Hantaviruses

Hantaviruses are the rodent-borne viruses of the genus Orthohantavirus, in the family Hantaviridae, that cause two severe human diseases: haemorrhagic fever with renal syndrome (HFRS), classically in the Old World, and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. People are infected not by an insect bite but by inhaling aerosols of infected rodent excreta, which sets the group apart from the arthropod-borne viruses of the same viral order.

Each virus is bound to a particular rodent host with which it has co-evolved, so the distribution of disease follows the range of the reservoir rather than any property of the virus itself. This reservoir-restriction is why the group divides so usefully by hemisphere and host, and why a person’s exposure history often points to the likely agent.

The two syndromes share one mechanism: the virus infects the lining of small blood vessels without destroying it, and disease follows from an immune-driven increase in vascular permeability. HFRS is common and usually survivable; HCPS is rare but highly lethal, with a case-fatality around 35 to 40%. One species, Andes virus, is the only hantavirus known to pass from person to person, a trait that changes how a suspected case must be managed.

Discovery and historical significance

The disease long preceded the virus. A severe febrile illness with kidney failure and bleeding, then called Korean haemorrhagic fever, struck thousands of United Nations troops during the Korean War of the early 1950s and drove a search for its cause that took two decades.

The breakthrough came in 1976, when Ho-Wang Lee isolated the causative agent, Hantaan virus, from the striped field mouse trapped near the Hantaan River in South Korea, giving the genus its name. The New World form of the disease was recognised much later: in 1993 a cluster of rapidly fatal respiratory illness among previously healthy young people in the Four Corners region of the United States led investigators to a new hantavirus, Sin Nombre virus, and its reservoir the deer mouse, defining the cardiopulmonary syndrome as a distinct entity.

Classification, structure, and genome

Classification

Hantaviruses that infect humans belong to the genus Orthohantavirus, subfamily Mammantavirinae, in the family Hantaviridae, part of the order Bunyavirales. The family is far broader than its human pathogens, with members now recognised in shrews, moles, bats and even fish and other lower vertebrates, but the species that cause human disease are essentially all carried by rodents, each virus co-evolved with a particular host that defines its identity and its range.

The human pathogens fall into two clades that map onto the two syndromes: Old World species (Hantaan, Seoul, Dobrava-Belgrade, Puumala) causing HFRS, and New World species (Sin Nombre, Andes) causing HCPS. This is the classical division rather than a strict rule, its clearest exception being the rat-borne Seoul virus, which causes HFRS but, following its reservoir, is distributed worldwide.

Medically important hantavirus species

Virus	Group	Syndrome	Rodent reservoir	Region	Case-fatality
Sin Nombre	New World	HCPS	Deer mouse (Peromyscus maniculatus)	North America	~35 to 40%
Andes	New World	HCPS	Long-tailed pygmy rice rat (Oligoryzomys longicaudatus)	South America	~35 to 40%
Hantaan	Old World	HFRS (severe)	Striped field mouse (Apodemus agrarius)	East Asia	~5 to 15%
Dobrava-Belgrade	Old World	HFRS (severe)	Yellow-necked mouse (Apodemus flavicollis)	The Balkans, Europe	~9 to 15%
Seoul	Old World	HFRS (moderate)	Brown rat (Rattus species)	Worldwide	~1 to 2%
Puumala	Old World	HFRS (mild)	Bank vole (Myodes glareolus)	Europe	under 1%

Virion structure

The virion is enveloped, roughly spherical and pleomorphic, about 80 to 120 nanometres across. Its surface carries a lattice of two glycoproteins, Gn and Gc, which mediate receptor binding and membrane fusion. There is no matrix protein, a general feature of the order. Within the envelope, each of the three genome segments is coated by nucleocapsid protein and associated with the polymerase to form a ribonucleoprotein.

Genome organisation

The genome is three segments of negative-sense RNA, totalling about 12 kilobases. The large (L) segment encodes the RNA-dependent RNA polymerase, the medium (M) segment a precursor cleaved into the Gn and Gc glycoproteins, and the small (S) segment the nucleocapsid protein, with some species encoding an additional nonstructural NSs protein that antagonises the interferon response. The segmented genome permits reassortment between related viruses, a route by which new variants can arise.

Replication cycle

Infection begins when the Gn and Gc spikes attach to cell-surface integrins. The distinction here is functionally important: pathogenic hantaviruses use beta-3 integrins, whereas non-pathogenic species use beta-1, and the beta-3 integrin also governs vascular permeability and platelet function, linking entry to disease. Bound virus is taken up by receptor-mediated endocytosis.

Acidification of the endosome then drives Gc-mediated fusion of the viral and endosomal membranes, releasing the three ribonucleoproteins into the cytoplasm, where the entire replication cycle takes place. The L polymerase transcribes the genome into messenger RNA, priming each transcript with a short capped fragment snatched from host messenger RNA, a mechanism shared across the order.

Newly synthesised glycoproteins fold in the endoplasmic reticulum and traffic to the Golgi, where progeny particles assemble and bud into Golgi vesicles. Mature virions are then carried to the cell surface and released by exocytosis.

