Epidemiology and diagnosis of hantavirus infections

INTRODUCTION — Hantaviruses comprise a genus (Orthohantavirus) of enveloped viruses within the order Bunyavirales. All medically important hantaviruses are carried by rodents of the families Muridae and Cricetidae. These pathogens are associated with two severe acute febrile illnesses:

●Hemorrhagic fever with renal syndrome (HFRS; caused by hantaviruses of the Old World)

●Hantavirus cardiopulmonary syndrome (HCPS; caused by hantaviruses of the New World), also known as hantavirus pulmonary syndrome (HPS)

The epidemiology and diagnosis of hantavirus infections, with a special emphasis on HCPS, will be reviewed here. The clinical manifestations, pathogenesis, and prevention of hantavirus infection are discussed separately. (See "Hantavirus cardiopulmonary syndrome" and "Kidney involvement in hantavirus infections" and "Pathogenesis of hantavirus infections".)

VIROLOGY — The precise number of identified hantavirus species is a matter of debate, but at least 30 distinct viral species exist in nature; at least a dozen are associated with human disease (table 1). There have been rare examples of hantaviruses first discovered in rodents that later proved to be human pathogens [1,2].

Hantaviruses have single-stranded, negative-sense ribonucleic acid (RNA) genomes that are divided into three segments. The L, or large, segment encodes the replicative enzymes, RNA-dependent RNA polymerase and endonuclease; the M (middle) segment encodes the envelope glycoproteins, Gn and Gc; and the S segment encodes the nucleocapsid protein, N [3,4].

The envelope glycoproteins may mediate attachment to cells via the beta-3-integrin cell surface molecule, which is found on endothelial cells and platelets throughout the body [3,5]. Other potential entry molecules have been more recently identified [6]. Hantaviruses also infect vascular endothelial cells in vivo. A broader tropism to Kupffer cells and renal epithelium has been demonstrated by some hantaviruses in animal models and humans.

RODENT RESERVOIRS — Although individual hantaviruses are known to infect specific species of mammals ranging from rodents to insectivores to bats, each pathogenic hantavirus is associated with a single species of wild rodent, which serves as its primary natural reservoir [7,8]. Serologic evidence of human exposure to hantaviruses from nonrodent hosts has been reported, but no specific disease entities have been linked to such exposure [9].

Approximately 5 to 20 percent of rodents of the predominant carrier species typically demonstrates anti-hantavirus antibodies, and seropositive animals usually have active, persistent infection. Hantaviruses have a worldwide distribution in accordance with the habitats of their respective hosts.

●Those that cause hemorrhagic fever with renal syndrome (HFRS) are carried by field mice and rats, except for Puumala virus, which is carried by a vole.

●Many native rodents of North and South America carry the etiologic agents of hantavirus cardiopulmonary syndrome (HCPS). The deer mouse is the major reservoir of the Sin Nombre virus, the most important cause of this syndrome in North America, although spillover infections of other rodent hosts are well known.

The viruses that cause HCPS are more closely related to one another than they are to any of the etiologic agents of HFRS [3,10]. The observation that closely related viruses infect closely related hosts and cause similar clinical syndromes has led to the belief that hantaviruses have coevolved over many millennia within their predominant reservoir host species [3]. There is, however, a hypothesis that horizontal viral transmission among rodent species in the same geographic area is an important driver in hantavirus evolution and diversification [11].

TRANSMISSION — Rodent contact is an important factor in the transmission of hantaviruses to humans. Many hantaviruses are shed in the urine, feces, or saliva of acutely infected reservoir rodents. It is suspected that much, if not all, transmission to humans occurs via the aerosol route, even if the exact nature of the aerosol is difficult to establish due primarily to the rarity of hantavirus infections.

