Global threats and regional trends: Navigating the complex landscape of human orthohantavirus infections

Abstract

Orthohantavirus infections constitute a significant global public health challenge, predominantly presenting as two distinct clinical syndromes: hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia and hantavirus pulmonary syndrome (HPS) in the Americas. Epidemiological data indicate considerable geographic variability in disease incidence, influenced by intricate interactions among ecological, socioeconomic, and public health determinants. In Asia, a notable reduction in cases has been achieved through enhanced economic conditions, strategic public health initiatives, and effective management of rodent populations. Conversely, Nordic countries continue to report high HFRS incidence, which is attributed to ecological conditions conducive to sustaining reservoir rodent populations. South America has experienced an upward trend in cases, raising concerns about potential large-scale outbreaks, while emerging reports from Africa suggest a possible expansion of endemic regions. Notably, Australia remains one of the few regions without documented orthohantavirus infections and presents a unique epidemiological profile. This review comprehensively examines the global distribution of orthohantavirus infections, analyzes key epidemiological trends, and discusses the environmental and socioeconomic determinants influencing disease dynamics, providing critical insights for public health preparedness and intervention strategies.

1. Introduction

Orthohantaviruses, which are zoonotic pathogens of significant global public health concern, persist in causing considerable human infections globally. Initially identified in 1913,^[1] cases of orthohantavirus infections were later reported in Japan and Sweden between 1932 and 1934, and they garnered heightened attention during the Korean War from 1951 to 1954.^[1]

Orthohantaviruses, classified within the Hantaviridae family and class Bunyaviricetes,^[1] are enveloped, negative-sense RNA viruses distinguished by a tripartite genome. This genome encodes the RNA-dependent RNA polymerase (L segment), glycoproteins GN and GC (M segment), and nucleocapsid protein (S segment). Rodents serve as the primary natural reservoirs for these viruses, with transmission predominantly occurring via inhalation of aerosolized particles from contaminated rodent excreta, including urine, feces, and saliva. Additional transmission routes encompass direct contact, ingestion, vector-borne mechanisms, and, in rare cases, transplacental transmission. The global distribution of orthohantaviruses is sustained through intricate ecological cycles involving a variety of animal hosts.

Human infections present as two distinct clinical syndromes: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome (HPS) in the Americas. This review offers a thorough analysis of the global epidemiology of orthohantavirus infections, integrating the most recent surveillance data and exploring the ecological factors influencing disease transmission and distribution patterns.

Hantaviridae are classified into seven genera, of which only the orthohantavirus genus is associated with human disease. Rodents serve as the primary reservoir for orthohantaviruses (Table 1). In the Americas, several orthohantaviruses, including Andes, Bayou, Black Creek Canal, Choclo, Laguna Negra, Maporal, and Sin Nombre, have been identified as etiological agents of HPS in humans. In contrast, other continents have reported distinct orthohantaviruses responsible for HFRS. Notably, the Seoul virus (SEOV) is recognized for its worldwide distribution and its ability to cause HFRS. Conversely, viruses such as Itapua, Lúxī, Hokkaido, Muju, Serang, and Maciel are geographically confined to specific countries and have not historically exhibited widespread distribution.

Table 1.

