Hantavirus infection

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Basir Gill, M.B.B.S, M.D.[2] Usama Talib, BSc, MD [3]

Hantavirus infection is a zoonotic disease caused by viruses of the genus Orthohantavirus, family Hantaviridae, order Bunyavirales.^[1] Hantaviruses are enveloped, negative-sense, single-stranded RNA viruses with a tripartite genome (small [S], medium [M], and large [L] segments) and are approximately 80–120 nm in diameter.^[2] Approximately 150,000–200,000 cases of hantavirus disease are reported worldwide each year.^[2][3]

Hantaviruses cause two major clinical syndromes: hemorrhagic fever with renal syndrome (HFRS), endemic in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS), endemic in the Americas.^[2] A milder form of HFRS caused by Puumala virus is termed nephropathia epidemica (NE).^[4] Although HFRS and HCPS are recognized as distinct clinical entities, they share overlapping symptoms, signs, and pathogenic alterations, and both can involve the kidneys and lungs.^[2]

Transmission to humans occurs primarily via inhalation of aerosolized viral particles shed in rodent urine, feces, and saliva, and rarely by rodent bites.^[2] Andes virus (ANDV) is unique among hantaviruses in that it can be transmitted from person to person.^[5]

Endothelial cells of capillaries and small vessels are the principal targets of hantaviruses, and increased vascular permeability is central to pathogenesis.^[2] Diagnosis is primarily serological (IgM ELISA), supplemented by RT-qPCR and clinical algorithms.^[2] There is no specific approved antiviral treatment or vaccine in Europe or the Americas; treatment is primarily supportive, with extracorporeal membrane oxygenation (ECMO) for severe HCPS.^[2][6]

The case fatality rate (CFR) varies by virus: HCPS caused by Sin Nombre virus (SNV) or ANDV carries a CFR of 30–45%, while HFRS caused by Hantaan virus (HTNV) or Dobrava virus (DOBV) has a CFR of 5–15%, and PUUV-associated NE has a CFR of less than 1%.^[2][7]

Ancient and early descriptions: HFRS was first clinically recognized in northeast China in 1931.^[8] A similar illness, termed “Korean hemorrhagic fever,” was recognized among United Nations troops during the Korean War in the 1950s, with a case fatality rate of 5–7%.^[2]

Discovery of Hantaan virus: In 1976, Ho Wang Lee isolated the first pathogenic hantavirus from the lungs of the striped field mouse (Apodemus agrarius) near the Hantaan River in South Korea. The virus was named Hantaan virus (HTNV) in 1978.^[8][2] Subsequently, several other hantaviruses were identified throughout Europe and Asia, including Puumala virus, Dobrava virus, and Seoul virus.^[2]

Discovery of HCPS and Sin Nombre virus: In May 1993, a cluster of unexplained deaths from acute respiratory failure was identified in the Four Corners region of the southwestern United States. The initial 17 patients presented with rapidly progressive respiratory and hemodynamic deterioration, with a case fatality rate of 76%.^[9] A genetically distinct hantavirus was identified as the causative agent and later named Sin Nombre virus (SNV), with the deer mouse (Peromyscus maniculatus) as its reservoir.^[2][10]

Person-to-person transmission: In 1996, the first documented person-to-person transmission of a hantavirus (ANDV) occurred during an outbreak in El Bolsón, Argentina, involving 16 epidemiologically linked cases.^[11] Since then, many HCPS-causing hantaviruses have been identified throughout the Americas.^[2]

Hantavirus infection can be classified based on the causative virus species and the resulting clinical syndrome.^[4]

Clinical Syndrome	Geographic Distribution	Primary Viruses	Rodent Reservoir	Case Fatality Rate
Hemorrhagic fever with renal syndrome (HFRS)	Europe, Asia	Hantaan virus (HTNV), Dobrava virus (DOBV), Seoul virus (SEOV)	Apodemus agrarius, Apodemus flavicollis, Rattus norvegicus	1–15%
Nephropathia epidemica (NE) (mild HFRS)	Europe (Finland, Germany, Sweden, Russia)	Puumala virus (PUUV)	Myodes glareolus (bank vole)	1%
Hantavirus cardiopulmonary syndrome (HCPS)	Americas	Sin Nombre virus (SNV), Andes virus (ANDV), Choclo virus (CHOV), Laguna Negra virus (LANV)	Peromyscus maniculatus, Oligoryzomys longicaudatus	12–45%

Hantaviruses belong to the genus Orthohantavirus, family Hantaviridae, order Bunyavirales.^[1] The family Hantaviridae contains viruses with genomes of approximately 10.5–14.6 kb, maintained in and/or transmitted by fish, reptiles, and mammals.^[1] Over 50 species have been described, of which more than 24 are recognized as pathogenic to humans.^[12]

Old World hantaviruses (HFRS-causing): HTNV, DOBV, PUUV, SEOV, Tula virus

New World hantaviruses (HCPS-causing): SNV, ANDV, Araraquara virus, Juquitiba virus, CHOV, LANV, Black Creek Canal virus, Bayou virus

Hantaviruses are RNA viruses of the genus Orthohantavirus, family Hantaviridae, order Bunyavirales.^[1] Each is made up of negative-sensed, single-stranded RNA viruses. Each viral particle is enveloped, 80–120 nm in diameter, and contains a genome with three segments:^[2][12]

Small (S) segment: encodes the nucleocapsid protein (N), and in some hantaviruses, a non-structural protein (NSs)

Medium (M) segment: encodes the glycoprotein precursor (GPC), which is cleaved into envelope glycoproteins Gn and Gc

Large (L) segment: encodes the RNA-dependent RNA polymerase (RdRp)

There are 5 genera within the order Bunyavirales that historically comprised the former family bunyaviridae: bunyavirus, phlebovirus, nairovirus, tospovirus, and hantavirus. All these genera include arthropod-borne viruses, with the exception of hantavirus, which is a genus of rodent-borne agents.