Very few patients who contract hantaviruses describe recent rodent bites. However, many describe having encountered living or dead rodents or having been in rooms with visible evidence of rodent infestation two to four weeks before developing symptoms. Indoor exposure, especially in the presence of an active, current infestation, may be especially important. As an example, virtually all patients infected with the Sin Nombre hantavirus in the United States had documented indoor exposure inside rodent-infested buildings [12]. Seroepidemiologic studies suggest that the risk of infection with hantaviruses is low in persons with occupational rodent contact in North America [13,14].

Informative examples of laboratory-acquired infections of hemorrhagic fever with renal syndrome (HFRS) have been studied in Europe, Asia, and especially in Russia. In a Russian outbreak in 1961, 113 cases were linked to the housing of hantavirus-infected rodents in poorly ventilated, poorly maintained animal research facilities. A number of laboratory-associated cases have involved individuals whose closest contact with rodents consisted of brief entry into laboratories that were housing infected reservoir rodents. The large number of such cases support the belief that airborne transmission is the normal route of exposure for man [15]. Modern laboratory protocols make new mass hantavirus outbreaks from labs much less likely.

Person-to-person transmission of hantaviruses is rare and has been confined only to a single hantavirus species, Andes virus. It is sometimes difficult to distinguish between interpersonal transmission among family members and common-source exposure to rodents [16,17]. The interval between exposure and the onset of symptoms for hantavirus infections range from one to six weeks, with a median of 14 to 17 days. Secondary cases that occur within seven days of a primary case are generally ascribed to common-source exposures rather than interpersonal transmission [17].

One prospective study of 476 household contacts of 76 persons with Andes virus infection in Chile demonstrated that the risk of hantavirus cardiopulmonary syndrome (HCPS) was 17.6 percent among sexual partners of the index case patient versus 1.2 percent among other household contacts [18]. Viral RNA was detected by reverse-transcriptase polymerase chain reaction in peripheral blood mononuclear cells 5 to 15 days before the onset of symptoms or the appearance of specific antibodies. Discovery of hantavirus RNA in the saliva of patients with Puumala virus-induced HFRS has suggested that there may be a risk of transmission from oral secretions, but live virus was not detected in saliva, and epidemiologic findings do not support such a concern [19].

Some attempts have been made to determine whether parasitic mites have any role in the maintenance or transmission of hantaviruses in nature [20,21]. The evidence in favor of such a role for mites is speculative [21].

THE RECOGNITION OF HANTAVIRUSES — Hantavirus outbreaks have probably occurred for centuries. After hantavirus illness was recognized by Western medicine, a review of centuries-old Chinese writings revealed descriptions of compatible syndromes dating to approximately 960 CE [22].

The event that brought hemorrhagic fever with renal syndrome (HFRS) to the attention of Western medicine was a carefully described outbreak among United Nations troops between 1951 and 1953 during the Korean conflict. More than 2000 troops were afflicted, with a case-fatality ratio of about 5 percent [23]. Rodents were suspected to be involved in the epidemiology, but more than two decades passed before the etiologic agent, Hantaan virus, was isolated from a striped field mouse [24]. In the next several years, other etiologic agents of HFRS were identified in Korea (Seoul virus) and Europe (Puumala and Dobrava viruses) [25-27].

Serologic surveys for hantavirus exposure in rodent populations suggested that hantaviruses were widespread in the United States [28]. However, the discovery of hantavirus cardiopulmonary syndrome (HCPS) was unanticipated by investigators, who had been searching for HFRS in the New World. In the 1980s, Seoul virus and a new species of hantavirus, Prospect Hill virus, were isolated in the United States from the commensal rat, Rattus norvegicus, and a vole species, respectively [29,30]. After a decade-long search, a very small number of human cases of HFRS due to Seoul virus were identified in the United States [31]. Such cases appear to be very rare [32,33], but an outbreak occurred in 2016. (See 'Outbreaks' below.)