Pathogenic orthohantaviruses and their respective reservoir hosts

Species[2]	Virus[2]	Primary rodent host	Disease	Distribution
Orthohantavirus andesense	Andes virus	Oligoryzomys longicaudatus	HPS	South America, Chile, Uruguay, Argentina and surrounding countries
	Castelo dos Sonhos virus	Oligoryzomys eliurus	HPS	South America, Brazil, Argentina and surrounding countries
	Lechiguanas virus	Oligoryzomys flavescens	HPS	South America, Uruguay, Argentina and surrounding countries
	Orán virus	Oligoryzomys longicaudatus	HPS	South America, Argentina and surrounding countries
Orthohantavirus bayoui	Bayou virus	Oryzomys palustris	HPS	United States
	Catacamus virus	Not known	HPS	Not known
Orthohantavirus nigrorivense	Black Creek Canal virus	Sigmodon hispidus	HPS	North America, USA
Orthohantavirus chocloense	Choclo virus	Oligoryzomys fulvescens	HPS	North and South America, Panama
Orthohantavirus dobravaense	Dobrava virus	Apodemus flavicollis	HFRS	Europe, Balkans, Russia
	Kurkino virus	Not known	HFRS	Russia
	Saaremaa virus	Apodemus agrarius	HFRS	Denmark, Europe
	Sochi virus	Apodemus ponticus	HFRS	Europe, Russia
Orthohantavirus hantanense	Amur virus	Apodemus peninsulae	HFRS	Far East of Russia, China, Republic of Korea
	Hantaan virus	Apodemus agrarius	HFRS	China, Republic of Korea, Russia
Orthohantavirus mamorense	Laguna Negra virus	Calomys laucha	HPS	South America, Brazil, Paraguay, Bolivia, Argentina
	Maripa virus	Not known	HPS	French Guyana
	Rio Mamoré virus	Oligoryzomys microtis	HPS	Bolivia, Brazil, Peru
Orthohantavirus maporalense	Maporal virus	Oligoryzomys delicatus	HPS	South America
Orthohantavirus luxiense	Lúxī virus	Eothenomys miletus	HFRS	China
Orthohantavirus puumalaense	Puumala virus	Myodes glareolus	HFRS	Europe, Russia, Asia and Americas
	Hokkaido virus	Myodes rufocanus	HFRS	Japan
	Muju virus	Myodes regulus	HFRS	Republic of Korea
Orthohantavirus seoulense	Gōu virus	Not known	HFRS	Not Known
	Seoul virus	Rattus norvegicus	HFRS	worldwide
Orthohantavirus sinnombreense	New York virus	Peromyscus leucopus	HPS	North America, USA
	Sin Nombre virus	Peromyscus maniculatus	HPS	North America, USA
Orthohantavirus thailandense	Serang virus	Rattus tanezumi	HFRS	Indonesia
	Thailand virus	Bandicoot indica	HFRS	Thailand, Sri Lanka
Orthohantavirus tulaense	Tula virus	Microtus arvalis	HFRS	Europe, Russia
Unclassified viruses	Anajatuba virus	Oligoryzomys fornesi	HPS	South America, Brazil
	Paranoa virus	Not known	HPS	Argentina and surrounding countries
	Araucaria virus	Oligoryzomys nigripes	HPS	South America, Brazil
	Juquitiba virus	Oligoryzomys nigripes	HPS	South America, Uruguay, Argentina and surrounding countries, Brazil
	Bermejo virus	Bolomys Lasiurus	HPS	South America, Bolivia, Paraguay, Argentina and surrounding countries

According to the classification system established by the International Committee on Taxonomy of Viruses, several additional viruses, including Artybash virus, Asama virus, Asikkala virus, Bowé virus, and Bruges virus, among others, are categorized within the genus Orthohantavirus. Nonetheless, there is currently no scientific literature providing evidence that these viruses are capable of causing diseases in humans.^[2] In contrast, the Maciel virus and Monongahela virus have not been classified by the International Committee on Taxonomy of Viruses. However, certain scholarly sources suggest that both viruses are capable of causing hantavirus pulmonary syndrome (HPS), with the Maciel virus being identified in Argentina and the Monongahela virus documented in North America.^[3–5] HFRS: Hemorrhagic fever with renal syndrome.

2. Distribution and epidemiological trends of orthohantavirus

2.1. Asia

2.1.1. East Asia

China is recognized as one of the world’s most heavily endemic regions for HFRS. However, extensive control measures have substantially mitigated the disease burden. The first documented outbreaks of orthohantavirus in China were reported in Heilongjiang Province in 1931. Following the establishment of a national epidemic reporting system in 1950, surveillance data indicated a total of 1,346,816 cases and 45,349 fatalities (case fatality rate [CFR]: 3.37%) from 1950 to 1999.^[6] The incidence of HFRS reached its zenith in 1986, with 115,806 reported cases, which led to the initiation of nationwide rodent control campaigns that successfully halved the number of cases by 1987. The introduction of large-scale vaccination programs in 1995 further contributed to the decline in incidence, with only 5,549 cases reported in 2023. Between 2000 and 2023, China documented 356,650 cases and 3,046 deaths (CFR: 0.85%),^[7,8] reflecting sustained epidemiological improvement (Figure 1).

Figure 1.

The incidence and mortality rates of hemorrhagic fever with renal syndrome in China from 1950 to 2023.

Republic of Korea has similarly experienced a significant burden of HFRS, although the incidence has markedly decreased since the 1990s. Following the first cases reported in 1951, the cumulative number of diagnoses reached 14,309 by 1986, with the number of annual hospitalizations ranging from 500 to 900.^[9] The implementation of vaccination programs in the 1990s contributed to a reduction in cases. Between 2001 and 2017, a total of 7,048 confirmed cases was documented, with a fatality rate of 1.26%.^[10] Recent data (i.e., from 2011 to 2023) indicate 5,261 cases,^[11] with a declining trend observed since 2016.

Japan presents a distinctive epidemiological context, characterized by the absence of reported human cases of orthohantavirus infection since 1984 despite the persistence of the virus in rodent populations. Historical documentation reveals instances of HFRS among Japanese soldiers in China between 1931 and 1942, with the first domestic case identified in 1960. National surveillance data from 1999 to 2015 corroborate the absence of HFRS and HPS cases, although the limited availability of data post-2015 necessitates continued vigilance.^[12] These divergent epidemiological trends across East Asia underscore the efficacy of sustained public health interventions while emphasizing the importance of ongoing surveillance in regions where enzootic transmission occurs.

