with a single rodent or insectivore host. Specific rodent-hantavirus pairs are so closely associated that it is generally believed that the rodent and its associated hantavirus have co-evolved. As a result of the long-standing co-evolution of rodent-hantavirus pairs, hantaviruses do not cause overt clinical disease in their well-adapted rodent hosts.
In the absence of any arthropod vector that would facilitate their transmission to possible alternative host species, hantaviruses developed a narrow host range. Phylogenetic analysis demonstrates that hantaviruses break into three distinct clades, each of which closely coincides with the subfamily of its rodent host.
- HTNV∗-like viruses (HTNV, SEOV, DOBV, and SAAV) carried by the subfamily Murinae (Old World rats and mice);
- PUUV-like viruses (PUUV, TULV, PHV, BLLV, ISLAV, TOPV, and KHAV) carried by Arvicolinae (voles and lemmings of the Northern hemisphere);
- SNV-like viruses (SNV, NYV, BAYV, BCCV, LANV, ANDV, ELMCV, RIOSV, and RIOMV) carried by Sigmodontinae (New World mice and rats).
- are found in a unique ecological niche, i.e. in a different primary rodent reservoir species or subspecies;
- exhibit at least a 7% difference in identity on comparison of the complete GPC and N protein sequences;
- show at least a 4-fold difference in two-way cross-neutralization tests;
- do not naturally form reassortants with other hantavirus species.
HTNV is the prototype species of the genus Hantavirus and remains until now the epidemiologically most important species in the genus.
HistoryHantavirus infections became a concern in the Americas after the description of an outbreak of acute respiratory distress occurred in the Four Corners area in 1993. The newly recognized disease, hantavirus cardiopulmonary syndrome, HCPS (or hantavirus pulmonary syndrome), was linked to infection by the newly-discovered Sin Nombre virus (SNV), and Peromyscus maniculatus (deer mouse) was identified as the reservoir. However, hantavirus infections have a much longer history. A review of ancient Chinese writings, dating back to approximately 960 AD, revealed descriptions closely resembling hemorrhagic fever with renal syndrome (HFRS), the syndrome caused by Old World hantaviruses. During the twentieth century, cases of acute febrile disease with renal compromise were described from several Eurasian countries and Japan, often in association with military engagements. HFRS as a distinct syndrome, however, was first brought to the attention of western medicine in association with an outbreak that occurred among United Nations troops during the Korean conflict between 1951 and 1954, where more than 3,200 soldiers were afflicted with Korean hemorrhagic fever (KHF). It took more than two decades until the etiologic agent, named after a small river called Hantaan near the village of Songnaeri in Korea, Hantaan virus (HTNV), was isolated from the striped field mouse Apodemus agrarius, detected in part by the binding of antibodies from patient serum samples to the lung tissues of healthy, wild-caught field mice in 1978. The virus was later found to represent the type species of a new genus Hantavirus of the family Bunyaviridae, although it was later apparent that the first hantavirus to be isolated was the shrew-borne Thottapalayam virus.
- Unlike other members of the family Bunyaviridae, hantaviruses are not transmitted by biting insects.
- Unlike other negative-strand RNA viruses, hantaviruses do not possess M- or matrix protein that normally orchestrates virus assembly.
- Since hantaviruses are enveloped viruses, they must bud through a host cell membrane to obtain their lipid envelope. It is an unusual characteristic of the Bunyaviridae that virus budding occurs at the Golgi apparatus.
- In contrast to the other viral hemorrhagic fever (VHF) viruses considered as potential agents for biological warfare (BW), hantaviruses (HTVs) are the only VHF viruses with a worldwide distribution.
- The Hantavirus coding strategy is the simplest of the five genera of Bunyaviridae, with all the three segments encoding only one protein in the virus complementary sense.
- Unlike other RNA viruses with a segmented genome (e.g., influenza A, rotavirus) there is little evidence of viral genome reassortments between different genogroups, although reassortants within Sin Nombre virus (SNV) genetic variants have been described.
- Recently, a homologous recombination (i.e. recombination between homologous parental RNAs through crossovers at homologous sites) in hantaviruses has been demonstrated This represents the first case of recombination in the negative-sense RNA viruses.