Rodents are the main natural hosts for pathogenic hantaviruses, although bats, moles, shrews, reptiles, and fish have also been shown to carry hantaviruses.^[2] Natural hosts are believed to be persistently infected with little biological effect. Rodents excrete hantaviruses in saliva, urine, and feces, and humans are infected primarily when inhaling aerosolized secreted viruses, or rarely by rodent bites.^[2] Dynamics of rodent populations and factors such as rainfall, temperature, land use, habitat changes, social development, and human behavior influence the interaction between rodent hosts and humans.^[2]

Data on environmental viability are limited. Puumala virus remained infectious for up to 15 days in bank vole bedding and remained viable at room temperature for 5 days in a wet environment and 24 hours when dry. HTNV survived in wet conditions for 8 days at 20°C and 9 days at 37°C.^[2]

Hantavirus infection must be differentiated from other diseases that present with hemorrhagic fever, acute respiratory distress syndrome, or acute kidney injury. Hemorrhagic fever caused by hantavirus can be differentiated from other diseases such as dengue, malaria and Ebola. The hantavirus cardiopulmonary syndrome can be differentiated from other diseases like histoplasmosis, coccidioidomycosis, brucellosis, tuberculosis and aspergillosis.^[2]

Disease	Key Differentiating Features
Leptospirosis	Conjunctival suffusion, jaundice, exposure to contaminated water; positive Leptospira serology or PCR
Dengue	Rash, retro-orbital pain, leukopenia; positive dengue NS1 antigen or serology; tropical/subtropical travel
Malaria	Cyclical fever, splenomegaly, anemia; positive blood smear or rapid diagnostic test; travel to endemic area
Ebola virus disease	Severe hemorrhage, diarrhea, contact with infected individuals; positive Ebola PCR; sub-Saharan Africa exposure
Pneumonic plague	Rapidly progressive pneumonia, hemoptysis, lymphadenopathy; gram-negative bipolar rods; southwestern US exposure
Influenza	Rhinorrhea, pharyngitis, seasonal pattern; positive influenza rapid antigen or PCR
Histoplasmosis	Chronic cough, mediastinal lymphadenopathy, hepatosplenomegaly; positive urine/serum Histoplasma antigen
Coccidioidomycosis	Erythema nodosum, arthralgia, southwestern US exposure; positive Coccidioides serology
Tuberculosis	Chronic cough, night sweats, weight loss, upper lobe infiltrates; positive AFB smear/culture or PCR
Aspergillosis	Immunocompromised host, halo sign on CT, hemoptysis; positive galactomannan or culture
Brucellosis	Undulant fever, sacroiliitis, hepatosplenomegaly, animal exposure; positive Brucella serology or culture
Rickettsiosis	Eschar, rash, tick exposure; positive rickettsial serology
Crimean-Congo hemorrhagic fever	Severe hemorrhage, tick exposure; positive CCHF PCR; endemic regions (Africa, Asia, southeastern Europe)
HELLP syndrome (in pregnancy)	Hypertension, proteinuria, elevated liver enzymes, hemolysis, low platelets; third trimester
Community-acquired pneumonia	Productive cough, focal consolidation, leukocytosis with toxic granulation; positive sputum culture

Key distinguishing features of HCPS include the combination of thrombocytopenia, hemoconcentration, leukocytosis with a left shift but without toxic granulation, and the presence of circulating immunoblasts on peripheral blood smear.^[2][9]

Hantavirus is usually transmitted via the inhalation of aerosolized viral antigens or rodent bites. The incubation period of hantavirus infection is 9 to 33 days, though ranges of 7 to 39 days in HCPS and 14 to 28 days in HFRS have been reported.^[12][2]

Following inhalation, the virus replicates in pulmonary macrophages and dendritic cells before disseminating to endothelial cells.^[12] The primary target cells of hantavirus infection are endothelial cells of capillaries and small vessels.^[2] Increased vascular permeability is central to pathogenesis and does not appear to be caused by a lytic effect of the virus, but rather by functional changes of the endothelial barrier through mechanisms that remain incompletely understood.^[2] These mechanisms include:

Binding of the virus to cell receptors (including β3 integrins) that regulate endothelial permeability

Increased innate immune responses and immunopathogenic mechanisms

Overexpression of vascular endothelial growth factor (VEGF), which promotes degradation of VE-cadherin and disrupts intercellular contacts^[12]

Activation of the plasma kallikrein-kinin system, leading to increased cleavage of high molecular weight kininogen, liberation of bradykinin, and dramatic increases in endothelial cell permeability^[13]

Infection is followed by impairment of the barrier function of endothelial cells, fluid extravasation, and subsequent organ failure.^[4]

The immune response plays a central role in hantavirus pathogenesis:^[12]

Elevated CD8+ T cell responses correlate with disease severity and systemic organ dysfunction

T regulatory cell (Treg) responses are downregulated during human infection, in contrast to the upregulated Treg response that promotes viral persistence in rodent hosts

A “cytokine storm” involving IL-6, IL-1β, TNF, and other pro-inflammatory cytokines contributes to endothelial dysfunction

Genetic vulnerability due to certain human leukocyte antigen (HLA) haplotypes is associated with disease severity^[6]

Endothelial cells in the lungs, kidneys, heart, liver, and spleen can be infected, as can macrophages, mononuclear blood cells, dendritic cells, and respiratory and tubular epithelium.^[2] According to histopathological studies:

HFRS-causing hantaviruses primarily affect renal medullary capillaries

HCPS-causing hantaviruses mainly affect pulmonary capillaries^[2][6]

In HFRS, endothelial activation leads to platelet activation and altered coagulation. Kidney biopsies show interstitial hemorrhage, microvascular inflammation with T cells and macrophages, and peritubular capillaritis.^[2]

Hantavirus infection has a diverse epidemiology and demographics due to the vast number of viruses classified under hantaviruses. Approximately 150,000–200,000 cases of hantavirus disease are reported worldwide each year, with the majority occurring in China.^[2][3]

HFRS: China reports 20,000–50,000 cases annually, accounting for the majority of global HFRS cases. In Europe, Finland reports the highest incidence of PUUV-associated nephropathia epidemica, with up to 3,000 cases per year. Germany, Sweden, and Russia also report significant numbers. SEOV-associated HFRS occurs worldwide due to the global distribution of Rattus norvegicus.^[2][8]

HCPS: The total number of hantavirus pulmonary syndrome (HPS) cases reported in the United States from 2004–2015 is 323. HPS cases have been reported in 30 states, including most of the western half of the country and some eastern states as well. Over half of the confirmed cases have been reported from areas outside the Four Corners area. The mean age of confirmed HPS cases is 38 years (range: 5 to 84 years).^[14] In South America, Argentina, Chile, Brazil, and Panama report the highest numbers of HCPS cases. Argentina reports 100–200 cases per year, and Chile reports 50–100 cases per year.^[2]