2.1.2. Southeast Asia

In Southeast Asia, the incidence of orthohantavirus infection has been relatively constrained, with sporadic cases reported only in Thailand, Singapore, and Indonesia. In 1985, a research team in Thailand collected serum samples from local individuals and utilized the indirect immunofluorescence assay (IFA) method to confirm the presence of orthohantavirus antibodies, thereby providing the first evidence of human infection with orthohantavirus in Thailand. Furthermore, the Thailand orthohantavirus strain was isolated during this period. Between May 1999 and November 2000, a cohort of 115 patients presenting with fever of unknown origin was enrolled at Siriraj Hospital for serological analysis. Among these patients, five tested positive for IgG antibodies and eight for IgM antibodies against orthohantavirus. This investigation represented the first documented clinical case of orthohantavirus infection in Thailand.^[13] In Singapore, three cases of orthohantavirus infection in humans were reported in 1996, with no further cases documented until 2024, when an additional case was identified.^[14,15] In Indonesia, the first case was reported in 2002, followed by a substantial hiatus (exceeding a decade) until 2018, when two more cases of human hantavirus infection were reported.^[16,17]

2.1.3. South Asia

In South Asia, orthohantavirus infections have been documented in both India and Sri Lanka, with India exhibiting a relatively low incidence of human cases compared to the higher prevalence observed in Sri Lanka. Notably, in 1964, researchers successfully isolated the Thottapalayam virus (TPMV), which is now known as Thottimvirus, from the spleen of the insectivore species Suncus murinus in India. Thottimvirus was historically classified within the Hantaviridae genus. However, following a virological reclassification, most of the viruses previously categorized under the Hantaviridae genus were reassigned to the Orthohantavirus genus. Recent scholarly proposals have advocated for the establishment of Thottimvirus as a distinct genus. Despite the early identification of TPMV in insectivores within India, documented human cases in the country have remained relatively scarce. In 2000, serological testing identified only nine patients as positive for orthohantavirus IgM or IgG antibodies, with one fatality directly linked to an orthohantavirus-related illness.^[18] Sporadic cases were subsequently reported in 2005, 2006, and 2007, with 23 cases,^[19] 47 cases,^[20] and one case reported,^[21] respectively. It is noteworthy that the first human orthohantavirus infection in Sri Lanka was documented in 1988. In Sri Lanka, serological screening of 1,032 patients with suspected HFRS revealed that 168 individuals tested positive for orthohantavirus IgM antibodies, thereby confirming acute orthohantavirus infection between 2013 and 2021.^[22] Furthermore, in 2024, an atypical case was reported in the country involving a patient infected with the Puumala virus (PUUV), who developed an unusual pulmonary infection.

2.1.4. West Asia

In West Asia, orthohantavirus has been documented across several countries, including Turkey, Georgia, Iran, Saudi Arabia, and Israel. Both outbreaks and sporadic cases of orthohantavirus infection have been reported in these regions over the years. In Turkey, a notable increase in orthohantavirus IgG-positive cases was observed in 1997 and 2004, followed by a significant outbreak in 2009. This outbreak resulted in 55 suspected cases of HFRS between February and June 2009, with 22 patients confirmed to have orthohantavirus infection.^[23] Furthermore, from 2012 to 2018, at least 20 cases of hantavirus infection were documented in a hospital in the country.^[24] While orthohantavirus cases are sparsely documented in Georgia, evidence from neighboring regions indicates their presence in the Caucasus. Notably, only a single male case was documented in 2008.^[25] In Iran, orthohantavirus cases have been reported since 1982, yet only one case had been officially recorded by 2013.^[26] Between 2014 and 2016, IgM and IgG antibodies for orthohantavirus were detected in 19 and four out of 113 serum samples analyzed, respectively.^[27] Another study identified two IgM-positive and seven IgG-positive patients.^[28] In Israel, a 1998 study found that 12.3% of patients with renal failure exhibited elevated PUUV antibodies, and 3.7% tested positive for hantavirus IgG.^[29] However, Israel did not report its first case of HFRS until 2022.^[30] In contrast, Kuwait, which is also located within the region, has not recorded any human infections with orthohantavirus.

2.1.5. Central Asia

A cross-sectional study carried out in 2023 in the western region of Kazakhstan identified a local orthohantavirus seroprevalence rate of 3.1%.^[31] Conversely, there is a marked paucity of data concerning human cases of orthohantavirus infection in other Central Asian nations, including Turkmenistan, Uzbekistan, Kyrgyzstan, and Tajikistan.

2.2. Europe

European countries maintain comprehensive datasets on human orthohantavirus infections. Annually, over 10,000 cases are reported across Europe, with fatality rates ranging from 0.1% to 15%.^[32,33] During the period between 2011 and 2020, six countries—namely, Russia, Finland, Germany, Sweden, France, and Croatia—each documented more than 1,000 cases, collectively accounting for a significant 97% of all reported cases in Europe, as depicted in Figure 2.