- Hantavirus' virions have a short 5-10 nm fringe of peplomers, which gives them a "fuzzy" ultrastructural appearance. Although not unique, the appearance of hantaviruses is quite distinct.
- Homologous recombination occurs in hantaviruses more frequently than in other negative-strand RNA viruses.
- Unlike other hemorologic fever viruses such as Ebola virus, the hantaviruses do not increase the permeability of endothelial cell monolayers in vitro, nor do they cause any cytopathic effects in the host endothelial cells. This points towards the role of host immune system in hantavirus pathogenesis.
EpidemiologyThere are estimated 100,000 to 200,000 cases of hantavirus infection each year worldwide. The annual incidence of infection in China and eastern Russia of HFRS is 30–168/100,000 population; in Sweden over a four-year cycle the incidence of nephropathia epidemica is 1.3–20/100000, and in USA the incidence of Sin Nombre HPS is 0.02/100 000 population. However with some hantaviruses subclinical infection is common with subclinical to clinical ratios of 14:1 to 20:1. For both HFRS and HPS infection is more common in males than females (M:F, 2:1 to 3:1) and most often in those aged 20–40 years. Milder infection can occur in children. Asymptomatic or non-specific mild infections result in underestimation of the number of hantavirus infections.
- Hemorrhagic fever with renal syndrome (HFRS)
- Hantavirus cardiopulmonary syndrome (HCPS)
- Nephropathis endemica (NE)
Major hantaviruses infecting humans
Lineage Strain Acronym Geography Reservoir Pathology Fatality (%) New World Sin Nombre SNV North America Peromyscus maniculatus (deer mouse) HCPS ~35 Choclo CHOV Panama Oligoryzomys fulvescens (fulvous pygmy rice rat) HCPS ~21 Andes ANDV Argentina, Chile Oligoryzomys longicaudatus (long-tailed pygmy rice rat) HCPS ~35 Laguna Negra LANV Argentina, Bolivia, Paraguay Calomys laucha (small vesper mouse), C. callosus (large vesper mouse) HCPS 5-15 Old World Hantaan HTNV China, Korea, Russia Apodemus agrarius (striped field mouse) HFRS 5-10 Seoul SEOV Worldwide Rattus rattus, (black rat), R. norvegicus (Norwegian rat) HFRS 1-2 Puumala PUUV Scandinavia, western Europe, Russia Myodes glareolus (bank vole) HFRS/NE 0.1-0.4 Dobrava-Belgrade DOBV Balkans Apodemus flavicollis (yellow-necked field mouse) HFRS 5-10
Field research focus:
- the maintenance of hantaviruses in their rodent reservoirs,
- factors that promote transmission;
- the prevalence and distribution of these viruses in nature;
- the prevalence of spillover in other animals with the rodent reservoir habitat;
- the evolution of these viruses in the context of their rodent hosts.
Laboratory researchUp to now hantavirus research is hampered by the lack of adequate animal models of hantavirus-associated disease. The Old World hantaviruses do not cause overt disease in any animal species apart from nonhuman primates, which have been shown to develop mild symptoms similar to HFRS in humans after infection with PUUV. In general, New World hantaviruses also do not induce symptoms that mirror human disease in animals. So far, only ANDV has been reported to cause HPCS-like disease in Syrian hamster. Therefore, it is difficult to dissect the role of host defense components in protective immunity against hantaviruses after infection/vaccination or to proof the concept of hantavirus-induced pathogenesis.
Hantaviruses have tripartite (containing three parts) negative-sense single stranded RNA genome. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation.
The genome segments are designated:
- The large (L) segment of approximately 6,500 nucleotides (nt) encodes a RNA-dependent RNA polymerase of ∼2,160 amino acids (aa);
- The middle (M) segment is 3,700-nt long, and encodes the envelope glycoprotein precursor (GPC), which is processed into two transmembrane glycoproteins, Gn (652 aa, formerly "G1") and Gc (488 aa, previously "G2") through a cotranslational proteolytic mechanism in the endoplasmic reticulum;
- The small (S) segment length varies from ∼1,700-2,100 nt, and encodes an RNA-binding nucleocapsid (N) protein that ranges between 428 and 436-aa for hantaviruses.