Males are disproportionately affected in both HFRS and HCPS, likely reflecting occupational and recreational exposure patterns. Seasonal peaks correlate with rodent population dynamics: HFRS peaks in autumn and winter in China, while PUUV-associated NE peaks in late autumn in northern Europe. HCPS in the Americas shows spring and summer peaks.^[8][2]

The most potent risk factor in the development of hantavirus infection is exposure to rodent excreta and close contact with hantavirus-infected humans.^[8]

Risk factors include:

Peridomestic rodent exposure: Living in or near rodent-infested dwellings, particularly rural or semi-rural settings

Occupational exposure: Forestry workers, farmers, military personnel, and laboratory workers handling rodents or rodent-contaminated materials

Recreational exposure: Camping, hiking, or entering enclosed spaces (cabins, sheds, barns) with rodent infestation

Cleaning activities: Sweeping or vacuuming areas contaminated with rodent droppings, urine, or nesting materials, which aerosolizes viral particles

Climatic and ecological factors: Increased rainfall and mild winters promote rodent population growth and subsequent human exposure^[8][2]

Person-to-person contact (ANDV only): Close contact with an ANDV-infected individual, including sexual contact, sleeping in the same room, or providing direct care^[11]

There are no screening recommendations for hantavirus infection.

Hantavirus infection should be suspected in patients who reside in or have recent (5–50 days prior) travel history to an endemic region, presenting with:^[2]

Persistent fever (>48 hours), headache, myalgia, and gastrointestinal manifestations (abdominal pain, vomiting, diarrhea)

In more advanced illness: cough, dyspnea, hypoxia, and bilateral pulmonary infiltrates

Acute renal dysfunction

In ANDV-endemic regions: close contact with an infected patient in the previous 40 days, particularly sexual contact or sleeping in the same room^[2]

HFRS classically progresses through five stages: febrile, hypotensive, oliguric, diuretic, and convalescent. After an incubation period of 2–6 weeks, prominent features include acute onset of high fever with headache, nausea, myalgia, and abdominal and back pain.^[2]

HCPS begins with a febrile prodrome (2–7 days) of myalgia, headache, chills, abdominal pain, vomiting, diarrhea, arthralgia, conjunctival injection, and retro-orbital pain. This is followed by the cardiopulmonary phase with sudden onset of cough, dyspnea, tachycardia, and hypotension, progressing within hours to non-cardiogenic pulmonary edema, respiratory failure, and often cardiogenic shock.^[2] The cardiopulmonary phase lasts 2–4 days, with most deaths occurring within the first 24 hours after hospital admission.^[2]

Patients with hantavirus infection usually exhibit prostration. Physical examination findings may include:^[2][4]

Fever and diaphoresis

Hypotension and signs of shock (mottling, prolonged capillary refill time)

Tachycardia and tachypnea

Petechiae (skin or mucosa; in ANDV, particularly axillae and extremities)

Abdominal tenderness (may mimic acute abdomen)

Epistaxis, menorrhagia, or gastrointestinal bleeding (more common in severe HFRS caused by HTNV and DOBV)

Bilateral crackles on lung auscultation

Conjunctival injection

Low blood pressure and abnormal cardiopulmonary examination^[4]

ELISA for IgM antibodies directed against hantavirus nucleocapsid protein is the most widely used diagnostic test. IgM antibodies are often present at onset of the febrile prodrome, and IgG antibodies are usually present by the end of the febrile prodrome.^[2] Immunochromatographic IgM assays have assay performance greater than 90% compared with EIA IgM assays.^[2]

Evidence of viral antigen in tissue by immunohistochemistry, or the presence of amplifiable viral RNA sequences in blood or tissue, with a compatible history of HPS, is considered diagnostic for HPS.^[2]

RT-qPCR, usually designed to detect the S segment, is sensitive and specific. Viral loads are higher in buffy coat than in plasma. RT-qPCR can detect ANDV RNA for up to 2 weeks before symptom onset and for weeks after resolution of symptoms.^[2][5]

In the cardiopulmonary phase, a presumptive diagnosis can be established using blood count or peripheral smear criteria. The presence of at least 4 out of 5 criteria has a sensitivity of 96% and a specificity of 99%:^[2]

Thrombocytopenia Left shift in the granulocytic lineage Absence of toxic granulation in the myeloid series Hemoconcentration Immunoblast population greater than 10% of the total leukocyte population

A platelet count greater than 115,000/μL at admission is associated with lower risk of progression to severe HCPS

A platelet count lower than 40,000/μL is associated with increased mortality

Positive quantitative proteinuria at hospital admission has been linked to mortality^[2]

Detection of proteinuria and hematuria with urine dipstick analysis supports the clinical suspicion of HFRS.^[2]

On chest X-ray, HCPS may manifest as non-cardiogenic pulmonary edema characterized by bilateral alveolar infiltrates.^[2] Radiographic progression from interstitial to alveolar edema may occur rapidly over hours.^[9]

On CT scan, hantavirus pulmonary syndrome is characterized by ground-glass opacities and interlobular and intralobular septal thickening. Pleural effusions may also be present.^[2]

There are no specific MRI findings associated with hantavirus infection. MRI may occasionally demonstrate pituitary hemorrhage or encephalitis in rare cases of central nervous system involvement.^[6]

On renal ultrasound, hantavirus hemorrhagic fever with renal syndrome may show parenchymal edema, increased echogenicity, and decreased corticomedullary differentiation.^[6]

There are no other specific imaging findings associated with hantavirus infection.