Figure 2.

The incidence of orthohantavirus infections in selected European countries from 2014 to 2023.

2.2.1. Northern Europe

In Northern Europe, the nations of Finland, Sweden, and Norway have historically experienced a significant impact from orthohantaviruses. However, in recent years, there has been a notable decrease in the incidence of orthohantavirus infections throughout this region, with case numbers consistently remaining low.

Between 1979 and 2023, Finland reported a cumulative total of 47,011 cases of orthohantavirus infection in humans.^[34–39] The first documented instance of hantavirus infection in humans in Finland occurred in 1964, with the PUUV being isolated in the 1980s. Annually, the number of reported cases ranged from 1,000 to 3,300, resulting in an average incidence of 31–39 cases per 100,000 individuals per year by 2021, positioning Finland as having the highest incidence rate globally.^[40] In Finland, the incidence of orthohantavirus infection gradually increased until 1997 and then surged significantly between 1998 and 1999. Subsequently, the number of cases fluctuated considerably from 1999 to 2023, reaching a peak in 2008 with 3,259 cases.^[34–39] (Refer to Figure 3 for data visualization).

Figure 3.

The incident cases of orthohantavirus infections in Finland.

In Sweden, a cumulative total of 7,244 human cases of orthohantavirus infection was documented from 1964 to 2013.^[41] This number declined to 1,412 cases during the period from 2014 to 2020.^[36–38] The first recorded instance of orthohantavirus infection in Sweden dates back to 1934, when the disease caused by the virus was identified as nephropathia epidemica (NE). According to data from the European Centre for Disease Prevention and Control (ECDC), Sweden experienced an average of nearly 500 cases annually from 1994 to 2020. However, 2007 witnessed a significant surge in numbers, and a record high of 2,195 cases was reached. Notably, approximately 90% of the reported cases in Sweden are concentrated in four northern regions: Norrbotten, Västerbotten, Jämtland, and Västernorrland.

In Norway, the first documented instance of orthohantavirus infection in humans was recorded in 1946. Subsequently, an average of 50 cases was diagnosed annually until 1998.^[42] According to statistics from the ECDC, a total of 1,824 cases was diagnosed in Norway between 1990 and 2023. The number of confirmed cases remained below 100 in all years except 1998, 2002, and 2003, when over 100 cases were reported, indicating an overall declining trend.^[34–39] In Denmark, a few cases have been reported over the past decades, with a study confirming that 184 patients were infected with orthohantaviruses between 1996 and 2012,^[43] including a pregnant woman at 30 weeks of gestation. In contrast, no cases of orthohantavirus infection in humans were reported in Iceland between 2005 and 2023.

2.2.2. Western Europe

In Western Europe, the incidence of orthohantavirus infections has generally been lower than in Northern Europe. Nevertheless, cases were reported in all countries except Monaco between 1979 and 2023. From 2006 to 2023, Belgium documented 2,059 cases, although the incidence exhibited a declining trend.^[34–39] In France, indigenous transmission was first identified in 1987. The annual incidence averaged approximately 60 cases.^[44] The majority of affected individuals were primarily engaged in agriculture, forestry, and related occupations. Moreover, a significant case in 2005 marked the first reported orthohantavirus infection during pregnancy. In addition, a case of Seoul virus infection was identified in the country, where the patient subsequently developed Guillain-Barré syndrome (GBS) in 2022.^[45] The Netherlands reported its first human case in 1984. Between 1994 and 2023, 151 cases were documented, predominantly affecting males.^[34–39] While PUUV is the primary causative agent, infections with SEOV have also been identified, including cases associated with citizens in 2016 and 2017. In Luxembourg, although the literature is limited, data from ECDC indicate 166 cases between 2000 and 2023, with a peak incidence in 2021,^[34–39] underscoring the necessity for increased attention to this pathogen. In Ireland, orthohantavirus antibodies were detected in 16 out of 727 residents in 1994, suggesting potential transmission.^[46] However, only two human cases were reported between 2011 and 2020, with no cases reported thereafter.^[35–39] The United Kingdom reported its first cases in 1977 among laboratory workers exposed to rats. Between 2005 and 2023, 18 cases were documented,^[34–39] and 29 seropositive cases were identified in 1993 among patients with acute kidney injury.^[47]