In the spring of 1993, an alarming series of cases of unexplained fever and acute respiratory distress syndrome (ARDS) were recognized among members of the Navajo tribe at the northern border between New Mexico and Arizona [34]. The case-fatality ratio was approximately 80 percent in the initial group of patients. Serum samples from these patients contained immunoglobulin (Ig)M antibodies that reacted against hantavirus isolates from Korea and Finland. In the subsequent weeks, the newly identified Sin Nombre virus was proven to be the etiologic agent for HCPS [35-39]. Investigators subsequently identified other new hantaviruses as etiologic agents of rare cases of HCPS in the United States and as common etiologic agents of HCPS in South and Central America [40-45]. Cases have been identified in 36 states in the United States since the 1993 outbreak, with the majority of cases occurring in non-Native Americans [46].

WORLDWIDE PREVALENCE — It is likely that many cases of hantavirus disease go unreported, due in part to clinical confusion with leptospirosis, dengue fever, malaria, coronavirus disease 2019 (COVID-19), and other entities, especially in tropical regions. China bears the highest annual incidence by far of hantavirus disease. From 16,000 to 100,000 or more cases of hemorrhagic fever with renal syndrome (HFRS) are reported every year in China, and thousands of cases are likely to occur in Russia (table 1). Chinese cases of HFRS are now most commonly caused by Seoul virus, with some cases caused by Hantaan virus.

Several thousand cases of HFRS due to Puumala and Dobrava viruses occur annually throughout Europe, but accurate counts are unavailable. Case-fatality rates range from <1 percent for nephropathia epidemica (Puumala virus-HFRS) to 2 to 10 percent (Hantaan or Dobrava viruses) [3]. Case-fatality ratios in China are 1 percent, with women having slightly higher case-fatality rates than men [47]. In 2012, two cases of HFRS due to Seoul virus were detected in the United Kingdom; one was traced to wild rats and the other to pet rats [48,49]. HFRS due to Seoul virus has also been observed rarely in the United States [31-33], but an outbreak of Seoul virus infections occurred in 2016. (See 'The recognition of hantaviruses' above and 'Outbreaks' below.)

As of January 2021, 833 cases of hantavirus cardiopulmonary syndrome (HCPS) had been documented in the United States, including a few that were retrospectively recognized after the disease was identified in 1993 [50-56]. Increased numbers of HCPS cases were reported in the United States from January through March 2006 [57] as well as from 1993 to 1994 and 1999 to 2000. These increases have been linked temporally to precedent El Niño Southern Oscillation (ENSO) climate events, but such linkage could be coincidental [12].

Canada reports 10 to 15 percent of North American cases each year [58]. Other countries that have experienced hantavirus activity include Argentina, Bolivia, Brazil, Chile, Ecuador, Panama, Paraguay, Peru, Uruguay, French Guiana, and Venezuela [2,59-61]. Collectively, more than 3000 cases of HCPS have been identified throughout the Americas, far less than the Eurasian total for HFRS. However, the case-fatality ratios are much higher for HCPS than for HFRS, typically ranging from 25 to 50 percent. Treatment is generally unsatisfactory for HCPS, whereas ribavirin may be effective against HFRS due to Hantaan virus. (See "Hantavirus cardiopulmonary syndrome".)

In all countries affected by hantavirus disease, there are regions that exhibit a high incidence of infection and others that are only rarely affected. In the United States, there are many more cases in the western and southwestern states such as New Mexico, Arizona, California, Washington, Colorado, Montana, and Texas than in the midwestern or eastern states [55]. Montane biomes in western states, such as in California, New Mexico, and Colorado, are particularly favored terrain for deer mice, and human infections are often acquired at elevations above 2000 meters [62]. Climatic influences imposed, for example, by the ENSO are thought to be important factors in the incidence of hantavirus disease, but the mechanism by which ENSO might influence the incidence of HCPS remains a matter of speculation [12]. The geographic locations that experience high hantavirus incidence can change dramatically and unexpectedly, and the potential impacts of climate change are highly unpredictable.

OUTBREAKS — As noted above, the event that brought hemorrhagic fever with renal syndrome (HFRS) to the attention of Western medicine was a large outbreak among United Nations troops between 1951 and 1953 during the Korean conflict. (See 'The recognition of hantaviruses' above.)