Additional diagnostic findings can include the histopathological analysis of lymph nodes, spleen, and liver, but these are rarely used in clinical practice. Autopsy findings in HCPS typically show heavy, edematous lungs with serous pleural effusions and interstitial pneumonitis with mononuclear cell infiltrates.^[10]

There is no specific treatment, cure, or vaccine for hantavirus infection. Treatment is primarily supportive. Infected individuals who are recognized early and receive medical care in an intensive care unit may have improved outcomes.^[2][15]

HCPS: Early recognition during the febrile prodrome and prompt transfer to a facility with ICU and ECMO capability is critical. Aggressive volume resuscitation should be avoided, as it may worsen pulmonary edema due to the underlying capillary leak. Judicious fluid management guided by hemodynamic monitoring is recommended.^[2]

HFRS: Supportive care includes careful fluid and electrolyte management, analgesics for pain, and monitoring for hemorrhagic complications. Hemodialysis may be required in the oliguric phase; approximately 5% of PUUV-HFRS and up to 15% of DOBV-HFRS patients require renal replacement therapy.^[2][6]

Ribavirin: An open-label trial in China demonstrated reduced mortality in HFRS when ribavirin was administered intravenously within the first 5 days of illness.^[2] However, ribavirin has not shown benefit in PUUV-associated HFRS or in HCPS. A randomized controlled trial of intravenous ribavirin for HCPS was terminated early due to futility.^[2][7]

Favipiravir: Has shown efficacy in animal models of hantavirus infection when administered before peak viremia, but human clinical trial data are lacking.^[7]

Icatibant: A bradykinin B2 receptor antagonist that has been used in individual cases of severe HFRS with reported clinical improvement, based on the role of the kallikrein-kinin system in hantavirus pathogenesis.^[2]

Convalescent plasma: An open-label study in Chile showed lower mortality in ANDV-associated HCPS patients treated with high-titer neutralizing antibodies from convalescent donors compared with historical controls.^[2] A randomized controlled trial was conducted but results remain pending full publication.^[2]

Methylprednisolone: A randomized, double-blind, placebo-controlled trial of high-dose intravenous methylprednisolone in HCPS showed no benefit in reducing mortality or disease severity.^[2]

Inotropes such as dobutamine or low-dose epinephrine are preferred for hemodynamic support in HCPS-associated cardiogenic shock, rather than aggressive volume resuscitation.^[2]

Vasopressors (norepinephrine) may be required for refractory hypotension.^[2]

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is the most important rescue therapy for severe HCPS with refractory cardiogenic shock. In a retrospective series, survival rates of approximately 70–80% were reported in patients with severe HCPS treated with early VA-ECMO, compared with near-universal mortality without mechanical circulatory support in this population.^[16][17]

Indications for ECMO in HCPS include:^[17]

Refractory cardiogenic shock despite inotropic support

Cardiac index less than 2.2 L/min/m² with rising lactate

Severe metabolic acidosis unresponsive to medical therapy

Hemodialysis or continuous renal replacement therapy may be required in HFRS patients with severe oliguric acute kidney injury.^[6]

Surgical intervention is not recommended for the management of hantavirus infection. Rare surgical indications may arise from complications such as pituitary hemorrhage or severe hemorrhagic complications requiring intervention.^[6]

Long-term follow-up is recommended for survivors of both HCPS and HFRS:

Post-HCPS: Persistent fatigue, reduced exercise tolerance, and impaired pulmonary function (reduced diffusing capacity) have been reported for up to 1–3 years after acute illness.^[2]

Post-HFRS/NE: Long-term renal follow-up is advisable. A study with up to 20 years of follow-up after nephropathia epidemica found that 8% of patients developed chronic kidney disease (CKD), and hypertension was frequent, although a causal relationship remained uncertain.^[18] Hormonal dysfunction, particularly involving the anterior pituitary, has been reported in up to 80% of PUUV patients at follow-up.^[6]

Monitoring of renal function, blood pressure, and pituitary hormones is recommended in HFRS/NE survivors.^[6][18]

Prevention of hantavirus infection centers on reducing human exposure to rodents and their excreta.^[19]

Seal holes and gaps in homes, garages, and outbuildings to prevent rodent entry

Store food in sealed containers and dispose of garbage promptly

Place snap traps in and around the home to decrease rodent infestation

When cleaning areas with evidence of rodent infestation:

Ventilate the area for at least 30 minutes before entering

Do not sweep or vacuum rodent droppings, urine, or nesting materials (this aerosolizes viral particles)

Wet contaminated areas with a 10% bleach solution or commercial disinfectant and allow to soak for 5 minutes before wiping up with damp towels

Wear rubber or latex gloves during cleanup^[19]

Eliminate rodent harborage areas (woodpiles, junk, dense vegetation) within 30 meters of the home

Use elevated platforms for camping and avoid sleeping on bare ground in endemic areas

Store food in rodent-proof containers when camping or hiking^[19]

Workers in high-risk settings (forestry, agriculture, military) should use appropriate personal protective equipment, including respirators (N95 or higher) when cleaning heavily contaminated enclosed spaces

Recent research results show that many people who became ill with HPS developed the disease after having been in frequent contact with rodents and/or their droppings around a home or a workplace. On the other hand, many people who became ill reported that they had not seen rodents or rodent droppings at all. Therefore, if living in an area where the carrier rodents are known to live, efforts should be made to keep the home, vacation place, workplace, or campsite clean.^[19]

In ANDV-endemic regions, suspected HCPS patients should be placed in contact isolation and droplet isolation

Household contacts of confirmed ANDV cases should be monitored for symptoms for at least 40 days after last exposure^[2][11]

Inactivated hantavirus vaccines (against HTNV and SEOV) have been used in China and South Korea, but clear efficacy data from randomized controlled trials are lacking.^[7] No approved vaccine exists in Europe or the Americas. Several vaccine candidates are in preclinical or early clinical development, including DNA vaccines and virus-like particle platforms.^[7][12]

Secondary preventive measures for hantavirus infection are similar to primary prevention. Early recognition of symptoms in exposed individuals and prompt medical evaluation may reduce morbidity and mortality. In ANDV-endemic areas, monitoring of close contacts of confirmed cases is essential.^[2]

Hantavirus infection during pregnancy poses risks to both the mother and fetus. Disease severity appears similar for PUUV, DOBV, and ANDV infections in pregnant women compared with non-pregnant adults, although HTNV infection may be more severe in the third trimester.^[2] Intrauterine transmission of hantavirus is very rare but has been documented. Transmission via breast milk has also been reported in isolated cases.^[2][20] Hantavirus infection in pregnancy may mimic HELLP syndrome or preeclampsia due to overlapping features of thrombocytopenia, elevated liver enzymes, and proteinuria.^[2]

Hantavirus infection is uncommon in children. In the United States, fewer than 7% of confirmed HPS cases have occurred in patients younger than 17 years, and the disease is rare in children under 10 years of age.^[21] Clinical presentation in children may be similar to adults, though data are limited.