2.2.3. Central Europe

In recent years, Central Europe has experienced a significant rise in orthohantavirus infections despite historically low incidence rates. In Germany, HFRS was first identified in 1998. Between 2001 and 2019, a total of 16,606 cases was documented, with annual incidences typically remaining below 1,000, except during outbreak years, such as 2010, 2012, 2017, and 2021.^[34–39,48] In Austria, the seropositivity rate stands at 1.2%, with 1,559 cases reported between 1993 and 2023.^[34–39] The annual average number of cases increased from 30 before 2014 to 90 between 2014 and 2020, indicating an upward trend.^[34–39,49] In Hungary, 55 HFRS cases were confirmed between 1987 and 1993,^[50] with the cumulative total reaching 436 cases by 2023, including an outbreak of 78 cases in 2000.^[34–39] In 2007, Poland initiated systematic surveillance, resulting in the documentation of 128 cases by 2017.^[51,52] The annual incidence remained stable at approximately 15 cases until 2023, with a notable outbreak of 50 cases occurring in 2014.^[35–39] In Slovakia, two deaths related to HFRS were reported in the 1950s,^[53] and 746 cases were documented between 2007 and 2023, indicating an increasing trend with two peaks observed in recent years.^[34–39] In Switzerland, only two cases were reported between 2000 and 2010,^[35,36] but a familial cluster of three cases, including a severe instance of multiple organ failure, was identified in 2019.^[54] The Czech Republic reported its first human cases in 1992, with a total of 164 cases documented by 2023,^[34–39] demonstrating a consistent upward trend.

2.2.4. Eastern Europe

In Eastern Europe, Russia bears the predominant burden of orthohantavirus infections, consistently reporting a high number of cases, whereas other countries in the region have experienced a decline in recent years. Historically, Russia, formerly part of the Soviet Union, was the first nation to systematically document orthohantavirus infections, with records dating back to 1913. The distribution of HFRS cases within Russia reveals substantial geographical disparities. Between 1990 and 2015, a total of 194,116 HFRS cases was reported, with the Privolzhsky Federal District exhibiting the highest incidence, accounting for 86.4% of the national morbidity.^[55] From 2000 to 2022, a cumulative total of 164,580 HFRS cases was reported across 69 of Russia’s 85 administrative regions, resulting in an average annual incidence rate of 4.9 cases per 100,000 population.^[56] Over the past two decades, Russia has experienced a consistent trend of HFRS morbidity, characterized by non-declining rates and cyclical epidemics occurring every three to four years and occasionally every two years.

In Estonia, limited data from the past decade (2010–2020) reveal 190 reported cases.^[36–38] Furthermore, a serological investigation detected Hantavirus IgG in 124 positive samples across 14 counties,^[57] indicating a major outbreak. In Latvia, seroprevalence studies conducted in 2002 revealed that 15 out of 333 samples tested positive for orthohantavirus IgG.^[58] From 2010 to 2023, fewer than eight cases were reported annually, except in 2012, when 12 cases were recorded.^[36–39] These findings imply that the reported cases might underestimate the actual prevalence of infections. In Lithuania, only nine cases were reported in 2004.^[34] In Ukraine, cross-reactivity to orthohantaviral antigens was observed in 1.6% of 966 healthy individuals tested.^[59] Several studies have identified orthohantavirus RNA or antibodies in various rodent species, suggesting that the prevalence of orthohantavirus is likely significantly underestimated. To date, no human cases of orthohantavirus infection have been reported in Belarus or Moldova, underscoring a gap in surveillance and reporting in these regions.

2.2.5. Southern Europe

Orthohantavirus infections are prevalent across Southern Europe; however, their pathogenicity seems to be decreasing. The first suspected case in the region was documented in 1952, with endemic transmission being confirmed by 1961. Infections have been recorded in 11 out of 17 surveyed countries, although a reduction in incidence has been noted in recent years. In Croatia, a total of 1,040 cases was reported from 2012 to 2023, including a notable outbreak in 2017 that accounted for approximately 400 cases. Nevertheless, the incidence rate declined over the subsequent three years.^[36–39] In Slovenia, the first case of HFRS was identified in 1954. Between 1985 and 2023, a total of 1,547 cases was documented, with a significant outbreak occurring in 2021 that accounted for 564 cases.^[34–39] In Bosnia and Herzegovina, data from 1990 to 2002 are limited; however, 354 cases were reported in 1995 and 136 cases in 2002. From 2005 to 2010, the annual incidence remained below 30 cases.^[34,35] In Montenegro, 169 cases of HFRS were diagnosed between 1995 and 2005,^[60] with an additional 106 cases reported in the following decade.^[61] Bulgaria recorded 399 cases of HFRS between 1954 and 1986, with a notably high fatality rate of 15.7%.^[62] Between 2002 and 2023, 99 confirmed cases were reported.^[35–39] In Serbia, sporadic cases were observed between 1979 and 1992, and epidemics in 1986 and 1989 resulted in 34 and 42 cases, respectively.^[63] A significant outbreak of 128 cases was reported in 2002, followed by 28 cases in 2017.^[64] Historically, Romania has underreported orthohantavirus infections, primarily due to limited diagnostic capabilities and a lack of awareness. Between 2005 and 2023, only 95 cases were documented.^[35–39] In Greece, the first case of HFRS was identified in 1982, and a total of 200 patients has been diagnosed since then.^[65] An outbreak in 1983 led to eight hospitalizations.^[66] Between 1997 and 2023, fewer than five cases were reported annually in most years.^[34–39] In Portugal, documentation is sparse, with 37 cases confirmed between 1993 and 2008.^[34–38] Albania reported 33 suspected HFRS cases between 2011 and 2016.^[67] In Spain, only two orthohantavirus cases have been confirmed over the past two decades.^[35–37] According to data from the ECDC, Italy reported no cases between 2005 and 2020. Furthermore, data for Malta, Cyprus, San Marino, Vatican City, and North Macedonia are unavailable, underscoring significant gaps in surveillance and reporting within these regions.