Each of the genomic segments has a slightly mismatched, conserved, inverted repeat at its 3' and 5' ends. This allows the genomic segments to form a panhandle structure that is believed to play an important role in virus morphogenesis.
RNA viruses show high mutation frequencies partly because of a lack of the proofreading enzymes that assure fidelity of DNA replication.
Analysis of the current collection of hantavirus genome sequences shows that the genetic diversity of hantaviruses is generated primarily by genetic drift, i.e. accumulation of point mutations and insertions/deletions of one or several nucleotides.
While mutation is the ultimate source of genetic variation, recombination can act on mutation to shape the genetic structure of populations.
Two distinct mechanisms can generate viral recombinant genomes:
- Reassortment occurs when two or more multipartite viruses co-infect a single host cell and exchange discrete RNA segments to form genetically novel progeny viruses. Reassortant strains of SNV were found in nature.
- Recombination occurs when one contiguous stretch of RNA is formed as a mosaic from more than one parent. Recombination events can occur between different genes (non-homologous/intergenic recombination) or between alleles of the same gene (homologous/intragenic recombination).
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by eukaryotes to accurately repair harmful breaks that occur on both strands of DNA and in process of meiosis. Homologous recombination is also used in horizontal gene transfer to exchange genetic material between different strains and species of bacteria and viruses.
To date, the strongest evidence for recombination in negative sense RNA viruses comes from hantaviruses. Phylogenetic analysis of the S segment indicated that the eastern Slovakian Tula hantavirus underwent homologous recombination and formed an independent lineage. Several studies reported recombination in Hantaan virus, Dobrava virus, Andes virus, and Puumala virus. Therefore, recombination appears to be a common occurrence in hantaviruses, relative to most other negative sense RNA viruses. This suggests there are unknown mechanisms contributing to hantavirus recombination.
Negative stained electron micrographs of hantaviruses show pleomorphic, enveloped virions that are approximately 100 nm in diameter. Virions have a short 5-10 nm fringe of peplomers, which gives them a "fuzzy" or tessellated ultrastructural appearance. While not unique, the appearance of hantaviruses is quite distinct.
Coded by the medium (M) segment, glycoproteins Gn (formerly, G1) and Gc (formerly, G2) are transmembrane proteins that are associated with the lipid envelope of the virion. The glycoproteins are believed to interact with host's integrin receptors to facilitate infection of endothelial cells, macrophages, and platelets.
N protein is the most abundant hantavirus protein found in the cytoplasm of infected cells. It is coded by the small segment (S) are associated with the hantavirus genome, coating each of the three genomic segments within the virion and forming ribonucleocapsids. Its transcript is detected in infected cells six hours post infection. N protein is responsible for encapsidation and packaging of the viral genome.
RNA-dependent RNA polymerase (RdRp)
The large (L) segment encodes a RNA-dependent RNA polymerase (RdRp). Several copies of the virus RdRp (~250 kDa) are believed to be packaged within each virion and associated with the virus ribonucleocapsids through non-covalent interactions. No proof-reading functions have been associated with the hantavirus polymerase protein, thus the viruses within the genus display tremendous genomic heterogeneity with nucleotide identities that can vary by as much as 50% between viruses within the Hantavirus genus. Because of its large molecular weight RdRp is difficult to express in bacteria, and thus remains the most uncharacterized protein in hantaviruses. RdRp mediates both transcription and replication of viral genome. During transcription RdRp synthesizes viral mRNA from negative sense vRNA template. During replication RdRp replicates vRNA genome via a cRNA intermediate. Thus it is likely that hantavirus RdRp has multiple activities, including endonuclease, replicase, transcriptase and RNA helix unwinding activities.
Hantavirus replication takes place in macrophages and vascular endothelial cells, especially in the lung and the kidney.
- The attachment of the virion particle to the cell's surface through interactions between the host's cell surface receptors and the viral glycoprotein. It has been shown that NYV, SNV, HTNV, SEOV, and PUUV, all viruses which cause either HPS or HFRS, use β3 integrin receptors to infect platelets and endothelial cells. In contrast, Prospect Hill virus (PHV), Tula virus (TULV), and Thottapalayam virus (TPMV), all non-pathogenic hantaviruses, use β1 integrin receptors to mediate infection of similar cell types. These data indicate that cellular tropisms play an important role in virus pathogenesis.