Data on hantavirus infection in immunocompromised patients are limited. There is no clear evidence that immunosuppression increases susceptibility or severity, although the immune-mediated component of pathogenesis suggests that the clinical course could differ in this population.^[6]

If left untreated, hantavirus infection may progress to multi-organ failure and death. The natural history varies by syndrome:

HCPS: Progresses from febrile prodrome (2–7 days) to cardiopulmonary phase (2–4 days) with rapid deterioration. Most deaths occur within the first 24 hours after hospital admission. Survivors typically enter a diuretic phase with gradual recovery over weeks to months.^[2]

HFRS: Progresses through five phases (febrile, hypotensive, oliguric, diuretic, convalescent) over 2–6 weeks. Recovery may take weeks to months.^[2]

Possible complications of hantavirus infection include:^[2][6][22]

Acute respiratory distress syndrome

Pulmonary edema (non-cardiogenic)

Cardiogenic shock and myocardial depression

Acute kidney injury and oliguric renal failure

Disseminated intravascular coagulation

Thrombocytopenia and hemorrhagic complications

Pituitary hemorrhage

Acute encephalomyelitis

Glomerulonephritis

Shock and multi-organ failure

The prognosis of hantavirus infection depends on the causative virus and clinical syndrome:

Syndrome / Virus	Case Fatality Rate
HCPS — Sin Nombre virus (SNV)	30–40%
HCPS — Andes virus (ANDV)	30–45%
HCPS — Choclo virus (CHOV), Laguna Negra virus (LANV)	12–15%
HFRS — Hantaan virus (HTNV)	5–10%
HFRS — Dobrava virus (DOBV)	10–12%
HFRS — Seoul virus (SEOV)	1–2%
NE — Puumala virus (PUUV)	1%

Early recognition, prompt ICU admission, and availability of ECMO for severe HCPS are associated with improved survival.^[2][16][15]

All suspected cases of hantavirus infection should be reported to public health authorities, as hantavirus disease is a notifiable disease in most jurisdictions

Patients with suspected HCPS should be transferred urgently to a facility with ICU and ECMO capability^[17]

Infectious disease consultation is recommended for all confirmed or suspected cases

Nephrology consultation for HFRS patients with acute kidney injury requiring renal replacement therapy^[6]

Pulmonology and critical care consultation for patients with respiratory failure

Endocrinology referral for survivors with suspected pituitary dysfunction^[6]

In ANDV-endemic regions, infection control teams should be notified for implementation of isolation precautions and contact tracing^[2]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Basir Gill, M.B.B.S, M.D.[2] Aditya Ganti M.B.B.S. [3]

Hantavirus infection is a zoonotic disease caused by viruses of the family Hantaviridae (formerly Bunyaviridae), transmitted primarily by rodents. The earliest clinical descriptions of hantavirus-like illness date to imperial China and medieval Europe, but the disease was first formally recognized in northeast China in 1931.^[1] In 1976, Ho Wang Lee isolated the first pathogenic hantavirus along the Hantaan River in South Korea and named it the Hantaan virus (HTNV) in 1978.^[1] The discovery of Sin Nombre virus during the 1993 Four Corners outbreak in the southwestern United States established hantavirus cardiopulmonary syndrome (HCPS) as a distinct clinical entity.^[2] The three major clinical entities caused by hantaviruses include hantavirus cardiopulmonary syndrome (HCPS), hemorrhagic fever with renal syndrome (HFRS), and nephropathia epidemica (NE).

Descriptions consistent with hemorrhagic fever with renal syndrome (HFRS) appear in ancient Chinese medical texts, though definitive attribution to hantavirus is retrospective.^[1]

In 1934, Swedish physicians described an epidemic condition with primarily renal involvement, later named “nephropathia epidemica” (NE) — the earliest formal European clinical description of what is now recognized as hantavirus disease caused by Puumala virus.^[3][4]

In 1931, HFRS was first clinically recognized in northeast China.^[1]

During World War II in 1942, a large epidemic among German and Finnish soldiers in Northern Finland involved more than 1,000 patients, most probably caused by Puumala virus.^[5]

During the Korean War (1951–1953), more than 3,000 cases of acute febrile illness with hemorrhagic manifestations and renal failure occurred among United Nations soldiers stationed near the Hantaan River in South Korea. The disease was termed “Korean hemorrhagic fever” and carried a case fatality rate of 5–7%.^[6][1]

In 1976, Ho Wang Lee isolated the first pathogenic hantavirus from the lungs of the striped field mouse (Apodemus agrarius) captured near the Hantaan River in South Korea.^[1]

In 1978, the virus was formally named Hantaan virus (HTNV), establishing the genus Hantavirus.^[1]

This landmark discovery triggered the subsequent identification of related viruses worldwide, including Seoul virus (SEOV) in Asia and Puumala virus (PUUV) in Europe.^[6][4]

Puumala virus (PUUV) was first discovered in the Puumala region of Finland in the early 1980s and identified as the causative agent of nephropathia epidemica.^[4]

Seoul virus (SEOV) was found to be carried by Rattus norvegicus (the brown rat) and caused laboratory outbreaks throughout Europe in the early 1980s, demonstrating the global distribution potential of hantaviruses via commensal rodents.^[4]

Dobrava virus (DOBV) was identified in the late 1980s and early 1990s in the Balkans, associated with severe HFRS carried by Apodemus flavicollis (the yellow-necked mouse).^[4]

In May 1993, an outbreak of an unexplained pulmonary illness occurred in the southwestern United States, in an area shared by Arizona, New Mexico, Colorado, and Utah known as “The Four Corners”.^[7]

A cluster of previously healthy young adults developed rapidly progressive noncardiogenic pulmonary edema and respiratory failure. The initial 17 patients had a mean age of 32.2 years and a case fatality rate of 76%.^[2]

A novel hantavirus was rapidly identified through molecular techniques and initially named “Four Corners virus,” later renamed Sin Nombre virus (SNV; Spanish for “virus without a name”). The deer mouse (Peromyscus maniculatus) was identified as the primary reservoir.^[2][6]

This discovery established hantavirus cardiopulmonary syndrome (HCPS, also called hantavirus pulmonary syndrome or HPS) as a distinct clinical entity, separate from the renal-predominant HFRS of the Old World.^[2]

In 1996, an outbreak in El Bolsón, Argentina involving 16 epidemiologically linked cases provided the first documented evidence of person-to-person transmission of a hantavirus — Andes virus (ANDV).^[8]

ANDV remains the only hantavirus with confirmed person-to-person transmission, a feature that distinguishes it from all other known hantaviruses.^[8][9]

On November 1, 2012, the National Park Service (NPS) announced a total of 10 confirmed cases of hantavirus infection in people who recently visited Yosemite National Park. Three of the 10 patients died. The cases were linked to signature tent cabins in Curry Village with evidence of rodent infestation.^[10]

In 2015, eighteen hantavirus infections with four deaths were reported nationally in the United States.