2.3. North America

In North America, orthohantavirus infections predominantly result in HPS, with the majority of cases documented in Canada, the United States, Panama, and Barbados. Although there has been a gradual decline in the incidence of HPS, the region continues to experience a high fatality rate associated with the disease. In the United States, orthohantavirus infections were first reported in 1959; however, the disease was not formally recognized until a later date. Systematic reporting of HPS cases commenced in 1993 through the U.S. Centers for Disease Control and Prevention (CDC). Between 1993 and 2022, a total of 828 cases was recorded, with a fatality rate of 33%.^[68] The annual incidence of cases remained below 50, exhibiting a declining trend from 48 cases in 1993 to 16 cases in 2022 (Figure 4).

Figure 4.

Orthohantavirus infection data in the United States (1993–2022), including annual numbers of cases (A), case fatality rate (B), survivors (C), and deaths (D). The horizontal axis spans from 1993 to 2022. Labels are placed every four years, so the last labeled year is 2021. The data for 2022 is also included in the chart but is not individually labeled.

Between 1989 and 2019, Canada reported 143 cases of orthohantavirus infection, with an associated fatality rate of approximately 30%.^[69,70] By 2024, Canada had confirmed more than 150 cases of HPS.^[71] In Panama, the first case was identified in the Los Santos region in 1999, followed by 12 cases and a fatality rate of 25%. From 1999 to 2010, over 100 cases were documented, with an annual average of approximately 12 cases.^[72,73] In Barbados, a highprevalence of orthohantavirus infection was observed, with 861 cases recorded between 2008 and 2016, corresponding to an average annual incidence of 33.03 cases per 100,000 individuals.^[74] A notable outbreak occurred in 2010, with an incidence rate of 100.16 cases per 100,000 people.^[74] In contrast, there is a lack of data on orthohantavirus infections for the broader Caribbean region, underscoring a significant gap in surveillance and reporting.

2.4. South America

Orthohantavirus infections represent a substantial public health concern in South America, exhibiting higher incidence rates than those observed in North America and maintaining a consistent fatality rate of approximately 35%. The majority of cases are concentrated in Brazil, Argentina, Chile, and other endemic areas, with sporadic outbreaks occurring throughout the continent (Table 2).

Table 2.

Presents the incidence of orthohantavirus infections in South America

Nation	First case	Period	Cases	Fatality rate (%)	Reference
Brazil	1993	1993–2002	200	40	[97]
		1993–2006	855	39.3	[98]
		1993–2007	884	39	[76]
		1993–2009	1,145	39.50	[75]
		1993–2013	1,906	40	[99]
		2001–2011	1,486	Not known	[100]
		2007–2015	1,060	39.0	[77]
Argentina	1996	1995–2008	710	25.8	[81]
		1996–2001	324	30	[75]
		1997–2017	902	21.4 to 25.8	[80]
		2009–2017	533	21.40	[82]
Chile	1975	1995–1998	33	54	[88]
		1995–2006	469	36	[89]
		1995–2012	786	20 to 60	[90]
		1995–2020	67/year	Not known	[72]
		2001–2009	Over 600	36	[18]
Venezuela	Not known	1989–2006	618	23	[91]
Uruguay	1997	1997–2020	9/year	Not known	[72]

Brazil accounts for the highest number of orthohantavirus cases in South America, with a fatality rate of approximately 39%.^[3,75–77] The first case of HPS was reported in 1993 in the southeastern region. Between 1993 and 2007, 884 cases were documented, with elevated incidence and fatality rates noted in the southern region.^[76] Between 2007 and 2015, 1,060 cases were reported, with a higher fatality rate observed in the northern region.^[77] Additionally, 32 pediatric HPS cases were diagnosed between 1999 and 2016, with a fatality rate of 34.4%.^[78] Recent reports in 2022 identified 22 new cases, underscoring the ongoing threat.^[79]