Some examples of subsequent outbreaks caused by hantaviruses include the following:

●In the spring of 1993, an alarming series of cases of unexplained fever and acute respiratory distress syndrome (ARDS) were recognized among members of the Navajo tribe at the northern border between New Mexico and Arizona and were found to be caused by Sin Nombre virus. (See 'The recognition of hantaviruses' above.)

●An outbreak of hantavirus infection occurred among 10 visitors to Yosemite National Park in California during the summer of 2012, including nine cases of HCPS and three fatal cases [63,64]. Nine patients had stayed in one group of insulated tent cabins. Rodent infestations were discovered in the insulation.

●In December 2016, a woman who kept pet rats in Tennessee, United States, developed an acute febrile illness with hematuria and elevated serum creatinine and was found to have Seoul virus infection [65]. She subsequently recovered. A family member who lived with the index patient also became ill and tested positive after handling rat droppings. Another case was reported from the District of Columbia in 2018 [66].

●In January 2017, an outbreak of Seoul virus infections in rat breeders and pet rat owners was identified in Wisconsin [65,67,68]. A subsequent investigation identified 24 persons infected with Seoul virus during the outbreak, which involved ratteries, pet stores, and households with pet rats across 11 states and Canada [68]. Recommendations for testing potentially exposed individuals and other information can be found on the United States Centers for Disease Control and Prevention's website.

Infected rats have also been recognized in commercial breeding colonies in the United Kingdom, and further intervention may be needed to reduce worldwide risk to potential rodent owners [69].

SEROPREVALENCE — Human past exposure to hantaviruses, as determined by the presence of specific IgG antibodies, varies greatly throughout the world. Epidemiologic data are conflicting regarding the incidence of asymptomatic infections. The ratio of symptomatic to asymptomatic infection for Hantaan virus was approximately one to five in the single population-based study that attempted to quantify this ratio [70]. In contrast, in other regions, the ratio of symptomatic infections to total infections is quite low. While Indigenous Peoples of the Paraguayan Chaco have seroprevalences of 40 percent, clinical onset of hantavirus cardiopulmonary syndrome (HCPS) is rare [71,72]. Similar high prevalence has been reported in Panama [73]. Hantavirus antibodies are considered to be relatively long lasting, with cases still readily diagnosed by presence of specific serum IgG as long as 36 or approximately 20 years after clinical symptoms [52-54].

It is not clear whether differences among hosts or variations in virulence among specific hantaviruses explain the variation in the incidence of infection and disease presentation. In the United States, the most affected populations reside in Arizona, Colorado, New Mexico, and Utah, where the seroprevalence is approximately 1 percent [74-76]. However, the adult population of the United States is believed to have a seroprevalence of less than 0.1 percent. Children uncommonly present with hemorrhagic fever with renal syndrome or HCPS, except in South America, where children as young as five years of age have died of HCPS [77]. However, in 2009, five cases of HCPS were reported among children 6 to 14 years of age in the western United States [76]. Several more cases involving children as young as 5 years have appeared in subsequent years in the United States [78].

The seroprevalence is likely higher in persons with close contact with rats but may vary with the type of rodent and degree of exposure. In a seroprevalence study in the United Kingdom, approximately one-third of owners and breeders of pet fancy rats (a common breed of domesticated rat) had antibodies to Seoul virus, whereas the seroprevalence in persons with occupational exposure to pet or wild rats was not increased relative to the general population [79]. These data suggest pet fancy rat owners/breeders are at particularly high risk for clinical or subclinical hantavirus infection.

SEASONALITY AND CYCLICITY OF HANTAVIRUS ACTIVITY — Hantavirus infections occur in seasonal outbreaks, which vary substantially in incidence from year to year and from site to site.

●Chinese outbreaks of hemorrhagic fever with renal syndrome (HFRS) occur in the spring as crops are planted, and a second, larger cluster of cases follows in the fall. At that time, workers are involved in the fall harvest and may become exposed by sleeping in poorly sealed huts with rodent infestations.