In January 2017, a multi-state outbreak of Seoul virus was identified among 7 states in the United States, representing the first known transmission of SEOV from pet rats to humans in the US and Canada. The investigation ultimately identified 31 rat-breeding facilities in 11 states and 17 people with evidence of recent SEOV infection.^[7]

In July 2017, 3 deaths were reported due to hantavirus infection in Washington state.

In 2018–2019, a major outbreak of ANDV-associated HCPS occurred in Epuyén, Chubut Province, Argentina, with 34 confirmed infections and 11 deaths. Genomic and epidemiological analysis identified 3 “super-spreaders” at social gatherings who drove transmission chains. The basic reproduction number (R₀) decreased from 2.12 to 0.96 after implementation of public health measures including isolation and contact tracing.^[8]

Prior to 2017, hantaviruses were classified within the family Bunyaviridae, genus Hantavirus.

In 2016–2017, the International Committee on Taxonomy of Viruses (ICTV) reclassified hantaviruses into the new family Hantaviridae within the order Bunyavirales, reflecting advances in molecular phylogenetics.^[11]

In 2024, the ICTV further promoted the order Bunyavirales to the class Bunyaviricetes to accommodate the rapidly increasing number of related viruses identified through metagenomic surveillance.^[11]

Year	Milestone
1931	HFRS first clinically recognized in northeast China
1934	Nephropathia epidemica described in Sweden
1942	Large epidemic among soldiers in Northern Finland (>1,000 cases)
1951–1953	“Korean hemorrhagic fever” among >3,000 UN soldiers during the Korean War
1976	Ho Wang Lee isolates Hantaan virus from Apodemus agrarius in South Korea
1978	Hantaan virus formally named; genus Hantavirus established
Early 1980s	Puumala virus discovered in Finland; Seoul virus causes laboratory outbreaks in Europe
1993	Four Corners outbreak; Sin Nombre virus identified; HCPS established as a clinical entity
1996	First documented person-to-person transmission of Andes virus in Argentina
2012	Yosemite National Park outbreak (10 cases, 3 deaths)
2017	Multi-state Seoul virus outbreak from pet rats in the United States
2017	ICTV reclassifies hantaviruses into family Hantaviridae, order Bunyavirales
2018–2019	Epuyén, Argentina ANDV outbreak (34 cases, 11 deaths); “super-spreader” transmission documented
2024	ICTV promotes order Bunyavirales to class Bunyaviricetes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Basir Gill, M.B.B.S, M.D.[2] Usama Talib, BSc, MD [3]

Hantavirus infection can be classified based on taxonomic classification of the virus, clinical syndrome, and phylogenetic host association. The family Hantaviridae (class Bunyaviricetes, order Elliovirales) encompasses seven genera and 53 species, with all human-pathogenic hantaviruses belonging to the genus Orthohantavirus within the subfamily Mammantavirinae.^[1][2] The two major clinical syndromes are hemorrhagic fever with renal syndrome (HFRS), caused by Old World hantaviruses in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS), also called hantavirus pulmonary syndrome (HPS), caused by New World hantaviruses in the Americas.^[3] Although HFRS and HCPS are recognized as distinct clinical entities, there are overlapping symptoms, signs, and pathogenic alterations.^[3] Nephropathia epidemica (NE) is a mild form of HFRS caused primarily by Puumala virus.^[3]

Hantaviruses belong to the family Hantaviridae, which was reclassified in 2024 under the order Elliovirales, class Bunyaviricetes (previously order Bunyavirales).^[2] The family encompasses seven genera and 53 species.^[4] All human-pathogenic hantaviruses belong to the genus Orthohantavirus within the subfamily Mammantavirinae.^[1] The family also includes subfamilies Actantavirinae (reptile-associated) and Repantavirinae (fish-associated), as well as genera Loanvirus, Mobatvirus, and Thottimvirus (associated with shrews, moles, and bats).^[1][5]

Hantavirids produce enveloped virions (80–120 nm in diameter) containing three single-stranded RNA segments with open reading frames that encode a nucleoprotein (N), a glycoprotein precursor (GPC), and a large (L) protein containing an RNA-dependent RNA polymerase (RdRP) domain.^[1] The total genome size is approximately 10.5–14.6 kb.^[1]

Taxonomic Rank	Classification
Realm	Riboviria
Kingdom	Orthornavirae
Phylum	Negarnaviricota
Subphylum	Polyploviricotina
Class	Bunyaviricetes
Order	Elliovirales
Family	Hantaviridae
Subfamily (human-pathogenic)	Mammantavirinae
Genus (human-pathogenic)	Orthohantavirus

Adapted from ICTV Virus Taxonomy Profile: Hantaviridae 2024.^[1][2]

Hantavirus infection can be classified on the basis of the clinical manifestations and the type of hantavirus responsible for the manifestation. The clinical manifestations include hantavirus cardiopulmonary syndrome (HCPS), hemorrhagic fever with renal syndrome (HFRS), and nephropathia epidemica (NE).^[3][6]

HFRS is endemic in Europe and Asia and is characterized by increased vascular permeability, coagulopathy, and acute kidney injury. The disease course may include five phases: febrile, hypotensive, oliguric, diuretic, and convalescent.^[3] HFRS-causing hantaviruses include Hantaan virus (HTNV), Dobrava-Belgrade virus (DOBV), Puumala virus (PUUV), Seoul virus (SEOV), and Tula virus (TULV, rare).^[3]

HCPS (also called hantavirus pulmonary syndrome, HPS) is endemic in the Americas and is characterized by respiratory failure and cardiogenic shock. HCPS begins with a febrile prodrome followed by a cardiopulmonary phase with sudden onset of cough, dyspnea, tachycardia, and hypotension, leading to non-cardiogenic pulmonary edema.^[3] The most common causes are Sin Nombre virus (SNV) in North America and Andes virus (ANDV) in South America.^[3]

NE (nephropathia epidemica) is a mild form of HFRS caused primarily by Puumala virus (PUUV), with a case fatality rate (CFR) 1%.^[3][7]

Although HFRS and HCPS are recognized as distinct clinical entities, there are overlapping symptoms, signs, and pathogenic alterations. Both syndromes can lead to renal failure, and virtually all patients with HCPS and more than half of patients with HFRS have respiratory symptoms.^[3]