In Argentina, cases of HPS were initially identified in the Patagonia region in 1995. An outbreak comprising 18 cases was documented in Argentina in 1996. Between 1997 and 2017, a total of 902 HPS cases was reported, with the highest fatality rates observed in the southwestern endemic region.^[80,81] In July 2022 alone, 32 cases were diagnosed, resulting in five fatalities.^[78] The fatality rate has varied over time, ranging from 21.4% to 40.5%.^[81,82] Furthermore, in recent years, an increase in rodent populations, driven by the country’s climatic conditions, has led to a total of 78 HPS cases in northwestern Argentina. Specifically, 42 human infections were recorded in 2022, followed by 36 cases in 2023.^[83] Notably, in Argentina, multiple studies have reported cases of human-to-human transmission of the Andes virus, and the emergence of “super-spreaders” has even been noted.^[84,85] However, in 2022, a review article collected thousands of records concerning human-to-human transmission of Andes virus, and ultimately demonstrated that the evidence to date does not support the existence of human-to-human transmission of Hantavirus. Therefore, further rigorous research on this claim may be required.^[86]

In Chile, serological evidence of orthohantavirus was first detected in 1975, with the first human case identified in 1995. Between 1995 and 2020, an average of 67 cases was reported annually,^[72,73] with CFRs ranging from 20% to 60%.^[87–90] In Venezuela, 618 cases were diagnosed between 1989 and 2006, with a fatality rate of 23%.^[91] The serological confirmation of orthohantavirus antibodies in 23 serum samples in 2002 underscored the virus’s presence.^[92] Since 2007, there has been an upward trend in the number of reported cases.

Uruguay documented its first case of HPS in 1997, with an average incidence of nine cases per year since then.^[72] In Paraguay, the first recorded case occurred in 1995, followed by 56 cases in 2011 and 18 cases in 2007.^[72] Bolivia experienced several minor outbreaks between 2002 and 2012, culminating in 40 reported cases in 2018.^[93] Notably, during the COVID-19 pandemic, Bolivia reported a case of coinfection involving the COVID-19 virus and orthohantavirus.^[94] In French Guiana, human cases were infrequent until 2022, when four HPS cases were identified. Subsequent serological assessments indicated that 14 individuals tested positive, suggesting a wider exposure.^[95] The absence of data from other South American countries underscores substantial deficiencies in surveillance and reporting mechanisms across the continent.

South America accounts for the largest number of HPS cases globally. This is attributed to its unique environment, which is conducive to the survival of orthohantaviruses and their hosts. For the hosts, the tropical rainforests and tropical savanna climates in South America provide superior conditions for reproduction. Coupled with the abundant local vegetation that offers ample food sources, the host density in this region is significantly higher than in other areas. For the viruses, the relatively low-temperature and humid environment in South America serves as a natural culture medium. Experiments have demonstrated that under conditions of 70%–90% relative humidity and 18–20°C, the biological decay rate of hantavirus aerosols is 4.1% per minute, with a survival time exceeding 90 minutes.^[96] In the tropical regions of South America, nighttime temperatures generally range from 20°C to 25°C, and humidity in some areas remains above 80% year-round. This prolongs the survival time of orthohantaviruses, thereby increasing their opportunities for transmission.

2.5. Africa

With the increasing awareness and adoption of advanced medical technologies for the detection of orthohantavirus, a growing number of African countries has commenced documenting cases associated with this virus. The first isolation of orthohantavirus in Africa was recorded in 1982 from Rattus norvegicus in the Nile River Delta, Egypt, followed by sporadic annual reports of human cases in 2000. Serological evidence of orthohantavirus was first identified in 1984, with antibodies detected across multiple African nations. Between 1985 and 1987, a comprehensive serosurvey involving 5,070 individuals in central Africa revealed an infection rate of approximately 6.15%.^[101] The first documented case of HFRS in Africa was reported in the Central African Republic in 1987.

In 2009, the Sangassou virus (SANGV) was isolated from the tree-dwelling rodent species Hylomyscus simus in Guinea, and subsequent investigations identified orthohantavirus infections in 11 patients.^[102] Seroprevalence studies conducted in Côte d’Ivoire and Gabon in 2016 revealed the presence of orthohantavirus antibodies in 19 out of 330 and 16 out of 346 blood samples, respectively.^[103] In 2017, Mozambique reported its first serological evidence of orthohantavirus infection, identifying four IgM-positive samples.^[104] Similarly, in Sudan, nine patients tested positive for IgG antibodies against orthohantavirus in 2019.^[105] These findings emphasize the widespread yet underrecognized presence of orthohantavirus across Africa, highlighting the necessity for enhanced surveillance and diagnostic capabilities in the region.