- Entry through the use of receptor-mediated endocytosis and the uncoating and release of the viral RNA segments immediately thereafter. The virion envelope fuses with the endosome membrane in a pH-dependent way, and nucleocapsids are released into the cytoplasm.
- Transcription of complementary RNA (cRNA) from the viral RNA (vRNA) genome using host-derived primers. Hantaviruses do not poly-adenylate their 3' tails, which makes them distinct from the eukaryotic mRNAs with which they coexist. Additionally, hantaviruses lack machinery for capping their 5' ends. Since capped 5' end is necessary for translation in mammalian cells, hantaviruses rely on stealing mRNA caps from host mRNAs, which is referred to as "cap snatching". This results in heterogeneous 5' extensions of host cell origin on virus mRNAs that are typically less than 20 nucleotides in length. Virus mRNA is truncated at its 3' end, thus deleting the 3' genomic sequence that allows panhandle structures to form
- Translation of L, M, and S mRNAs into viral proteins using host machinery. The L and S segments (NP and RNA polymerase mRNA) are translated at free ribosomes, and the M-segment (glycoproteins) transcription occurs on membrane-bound ribosomes, which is cotranslated on rough endoplasmic reticulum.
- Replication and amplification of vRNA, assembly with the N protein, and transport to the Golgi apparatus. Cytoplasmic accumulation of virus nucleocapsid protein is believed to be the mechanism for initiation of switching from mRNA synthesis to cRNA synthesis, and thus synthesis of more vRNA.
- Assembly of all components at the Golgi apparatus or, possibly for New World viruses, at the plasma membrane (alternative assembly). Mature genomic vRNA associates with nucleocapsid proteins in the cytoplasm, forming the virus ribonucleocapsids. It is then believed that the viral ribonuclecapsids form a panhandle structure through complementary base pairing of the 3' and 5' ends of the viral genomes. This is thought to be important to virus morphogenesis and budding.
- Viral egress via the fusion of the Golgi vesicle harboring the mature virion particles with the plasma membrane, and release by exocytosis. Since hantaviruses are enveloped viruses, they must bud through a host cell membrane to obtain their lipid envelope. It is an unusual characteristic of the Bunyaviridae that virus budding occurs at the Golgi apparatus. Virus filled vesicles are then thought to traffic from the Golgi to the plasma membrane where vesicle fusion leads to release of intact enveloped virions
Muridae family rodents are reservoirs for hantaviruses. Thottapalayam (TPMV) virus is an exception because it was isolated from an insectivorous shrew, Suncus murinus. TPMV was also the first hantavirus to be isolated in cell culture; however, it was not thought to be a hantavirus until a partial genomic sequence was determined in 1992 showing genetic homology with known hantaviruses.
Each of the currently recognized ~20 species of rodent-borne hantaviruses is predominately associated with a single specific rodent host in which it establishes a persistent, most likely lifelong, infection that does not cause any deleterious effects in their well-adapted rodent host species.
It is currently estimated that there are approximately 2,000 species of murid rodents, of which less than 100 have been thoroughly screened for hantaviruses, and only 22-23 different hantaviruses have been described. This means that roughly one quarter of rodents screened for hantaviruses are positive, and that approximately 1900 murid rodents have not been thoroughly tested for the presence of hantaviruses. Since hantaviruses are a newly emerging and recently recognized group of human pathogens, with case fatality rates as high as 50%, this certainly piques one's interest regarding how many species of hantaviruses might truly exist. As was experienced in the recent Sin Nombre outbreak in the U.S., many of these supposed hantaviruses may be an underappreciated causes of human disease.
In surveys of trapped rodents seroprevalences of up to 50% have been described for Seoul virus in rats, 5–16% for Puumala in bank voles and 2–7.7% for new world hantaviruses in rodents in North and South America. It is known that acutely infected rodents are transiently viremic with peak viremia occurring 7-14 days postinfection.