●In Scandinavia, cyclical outbreaks of HFRS occur every several years and appear to be immediately preceded by irruptions of wild voles [80-82].

●In Chile, a 2001 outbreak of human disease was associated with an abrupt increase in abundance of the colilarga (Oligoryzomys longicaudatus), the mouse species reservoir for Andes virus [83].

PATTERNS OF INFECTION — Well over 90 percent of United States and Canadian cases of hantavirus cardiopulmonary syndrome (HCPS) are sporadic.

By contrast, approximately 25 to 30 percent of cases of HCPS in Chile occur in clusters [84]. It is usually presumed that these cluster-cases patients were exposed to a common source, such as an infectious rodent that was actively shedding an unusually large amount of virus. However, person-to-person transmission has been suspected in some patients who developed symptoms many days or weeks after those of the index patient in locations distant from the rodent infestation [18].

Cases of HCPS have occurred during pregnancy. In one series, the clinical presentation did not differ for five pregnant patients compared with historical controls with HCPS who were not pregnant [85]. One maternal and two fetal deaths were reported, but no evidence of vertical transmission of Sin Nombre virus was documented. Breast milk can be positive for Sin Nombre virus RNA, but breastfeeding has not been linked to transmission of virus [86]. Neonatal infections with hantaviruses are very rare [87].

DIAGNOSIS — Serologic methods are preferred for diagnosis of either human or rodent hantavirus infections in most laboratories. Algorithms have been developed to help distinguish hantavirus infection from leptospirosis clinically but are not sufficient for diagnosis [88].

Serologic tests — Serologic tests are the main methods for diagnosis of either acute or remote infection by hantaviruses, although none has been approved by the US Food and Drug Administration. By the time symptoms are evident, patients uniformly have antiviral antibodies of the IgM class and most have antibodies of the IgG class [89,90]. Diagnostic assays include enzyme-linked immunosorbent assays (ELISAs), strip immunoblot tests (SIAs), Western blot, indirect immunofluorescence (IFA), complement fixation, and hemagglutinin inhibition as well as focus or plaque reduction neutralization tests to detect antibodies to hantavirus antigens [91].

Acute infection can be distinguished from remote (past) infection by the presence of specific anti-hantavirus IgM in the former (usually the nucleocapsid or N antigen is used) or a fourfold rise in titers of anti-hantavirus IgG. Sin Nombre virus (SNV) infection can be distinguished from infections by other hantaviruses with the SIA by virtue of the reaction of anti-SNV serum samples against the SNV Gn antigen [75].

In the United States, those state health departments that offer hantavirus diagnostic testing use IgG and mu-capture IgM ELISAs developed and distributed by the United States Centers for Disease Control and Prevention. These ELISAs use recombinantly expressed N antigen. This test has also been used in Canada [90]. A Western blot assay using recombinant antigens and isotype-specific conjugates for IgM-IgG differentiation has also been developed, which performs similarly.

Hantaan virus and Seoul virus infections are often diagnosed in the Asian centers where hemorrhagic fever with renal syndrome (HFRS) occurs using bead agglutination (HantaDia), ELISA, and IFA formats [92]. European laboratories favor ELISA, with some using protein antigens synthesized through recombinant deoxyribonucleic acid (DNA) technology, although IFA is still used by some [93-96]. South American reference laboratories usually use ELISA [97].

Polymerase chain reaction — For hantaviruses that cause fulminant infection with high case-fatality rates (Andes, Sin Nombre, Dobrava, and possibly Hantaan viruses [98]), it is generally possible to detect viral RNA by nested reverse-transcriptase polymerase chain reaction (RT-PCR) using peripheral blood mononuclear cells or serum during the early stages of pulmonary disease. However, viral RNA usually disappears from the circulation after a few days, and serologic techniques have high diagnostic accuracy. For the infections caused by Puumala virus, which typically causes mild infection, RNA can be detected in only a small minority of patients (usually those who have an unusually severe infection). For these reasons, few if any clinical laboratories offer a routine RT-PCR diagnostic test. RT-PCR is more useful as a backup or confirmatory diagnostic test or for identifying possible sites of infection [91].