The most severe forms of HCPS are associated with Sin Nombre virus, Andes virus, Araraquara virus, and Juquitiba virus, all with CFRs between 30% and 45%. Choclo virus (CHOV) and Laguna Negra virus (LANV) have a CFR between 12% and 15%.^[3] Andes virus is unique among hantaviruses for documented person-to-person transmission.^[3]

Virus	Abbreviation	Primary Rodent Host	Geographic Distribution	CFR
Sin Nombre virus	SNV	Peromyscus maniculatus (deer mouse)	North America (western USA, Canada)	~36%
Andes virus	ANDV	Oligoryzomys longicaudatus (long-tailed colilargo)	Argentina, Chile	30–45%
Araraquara virus	ARAV	Necromys lasiurus	Brazil	30–45%
Juquitiba virus	JUQV	Oligoryzomys nigripes	Brazil, Argentina	30–45%
New York virus	NYV	Peromyscus leucopus (white-footed mouse)	North America (eastern USA)	—
Monongahela virus	MGLV	Peromyscus leucopus	North America (eastern USA)	—
Bayou virus	BAYV	Oryzomys palustris (marsh rice rat)	North America (southeastern USA)	—
Black Creek Canal virus	BCCV	Sigmodon hispidus (hispid cotton rat)	North America (southeastern USA)	—
Muleshoe virus	MULEV	Sigmodon hispidus	North America	—
Choclo virus	CHOV	Oligoryzomys fulvescens	Panama	12–15%
Laguna Negra virus	LANV	Calomys callosus	Argentina, Paraguay, Bolivia	12–15%
Bermejo virus	BMJV	Oligoryzomys chacoensis, O. flavescens	Bolivia, Argentina	—
Lechiguanas virus	LECV	Oligoryzomys flavescens	Argentina	—
Oran virus	ORNV	Oligoryzomys chacoensis	Argentina	—
Maciel virus	MCLV	Bolomys obscurus	Argentina	—
Castelo Dos Sonhos virus	CASV	Oligoryzomys spp.	Brazil	—

Adapted from Vial et al. 2023,^[3] Jiang et al. 2017,^[6] and Avšič-Županc et al. 2019.^[7] CFR = case fatality rate. “—” indicates insufficient data for reliable CFR estimate.

HFRS caused by Hantaan virus, Amur virus, and Dobrava-Belgrade virus (genotype Dobrava) are more severe, with mortality rates from 5% to 15%, whereas Seoul virus causes moderate disease and Puumala virus and Saaremaa virus (DOBV-Aa genotype) cause mild forms of disease with mortality rates 1%.^[7][3]

Virus	Abbreviation	Primary Rodent Host	Geographic Distribution	Severity / CFR
Hantaan virus	HTNV	Apodemus agrarius (striped field mouse)	China, Russia, Korea	Severe; CFR 5–15% (historically), ~1–1.3% (modern)
Amur virus	AMRV	Apodemus peninsulae (Korean field mouse)	China, Russia, Korea	Severe; CFR 5–15%
Dobrava-Belgrade virus (genotype Dobrava, DOBV-Af)	DOBV	Apodemus flavicollis (yellow-necked mouse)	Balkans, southeastern Europe	Severe; CFR 10–12%
Dobrava-Belgrade virus (genotype Sochi, DOBV-Ap)	DOBV-Ap	Apodemus ponticus (Black Sea field mouse)	Southern Russia (Sochi district)	Moderate to severe
Dobrava-Belgrade virus (genotype Kurkino)	DOBV-Kurkino	Apodemus agrarius (striped field mouse)	Central Europe (Germany, Poland, Lithuania)	Mild; no lethal outcomes reported
Saaremaa virus (DOBV-Aa genotype)	SAAV	Apodemus agrarius (striped field mouse)	Estonia, Russia, Finland, Germany, Denmark, Slovenia	Mild; CFR 1%
Seoul virus	SEOV	Rattus norvegicus (brown rat), R. rattus	Global (via international shipping)	Moderate; CFR 1–2%
Puumala virus	PUUV	Myodes glareolus (bank vole)	Northern/western Europe, Russia	Mild (NE); CFR 1% (0.1–0.4%)
Thailand hantavirus	THAIV	Bandicota indica	Thailand	Rare; limited data
Tula virus	TULV	Microtus arvalis (common vole)	Europe	Very rare; only a few human cases reported

Adapted from Vial et al. 2023,^[3] Avšič-Županc et al. 2019,^[7] Vaheri et al. 2013,^[8] and Klempa et al. 2013.^[9] CFR = case fatality rate.

Nephropathia epidemica is a mild form of HFRS caused primarily by Puumala virus (PUUV) and, to a lesser extent, by the Saaremaa virus (DOBV-Aa genotype). NE is the most common hantavirus disease in Europe, with Finland reporting the highest number of cases.^[3][8]

Virus	Primary Rodent Host	Geographic Distribution
Puumala virus (PUUV)	Myodes glareolus (bank vole)	Northern/western Europe, Russia, Finland
Saaremaa virus (DOBV-Aa)	Apodemus agrarius (striped field mouse)	Estonia, central/eastern Europe

Dobrava-Belgrade virus (DOBV) has a complex taxonomy with four recognized genotypes that differ in phylogeny, host reservoir, geographic distribution, and pathogenicity for humans:^[9][8]

Genotype	Alternate Name	Rodent Host	Geography	Pathogenicity
Dobrava (DOBV-Af)	DOBV	Apodemus flavicollis (yellow-necked mouse)	Balkans, southeastern Europe	Severe; CFR up to 12%
Kurkino	DOBV-Kurkino	Apodemus agrarius (striped field mouse)	Central Europe (Germany, Poland, Lithuania, Czech Republic)	Mild; no lethal outcomes reported
Sochi (DOBV-Ap)	DOBV-Ap	Apodemus ponticus (Black Sea field mouse)	Southern Russia (Sochi district)	Moderate to severe
Saaremaa (DOBV-Aa)	SAAV	Apodemus agrarius (striped field mouse)	Estonia, Russia, Finland, Germany, Denmark, Slovenia, Croatia, Slovakia	Mild

Adapted from Klempa et al. 2013^[9] and Vaheri et al. 2013.^[8]