Transmission in rodents
In rodents, transmission seems to occur by close contact between infected and naïve rodents through aerosolized urine, feces. For example, urine appeared to be the mode of transmission of Seoul virus between rats housed in the same cages, and airborne spread of Hantaan could occur between A. agrarius when housed as far apart as 4 m. Transmission has also been suggested to occur through fighting, biting, and sexual behavior. There is no evidence to support vertical transmission as a common means of transmitting hantaviruses from an infected dam to her pups.
Cross-species transmission is a major process during spread, emergence, and evolution of RNA viruses. For example, ANDV is the predominant etiologic agent of HCPS in South America, and O. longicaudatus the main rodent reservoir. Spillover in at least four other rodent species that co-occur with the reservoir have been identified. In North America, spillover of Bayou virus (BAYV) may have occurred from the main reservoir O. palustris to S. hispidus, R. fulvescens, P. leucopus, and B. taylori. Hantavirus spillover is more likely to occur between sympatric (exist in the same geographic area and regularly encounter one another) host populations, and closely related species. An interesting exception is found between Oxbow virus (OXBV) and Asama virus (ASAV) in which a host-switch process seemed to have occurred between mammals belonging to two families (Talpidae and Soricidae), likely as a result of alternating and recurrent co-divergence of certain taxa through evolutionary time.
Transmission in humans
Similar to rodent mode of transmission, humans acquire hantaviruses primarily via the respiratory route through aerosolized rodent excreta (urine, feces). The infective dose is unknown but presumed to be low by analogy with transmission between rodent hosts and because persistently infected rodents do not excrete large amounts of virus. In the Americas, person-to-person transmission has not been observed for the majority of hantaviruses; however, cases of person-to-person transmission of ANDV have been reported, although rarely, in Argentina and Chile. Recent surveillance data showed PUUV RNA in saliva of patients; however, inhibitory substances in saliva may prevent the transmission of live virus.
There is significant risk of human occupational exposure to hantaviruses. Mammalogists and agricultural and forestry workers are at the highest risk of occupational exposure to hantaviruses. Personnel that work in laboratory animal facilities or scientists that trap or work with wild rodents or with murine cell lines are also at risk.
Other possible hosts
The recent reports on the detection of hantavirus specific antibodies in domestic animals, small mammals, and in wildlife together with the replication of hantaviruses in bovine aortic endothelial cells are further evidence that Rodentia, Insectivora, Lagomorpha, and Carnivora cannot be considered anymore as the only reservoir and/or transmission source for hantaviruses. The detection of hantavirus antigens in the lung suspension of different bird species captured in the far east region of Russia by ELISA is of particular importance in view of hantavirus transmission and ecology. The birds identified to be infected with hantaviruses belonged to the orders Columbiformes (pigeons), Passeriformes (song birds), Galliformes (chicken-like), Strigiformes (owls), and Ciconiformes (wading birds kike herons, storks). The confirmation of this discovery is still open.
Diagnosis of hantavirus infection in humans depends upon initial clinical suspicion raised by pulmonary or renal syndrome occurring after possible exposure to rodents and their secreta (outdoors, laboratory, field or agricultural work). A variety of other pathogens and noninfectious conditions may cause similar symptoms and need to be considered.
"Gold standard" for detection of known and as yet undiscovered hantaviruses is by reverse transcription-PCR (RT-PCR), which is highly sensitive especially if certain strain is suspected, but caution must be used in choosing appropriate primer sets and in interpreting results. However, laboratory diagnosis of acute hantavirus infection has to be primarily based on serology, since the viremia of human hantavirus infections is short-termed and viral RNA cannot be regularly detected in the blood or urine of patients in hospitals.
Serologic tests monitor antibody responses to a given agent; thus, actively replicating virus does not need to be present in the animals that are being tested to determine if exposure has occurred. A further benefit to using serologic tests is that antibody- negative carrier states have not been documented for the hantaviruses therefore, if an immunologically competent animal is infected it should develop a measurable antibody response.
Diagnosis of hantaviruses of unknown origin in humans as well as arbitrary animal hosts is very challenging due to their heterogeneity. Serologic tests, particularly the immunofluorescent antibody test (IFAT), have historically been the diagnostic test of choice for subtyping and classifying arboviruses and currently is a method of choice for identifying new members of the family Bunyaviridae.