Autopsy testing — At autopsy, viral antigen can be readily detected by immunohistochemistry using antibodies to the viral N antigen. The N antigen stains in a cytoplasmic, punctuate pattern and localizes especially to the vascular endothelium in lungs and the glomerular capillary endothelium in the kidney [99,100]. Nested RT-PCR can be used to detect viral RNA in frozen or even fixed, paraffin-embedded tissues obtained at necropsy [36,39].

MOLECULAR EPIDEMIOLOGY — Detection of individual viral genetic sequences has been used as an investigational tool for molecular epidemiologic research. While it appears that particular viral genotypes may remain stable in a given small geographic area for years, it is very unlikely that one will encounter two viruses of identical sequence across a distance of several kilometers or more [101]. Thus, reverse-transcriptase polymerase chain reaction (RT-PCR) amplification followed by DNA sequencing of the PCR product from a human sample can provide useful information about the viral species involved and the precise site of exposure. By comparing the viral RNA sequence from a given patient with those obtained from nearby infected rodents or even from other patients in the region, it may be possible to distinguish infections acquired peridomestically from those acquired at a workplace.

To conduct this type of investigation, it is necessary to collect at least 3 to 10 seropositive rodents from each candidate site of exposure. In the experience of the University of New Mexico's Center for Infectious Diseases and Immunity, a virus of identical sequence to that of the case-patient can be identified in at least two of three attempts where an adequate investigation is completed [101].

SUMMARY

●Rodent reservoirs – Both Old World (hemorrhagic fever with renal syndrome [HFRS]) and New World (hantavirus cardiopulmonary syndrome [HCPS]) hantaviruses are carried and transmitted by wild rodents. Infections come in endemic and epidemic forms, often in response to natural rodent irruptions. Eleven pathogenic species of hantavirus have been identified throughout the world, with distributions corresponding to those of their rodent carriers (table 1). Patients acquire the infection via aerosols of rodent excreta, usually in closed, poorly ventilated buildings or during cleaning. (See 'Introduction' above and 'Rodent reservoirs' above and 'Transmission' above.)

●Geographic distribution – China bears the highest annual incidence of hantavirus disease. From 16,000 to 100,000 or more cases of HFRS are reported every year in China, and thousands of cases are likely to occur in Russia. By comparison, only 833 cases of HCPS have been documented in the United States. Clinical episodes of hantavirus disease also occur in other parts of the world, such as Europe and South America (table 1). (See 'Worldwide prevalence' above.)

●Mortality varies by viral species – Case-fatality ratios are highly dependent upon the species of infecting virus. In some regions of the world, there is evidence for considerable numbers of asymptomatic or subclinical infections, but, in other regions, it is difficult to find persons who have been exposed without a history of disease. (See 'The recognition of hantaviruses' above and 'Worldwide prevalence' above.)

●Serologic diagnosis – Serologic tests are the main methods for diagnosis of either acute or remote infection by hantaviruses. By the time symptoms are evident, patients uniformly have antiviral antibodies of the immunoglobulin (Ig)M class and most have antibodies of the IgG class. Acute infection can be distinguished from remote (past) infection by the presence of specific anti-hantavirus IgM in the former (usually the nucleocapsid or N antigen is used) or a fourfold rise in titers of anti-hantavirus IgG. (See 'Serologic tests' above.)

●Role of polymerase chain reaction – For hantaviruses that cause fulminant infection with high case-fatality rates (Andes, Sin Nombre, Dobrava, and possibly Hantaan viruses), it is generally possible to detect viral RNA by nested reverse-transcriptase polymerase chain reaction using peripheral blood mononuclear cells or serum during the early stages of pulmonary disease. However, viral RNA usually disappears from the circulation after a few days. (See 'Polymerase chain reaction' above.)