2.6. Oceania

Compared to other continents, Oceania has documented relatively few cases of orthohantavirus infection, with isolated instances of HFRS primarily reported in Fiji. Although comprehensive research and numerous studies have been conducted in Australia, there is a lack of evidence for hantavirus infections in both human and animal populations, highlighting the distinct epidemiological characteristics of this region.^[106,107] A possible reason for this distinct epidemiological pattern is that Australia has unique geographical features. It has been separated from other continents by marine barriers for a considerable period, which has significantly reduced the probability of hantaviruses being introduced through animal migration and human activities.^[108] In addition, the hosts on which hantaviruses depend are scarce in Australia, and as native Australian rodent species have no phylogenetic relationship with the hosts of hantaviruses, they cannot support the in vivo replication of hantaviruses. Furthermore, hantaviruses prefer low-temperature and humid environments, and most areas in Australia are relatively arid, which is not conducive to the survival of hantaviruses. Although Australia has many natural advantages in preventing the transmission of hantaviruses, some studies have suggested that with the increasingly developed international transportation and the successive reports of hantavirus infections in neighboring countries, there is a potential risk of hantavirus invasion in Australia.

3. Challenges in reducing orthohantavirus infections and potential strategies

The global distribution of orthohantavirus infections is influenced by a complex interplay of ecological, socioeconomic, and behavioral factors. The significant reduction in infection rates in China illustrates the effectiveness of targeted public health interventions, improved living conditions, and agricultural reforms aimed at minimizing human–rodent interactions.^[109] As urbanization advances and rural populations decrease, the corresponding risk of hantavirus transmission declines, underscoring the impact of socioeconomic development on disease control. Conversely, the stable infection rates in Russia highlight ongoing challenges related to environmental and ecological factors, which require continuous public health initiatives.^[56] Additionally, the high incidence in Nordic countries underscores the need to understand local ecological dynamics, particularly as climate change may increase rodent populations and the associated risks of human exposure.

The increasing incidence of cases in South America accentuates the critical need for improved surveillance, swift response mechanisms, and proactive public health interventions to mitigate outbreaks. Concurrently, the appearance of hantavirus cases in Africa indicates an escalating public health issue, potentially exacerbated by environmental changes and heightened human intrusion into wildlife habitats. Climate change, evidenced by extreme weather events such as floods and droughts, may further exacerbate the risk of orthohantavirus dissemination to previously unaffected regions. This risk underscores the significance of ecological research in the prediction and prevention of outbreaks.^[110]

Effective governmental interventions, encompassing rodent population control and vaccination initiatives, are essential for mitigating the risks associated with orthohantavirus. Simultaneously, evolving human behaviors—such as the increase in outdoor recreational activities and the growing trend of keeping rodents as pets—may inadvertently contribute to the transmission of the virus.^[111,112] For vaccines, since the discovery of hantaviruses, global efforts have continuously intensified to advance research, development, and technological innovation targeting hantavirus vaccines. The first inactivated hantavirus vaccine was successfully developed in Republic of Korea in 1988, and over the next three decades, vaccine technologies achieved a series of progressive advancements and iterative improvements. Beyond the ongoing optimization of inactivated vaccines, novel technical platforms—including recombinant subunit vaccines, viral vector vaccines, DNA vaccines, virus-like particle vaccines, and mRNA vaccines—have emerged sequentially.^[113]

However, the prevention and control of hantavirus still face multi-dimensional challenges: At the host level, rodents exhibit strong ecological adaptability and high rates of asymptomatic infection, making precise control difficult and prone to causing conflicts in ecological balance. In terms of surveillance, capacities of primary medical institutions are weak, viral genotypes are diverse, and there is a lack of linkage among “host-environment-human population”, which hinders timely early warning. Regarding vaccines, existing vaccines have low coverage and narrow protective spectra, with research and development lagging behind viral mutations. In clinical diagnosis and treatment, early symptoms are easily confused with common diseases, specific drugs are lacking, and the threshold for severe case treatment is difficult to overcome. Moreover, the public has insufficient awareness of transmission routes, and protective habits in high-risk scenarios are difficult to develop. Changes in the ecological environment exacerbate the risk of host spread, while barriers exist in interdisciplinary and international cooperation. Therefore, future research can be deepened from three aspects: first, strengthened surveillance is needed in low-data regions, and cross-border cooperation should be undertaken to fill epidemiological gaps; second, interdisciplinary collaboration is required to construct multi-factor coupling models such as “ecology-climate-society” and quantify key variables driving virus transmission; and third, practical cases of prevention and control should be systematically integrated to provide more specific references for the formulation of regionalized prevention and control strategies.

Author Contributions

Hong Jiang and Li-Mei Wang contributed to the study conception, design, and manuscript drafting. Jiang-Nan Song performed data collection, analysis, and figure preparation. Duo Chen conducted literature data collection and organization. All authors have edited the manuscript and approved the final manuscript.

Conflicts of Interest

None.

Funding Statement

This work was supported by the Discipline Innovation and Development Program of TangDu Hospital, the Fourth Military Medical University (2021LCYJ025) and the Discipline Boosting Program Project of TangDu Hospital, the Fourth Military Medical University (2024JSYX010).