The enzyme-linked immunosorbent assay (ELISA) is commonly used in diagnostic testing labs because it is rapid, sensitive and specific, and it is easily automated, making it a cost effective test. Many diagnostic ELISAs utilize recombinant nucleocapsid proteins as an antigen source, as the nucleocapsid protein is the most antigenic and cross-reactive of the four hantavirus proteins, and because use of a recombinant protein as the antigen source avoids the biohazard associated with handling intact infectious virus. A strip immunoblot assay has also been developed for the rapid diagnosis of SNV infections, which takes advantage of the immunogenicity of a recombinant, truncated, 59 amino acid N-terminal nucleocapsid protein. The strip immunoblot is both rapid and sensitive for the diagnosis of PUUV and SNV infections; however, it lacks sensitivity for detecting HTNV and SEOV infections.
There are two major clinical presentations of hantavirus infection — hemorrhagic fever with renal syndrome (HFRS) caused by Old World hantaviruses such as HTNV, SEOV, PUUV, and DOBV, found worldwide in various forms and hantavirus pulmonary syndrome (HPS), found only in the Americas. The latter emerged in the New World in May 1993 when a cluster of deaths occurred in the Four Corners area of the U.S. desert Southwest among a group of young, previously healthy individuals nearly one-half of whom died from fulminant pulmonary edema.
Both hantavirus syndromes in humans do not truly represent two clinically distinct diseases, rather they represent a continuum from renal disease in HFRS to pulmonary disease in HPS. For example, there are subclinical and clinical pulmonary sequelae to HFRS infection in humans, as well as the previously described renal complications that arise from HPS. This is most likely a result of the fact that hantaviruses infect and replicate primarily within endothelial cells, which are widely distributed. The particular cellular tropisms of individual hantaviruses are most likely responsible for the varying course and severity of human diseases that are seen.
Both syndromes appear to be produced by immune and inflammatory mediators that result in an enormous increase in vascular permeability. A critical feature of both syndromes is a transient (∼ 1–5 days) capillary leak involving the kidney and retroperitoneal space in HFRS and the lungs in HCPS. The resulting leakage is exudative in character, with chemical composition high in protein and resembling plasma.
The period between virus acquisition and onset of symptoms is 1-3 weeks depending on the virus.
Hemorrhagic fever with renal syndrome (HFRS)
HFRS is most commonly a disease found in the human population in Eurasia, is caused by Hantaan, Seoul, Dobrava, and Puumala viruses, and is associated with rodents of the subfamilies Murinae and Arvicolinae. From 150,000 to 200,000 cases of HFRS are diagnosed in China annually. Additionally, a significant but unknown number of cases are diagnosed in Korea and Russia each year. Several thousand cases are also reported in the Balkans, Western Europe, and Scandinavia. Further, sporadic cases of HFRS are reported worldwide due to the global distribution of the Norwegian rat (Rattus norvegicus).
The severity of disease varies with the virus and with human host characteristics. In HFRS, Hantaan and Dobrova/Belgrade tend to produce the most severe disease, with mortality rates of 5–35%, Puumala is the least severe (called nephropathia epidemica: NE) with a mortality rate of less than 1% and Seoul is intermediate in severity with a 1% mortality rate
The disease has distinct 5 stages:
- Febrile phase Also, prodromal period of "flue-like" illness that may include abdominal pain, thirst, nausea and vomiting, dizziness, and blurred vision. Visual disturbances include sudden myopia, which is pathognomonic for NE, which occurs in one-third of patients (sudden shortsightedness of 1 diopters), and loss of vision and other ophthalmological manifestations may also occur. Lasts for 3-5 days.
- Hypotensive phase Approximately 11 to 40% of persons with febrile illness develop hypotension. Due to the vascular leak syndrome which accompanies the hypotensive phase, thirst, periorbital edema, hemoconcentration, and postural hypotension are common. Approximately one third of all patients during this stage of HFRS develop shock and mental confusion. Approximately one third of human deaths occur during the hypotensive phase due to vascular leakage and acute shock. Lasts from hours to days.