Pathogenesis

The central and initially surprising fact of hantavirus disease is that the virus is not directly cytopathic: it infects the endothelial cells lining small blood vessels without killing them. Disease results instead from a functional, reversible increase in vascular permeability, driven by the immune response to infection.

Activated T cells and a surge of inflammatory cytokines loosen the junctions between endothelial cells, and the beta-3 integrin used for entry, being a regulator of vascular integrity and platelet function, is itself disturbed. Plasma leaks from the circulation into the tissues, and thrombocytopenia is near-universal, from consumption at the damaged endothelium rather than failure of production. Because the injury is functional rather than structural, survivors recover without lasting vascular damage.

The immune response is double-edged. A vigorous cytotoxic (CD8) T-cell response, rather than the virus itself, is closely associated with severe disease, and its intensity tracks the degree of capillary leak. The cytokines it drives, including tumour necrosis factor, interferons and several interleukins, together with locally released vascular endothelial growth factor (VEGF) and bradykinin, loosen the endothelial junction protein VE-cadherin and open the vascular barrier. Conversely, a high neutralising-antibody titre early in illness predicts a better outcome, so it is the balance and timing of the immune response, more than viral load alone, that shapes how severe the disease becomes.

Where the leak does its greatest harm distinguishes the two syndromes, though the difference is one of emphasis. In HFRS it falls predominantly on the kidney, producing acute kidney injury, while in HCPS it falls predominantly on the lung, flooding the alveoli to produce non-cardiogenic pulmonary oedema. The organs overlap in practice: HFRS, especially from Puumala virus, often causes respiratory symptoms, and HCPS, especially from Andes virus, frequently involves the kidney.

Epidemiology

Hantavirus disease follows the geography of its rodent reservoirs: because each virus is tied to a particular host, the distribution of human disease tracks the range of that rodent rather than any property of the virus. Infection almost always follows the inhalation of aerosolised excreta from an infected rodent, so exposure is typically rural, domestic or occupational, in settings such as farms, rural dwellings, forestry work and grain stores.

HFRS is by far the more common syndrome, with tens of thousands of cases a year, most of them in China, alongside a large European burden of mild Puumala infection. HCPS is rare, in the low hundreds of cases a year across the Americas, but far more lethal. Seoul virus is the exception to the group’s otherwise tidy geography: its reservoir, the brown rat, has followed shipping to every continent, making it the one hantavirus with a genuinely worldwide distribution. New World outbreaks are episodic, rising in wet years when heavy rain drives a boom in rodent numbers and closer contact with people. Andes virus is exceptional again in that it can also spread directly from person to person, which extends its epidemiology beyond rodent contact and shapes how a suspected case is managed.

Natural history

After an incubation of about two to three weeks, both syndromes open with a nonspecific febrile prodrome and then follow different courses.

HFRS classically evolves through five phases: febrile, hypotensive, oliguric, diuretic and convalescent, with the greatest danger during the hypotensive and oliguric stages. HCPS moves faster: a prodrome of a few days gives way abruptly to the cardiopulmonary phase, which can prove fatal within a day or two, followed in survivors by a diuretic recovery. Recovery from either syndrome is usually complete, without the chronic sequelae seen after some other viral infections.

Clinical presentations and complications

The two syndromes share an early febrile phase but diverge in the organ they strike and in their lethality.

Feature	HFRS (Old World)	HCPS (New World)
Predominant organ	Kidney	Lung
Classic phases	Febrile, hypotensive, oliguric, diuretic, convalescent	Febrile prodrome, cardiopulmonary, diuretic, convalescent
Hallmark	Acute kidney injury, haemorrhage	Non-cardiogenic pulmonary oedema, shock
Case-fatality	under 1% (Puumala) to ~15% (Hantaan, Dobrava)	~35 to 40%
Ribavirin	Benefit if given early	No proven benefit

Haemorrhagic fever with renal syndrome

HFRS begins with fever, headache, back and abdominal pain, and the characteristic facial flushing and conjunctival haemorrhage. As it progresses, increased vascular permeability produces hypotension that can tip into shock and disseminated intravascular coagulation, followed by an oliguric phase of acute kidney injury that is the usual time of death. Bleeding, from petechiae to frank haemorrhage, occurs but is rarely the fatal event; kidney failure and shock are. A diuretic phase of recovering urine output and a prolonged convalescence follow in survivors. Severity varies by species, from the often severe Hantaan and Dobrava disease to the mild course of Puumala infection.

Hantavirus cardiopulmonary syndrome

HCPS compresses into a faster and more lethal illness. A febrile prodrome of fever, myalgia and gastrointestinal symptoms, typically lasting three to five days, gives way abruptly to the cardiopulmonary phase: rapidly worsening non-cardiogenic pulmonary oedema, hypoxia and cardiogenic shock from depressed myocardial function, which can kill within a day or two of admission. Unlike HFRS, true haemorrhage is uncommon despite the profound capillary leak. Patients who survive the first 48 hours usually recover through a diuretic phase.