- Oliguric phase Approximately 40 to 60% of persons with febrile illness develop oliguria. Oliguria is urine output of less than 400 ml per day. The oliguric phase lasts from 1 to 16 days. Nearly one-half of deaths occur in this phase. Dialysis is required for approximately 40% of HTNV and 20% of SEOV patients. Death is usually due to complications from renal insufficiency, shock, or hemorrhage.
- Diuretic phase Renal (kidney) function improves. Patients that survive and progress to the diuretic phase generally show improved renal function, but may still die as a result of shock or pulmonary complications. Lasts from a few days to several weeks.
- Convalescence Gradual recovery. May last from weeks to months before full recovery.
Hantavirus pulmonary syndrome (HPS)
HPS is associated with pulmonary disease. Retrospective analysis indicates that HPS is not a new disease, simply that its etiology and case presentation were previously underappreciated. It is caused by a newly recognized clade of hantaviruses that have only been found in New World rodents of Sigmodontinae subfamily.
In HPS the site of vascular leakage is primarily in the lungs rather than the retroperitoneal space. In contrast to HFRS disease, the urinary system, including the kidneys, is largely unaffected in HPS. HPS is a more severe disease than HFRS, with a mortality rate of about 40%. Death generally results from shock, pulmonary edema, and cardiac complications with oxygen saturation rates frequently less than 90%.
Cases of HPS have been reported for the following American countries: the United States, Canada, Argentina, Bolivia, Brazil, Chile, Panama, Paraguay, and Uruguay.
The clinical course of HPS is divided into three periods:
- Febrile phase Also, prodromal period of "flue-like" illness that may include myalgia, malaise, and fever. Other early symptoms include gastrointestinal disturbance, headache and chills. Lasts for 3-5 days.
phase Characterized by acute onset of pulmonary edema. At this stage, cough is generally present. One to 3 days after the onset of respiratory symptoms, the disease produces a leaking syndrome in the lung capillaries. Gross pathologic findings show that the lungs of patients with HPS are dense, rubbery, and heavy, usually weighing twice as much as the average lung. The pathologic lesions are primarily vascular with variable degrees of generalized capillary dilation and edema. Yet it is not hypoxemia, due to the prominent pulmonary edema, that leads to death in most fatal cases of HCPS, but rather intoxication of the heart by as-yet-undefined mediators that leads to the low cardiac output state and the associated shock syndrome
- Convalescence Gradual recovery. May last from weeks to months before full recovery.
Autopsy specimens from humans who died of HPS revealed higher than normal numbers of cytokine-producing cells in the lungs and spleens as assessed by immunohistochemical staining for interleukin (IL)- 1α, IL-1β, IL-2, IL-4, IL-6, tumor necrosis factor (TNF)-α, TNF- β, and interferon-γ. These findings have led to speculation that vascular endothelial injury associated with HPS and HFRS is not a direct result of viral replication, but rather is the result of the host inflammatory response to the virus. Hantavirus-specific CD4+ and CD8+ cytotoxic T lymphocytes have been isolated from pulmonary tissues of patients who died from HPS. These results clearly indicate that activated T cells are intimately involved in the pathogenesis of hantavirus infection. Further, the major histocompatibility (HLA) type of affected patients has also been associated with the clinical disease course, as might be expected in an immunopathologic disease. Yet exact mechanism of how hantaviruses induce HPS and HFRS is not clear.
Several observations suggest that previously infected individuals are protected life-long from reinfection. There are no known re-infections with the homologous hantavirus. Closely related hantaviruses, such as Seoul and Hantaan viruses, seem to cross-protect against re-infection in experimental animals, and one might expect cross-protection among the hantaviruses derived from sigmodontine rodents.Back to top
Currently, there is no specific therapy available for both HFRS and HPS. Several drugs have been tried with various effects including IFN-α, steroids, and cyclophosphamide. Ribavirin treatment was shown to significantly reduce mortality rate when administered early after the onset of HFRS and is often used in treatment of HFRS in China. However, ribavirin was ineffective for the treatment of HPS in the cardiopulmonary stage.
The cornerstone of treatment remains supportive measures. The management must include early admission to an intensive care unit where blood and tissue oxygenation, cardiac output, central blood pressure and cerebral pressure can be monitored. Maintaining fluids balance is very important; it must be carefully monitored according to the patient's fluid status, amount of diuresis, and kidney function. Usually one or two hemodialysis sessions are needed for HFRS treatment, while mechanical ventilation when indicated and appropriate use of pressures are crucial to HPS patients.
Since hantaviruses are carried by rodents and spread via aerosol and biting, the central means for prevention of infection is the reduction of rodent exposure. Effective measures include rodent proofing of homes, proper storage of food, disinfection and removal of trapped rodents and their excreta.
Inactivated and recombinant vaccine strategies have been used for development of vaccines against hantaviruses. In Korea, a formalin-inactivated HTNV vaccine, Hantavax (Korea Green Cross, Seoul, Korea), that is produced from rodent brain–derived virus, is commercially available. Hantavax was shown to induce high titers of IgG-specific antibodies in almost 100% of human volunteers after three vaccinations accompanied by the production of neutralizing antibodies in approximately 80% of test individuals; however, the antibody titers declined very rapidly within months, and boosters yielded no satisfactory protection rates. In China, 4 million doses of five commercially available hantavirus vaccines are annually produced.
Rodent population dynamics are affected by seasonal changes of weather and climate.
The following regulators of zoonotic virus prevalence and transmission were suggested:
- environmental regulators (weather and food) that affect transmission rates through their effect on reproductive success and population densities;
- anthropogenic factors, such as disturbance, that impact the complexity of the ecosystem;
- genetic factors that could influence shedding;
- behavioral factors (e.g., fighting or communal);
- physiological factors control the host response to and length of infection.
These five factors can differentially impact the biology and ecology of the host-virus ecosystem and, consequently, the risk of disease transmission to humans. For example, disturbed rodent habitats, such as those caused by deforestation and extensive agriculture, may favor opportunistic or generalist species that may be reservoirs for hantaviruses. Environmental changes commonly decrease rodent diversity, which could enhance more host species interaction and, hence, more hantaviral transmission events within a single species. As a consequence, this may activate a cascade with a greater transmission of the virus among rodents, leading to a greater the risk of spillover of rodents with virus into human activities.
It can reasonably be concluded that climate change should influence hantaviruses through impacts on the hantavirus reservoir host populations. We can anticipate changes in the size and frequency of hantavirus outbreaks, the spectrum of hantavirus species and geographical distribution (mediated by changes in population densities), and species composition and geographical distribution of their reservoir hosts. The early effects of global warming have already been observed in different geographical areas of Europe. Elevated average temperatures in West-Central Europe have been associated with more frequent Puumala hantavirus outbreaks, through high seed production (mast year) and high bank vole densities. The US Four Corners outbreak in 1993 was preceded by a dramatic increase in rainfall associated with the 1992–1993 El Nin˜o. This led to increased rodent food resources and a focal 20-fold increase in the rodent population, followed by invasion of buildings by rodents, and an increased risk of human disease. On the other hand, warm winters in Scandinavia have led to a decline in vole populations as a result of the missing protective snow cover.
Increasing intensity and frequency of extreme climatic events, such as floods, droughts or hurricanes, represent extremely important contributory factors in the context of climate change and its impact on hantavirus disease in humans. A 30-year study of a desert rodent community affected by two major floods demonstrated that extreme climatic events can decimate resident populations, alter species composition and interspecific interactions, influence invasion dynamics and thereby result in a rapid, wholesale reorganization of the community. If hantavirus reservoir hosts form part of the affected community, dramatic changes in hantavirus incidence and species spectrum can be expected. Different hantavirus species could assume dominance, together with their natural host, whereas others could be eliminated from the affected geographical region. In such situations, currently unrecognized hantaviruses and reservoir hosts could replace the eliminated species. For example, shrews and the recently recognized shrew-associated hantaviruses, currently of unknown pathogenic potential, might be better adapted to the new climatic conditions.
In conclusion, it is difficult to predict how extensive the climate change effects will be. Nevertheless, hantaviruses will remain a significant public health threat in the near future.
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