Diagnosis

Diagnosis rests chiefly on serology, because patients usually present after the short viraemic phase, once antibody is already rising. Immunoglobulin M (IgM) is detectable at symptom onset in most cases, with a rising immunoglobulin G (IgG) titre confirming recent infection; capture enzyme-linked immunosorbent assay (ELISA) is the standard method.

Reverse-transcriptase polymerase chain reaction (RT-PCR) can detect and genotype the virus early in illness but is not used alone, because false positives are a risk and viraemia is short. Marked cross-reactivity between hantavirus species means a positive screen is often confirmed with a species-specific or neutralisation assay. The laboratory picture, a falling platelet count with haemoconcentration, atypical lymphocytes and, in HFRS, proteinuria and rising creatinine, supports the clinical diagnosis.

Management

There is no specific antiviral of proven benefit for the New World disease, and management of both syndromes is supportive, with outcome depending heavily on early recognition and the right organ support.

HFRS is managed through its phases with careful attention to fluid balance and renal replacement therapy during the oliguric phase, which has substantially reduced mortality. HCPS is a critical-care diagnosis: meticulous fluid restriction to avoid worsening the pulmonary oedema, inotropic and vasopressor support for the cardiogenic shock, and extracorporeal membrane oxygenation (ECMO) for the most severe cardiopulmonary failure, which improves survival in referral centres.

The antiviral ribavirin has a benefit in HFRS when started early in the course but has shown no benefit in HCPS in controlled trials. Corticosteroids have not been shown to help either syndrome.

Prevention and public health

Vaccination

There is no widely licensed hantavirus vaccine. Inactivated vaccines against Hantaan and Seoul viruses are used in parts of Asia, chiefly China and Korea, but none is available elsewhere, and no vaccine exists against the New World species, so prevention depends on avoiding exposure.

Infection prevention and control

The core of prevention is reducing contact with rodents and their excreta: sealing dwellings against rodents, storing food securely, and ventilating then wetting contaminated areas before cleaning rather than sweeping or vacuuming dry, which aerosolises the virus. Andes virus is the exception that demands more: a suspected case requires isolation and personal protective equipment as for a person-to-person respiratory pathogen, because it can transmit between people.

Surveillance and notification

Because most human infection signals the presence of an infected rodent population, hantavirus cases are notifiable in many countries and prompt environmental and veterinary investigation. Surveillance of both human cases and rodent reservoirs guides risk assessment, particularly ahead of the wetter seasons that precede New World outbreaks.

Outbreak response

The person-to-person capacity of Andes virus means an Andes outbreak is managed very differently from a rodent-acquired cluster, with contact tracing, monitoring of contacts through the incubation period, and isolation of cases. The 2026 outbreak of Andes virus aboard an expedition cruise ship, in which human-to-human transmission contributed to spread among passengers and crew, is a recent illustration of why this capability matters.

South African context

South Africa has no documented local human hantavirus disease. The severe renal and cardiopulmonary syndromes described here are not acquired within the country.

The position in local rodents is more nuanced. Southern African rodents do carry native, generally mild African hantaviruses, such as Sangassou virus, but not the New World species that cause hantavirus cardiopulmonary syndrome. The practical message for South African clinicians is that the country’s own rodents are not a source of severe disease, and that the realistic local risk is an imported Andes virus case in a traveller returning from South America.

Hantavirus infection is a Category 1 notifiable medical condition, requiring notification within 24 hours, and specialised testing and outbreak support are provided by the National Institute for Communicable Diseases. Because of the Andes virus person-to-person risk, suspected cases are admitted to designated isolation facilities, of which Tygerberg Hospital is one of the Western Cape sites, and their contacts are assessed and monitored through the incubation period.

References and recommended reading

• Spiropoulou CF, Bente DA. Orthohantavirus, Orthonairovirus, Orthobunyavirus, and Phlebovirus. In: Fields Virology, 7th edition, Chapter 17. Philadelphia: Wolters Kluwer; 2023. The principal source for hantavirus clinical syndromes, pathogenesis and epidemiology.
• Barr JN, Weber F, Schmaljohn CS. Bunyavirales: The Viruses and Their Replication. In: Fields Virology, 7th edition, Chapter 16. Philadelphia: Wolters Kluwer; 2023. The source for genome organisation, replication and Golgi assembly.
• Mertz GJ, Ahlm C, Jonsson CB. Bunyaviridae. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition, Chapter 44. Washington: ASM Press; 2016. The foundational account of the HFRS and HCPS syndromes and their rodent reservoirs.
• Burrell CJ, Howard CR, Murphy FA. Bunyaviruses. In: Fenner and White’s Medical Virology, 5th edition, Chapter 29. Academic Press / Elsevier; 2017. The foundational account of hantavirus reservoir ecology and transmission.
• World Health Organization. Hantavirus cluster linked to cruise ship travel, multi-country. Disease Outbreak News; 2026. The source for the 2026 Andes virus cruise-ship outbreak.
• National Institute for Communicable Diseases. Hantavirus Pulmonary Syndrome: Frequently Asked Questions. NICD; 2026. The source for the South African hantavirus situation.