A newer framework proposes classifying orthohantaviruses into three phylogenetically based rodent host groups rather than the traditional Old World versus New World geographic dichotomy. This framework better accounts for the fact that related arvicoline rodents and their orthohantaviruses are found in both hemispheres, making the geographic dichotomy imprecise.^[10]

Host Group	Rodent Subfamily/Family	Representative Viruses	Geography	Primary Syndrome
Murinae-associated	Family Muridae	HTNV, SEOV, DOBV	Asia, Europe	HFRS
Arvicolinae-associated	Subfamily of Cricetidae	PUUV, Tula virus	Europe, parts of North America	Mild HFRS / NE
Sigmodontinae/Neotominae-associated	Subfamily of Cricetidae	SNV, ANDV, and other New World viruses	Americas	HCPS

Adapted from Mull et al. 2023.^[10]

There are currently 58 distinct orthohantaviruses recognized, with over 24 recognized as pathogenic to humans. Case fatality of pathogenic orthohantaviruses ranges from 0.1% to 50%.^[10]

Approximately 200,000 cases of hantavirus infection are reported worldwide per year.^[10] Key epidemiological data by region include:

China: A mean of 12,800 HFRS cases per year (2004–2016), with a CFR of 1.3%.^[3]

European Union: A mean of 3,100 HFRS cases per year; Finland reports 43%, Germany 30%, and Sweden 6% of all cases. CFR ranges from 0.03% (Germany) to 0.4% (Sweden) for PUUV, and 10–12% for DOBV in the Balkans.^[3]

Russia: Approximately 7,300 HFRS cases per year, with an overall CFR of 0.4%.^[3]

Americas: Approximately 300 HCPS cases per year, mainly in Argentina, Brazil, and Chile.^[3]

South Korea: 300–600 cases per year; CFR has decreased from 5–7% (1950s) to 1% (2011–2016).^[3]

From serosurveillance studies in Finland, only around 15% of infected people are diagnosed and reported.^[3] The incubation period ranges from 2 to 6 weeks.^[3] Transmission mainly occurs via inhalation of aerosolized rodent excreta (urine, feces, saliva). Person-to-person transmission has been documented only for Andes virus.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Basir Gill, M.B.B.S, M.D.[2] Aditya Ganti M.B.B.S. [3]

Hantavirus is usually transmitted via the inhalation of aerosolized viral antigens from rodent excreta (urine, feces, saliva) or, rarely, via rodent bites. The incubation period of hantavirus infection is 2 to 6 weeks.^[1] Following inhalation, the virus replicates in pulmonary macrophages and dendritic cells. The primary target cells of hantavirus infection are endothelial cells of capillaries and small vessels. Increased vascular permeability is central to pathogenesis and does not appear to be caused by a lytic effect of the virus, but rather by functional changes of the endothelial barrier.^[1] According to histopathological studies, HFRS-causing hantaviruses primarily affect renal medulla capillaries, whereas HCPS-causing hantaviruses mainly affect pulmonary capillaries.^[1] The central phenomena behind the pathogenesis of both hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) are increased vascular permeability and acute thrombocytopenia.^[2] The pathogenesis is a complex multifactorial process that includes contributions from immune responses, platelet dysfunction, deregulation of endothelial cell barrier functions, activation of the complement system, the kallikrein-kinin system, and coagulation pathways.^[2][3]

Each hantavirus species is associated with a specific rodent host in a given geographic region. Rodent subfamilies associated with hantaviruses include:

Arvicolinae (Europe): hosts for Puumala virus, Tula virus

Murinae (Europe and Asia): hosts for Hantaan virus, Seoul virus, Dobrava-Belgrade virus

Sigmodontinae/Neotominae (Americas): hosts for Sin Nombre virus, Andes virus, and other New World hantaviruses

Hantavirus is usually transmitted via the inhalation of aerosolized viral antigens from rodent excreta. Human-to-human transmission has been documented only for Andes virus.^[1]

The incubation period of hantavirus infection ranges from 2 to 6 weeks.^[1] Earlier estimates based on HCPS cases in the United States reported a median incubation period of 9 to 33 days.^[4]

Following inhalation, the virus replicates in pulmonary macrophages and dendritic cells.^[1] Endothelial cells in the lungs, kidneys, heart, liver, and spleen are subsequently infected. Macrophages, mononuclear blood cells, dendritic cells, and respiratory and tubular epithelium can also be infected.^[1]

Pathogenic hantaviruses (both HFRS- and HCPS-causing) enter endothelial cells via αvβ3 integrins, which are highly expressed on endothelial cells, platelets, and macrophages.^[5] Non-pathogenic hantaviruses (e.g., Prospect Hill virus) use α5β1 integrins instead. Since β3 integrins regulate vascular permeability and platelet function, this receptor usage correlates with common elements of hantavirus pathogenesis.^[5]

Hantaviruses attach to β3 integrin receptors of endothelial cells and stimulate T cells. Neutralizing antibodies (NAbs) are produced as a result of stimulation and β3 integrins are inactivated. Inactivation of virus-bound β3 integrins contributes to deregulation of vascular endothelial growth factor receptor 2 (VEGFR2) and diminished antagonism of vascular endothelial growth factor (VEGF).^[6] Pathogenic hantaviruses also selectively inhibit β3 integrin-directed endothelial cell migration.^[7]

The β3 integrin and VEGFR2 form a functional complex on endothelial cells. Hantavirus infection upregulates expression of both β3 and VEGFR2 but blocks the function of the VEGFR2-β3 integrin complex, contributing to cytoskeletal reorganization and hyperpermeability in response to VEGF.^[6] Overexpressed VEGF promotes degradation of VE-cadherin, an adhesion molecule critical for endothelial barrier integrity, leading to loss of endothelial barrier function and increased vascular permeability.^[8]

The Andes virus nucleocapsid (N) protein activates the GTPase RhoA in pulmonary microvascular endothelial cells, causing VE-cadherin internalization from adherens junctions and endothelial permeability.^[9] ANDV N protein binds RhoGDI (Rho GDP dissociation inhibitor), the primary RhoA repressor that normally sequesters RhoA in an inactive state. By sequestering RhoGDI, the N protein reduces the amount available to suppress RhoA. In response to hypoxia and VEGF-activated protein kinase Cα (PKCα), ANDV N protein additionally directs the release of RhoA from S34-phosphorylated RhoGDI, synergistically activating RhoA and endothelial permeability.^[9] This provides a fundamental edemagenic mechanism that permits ANDV to amplify permeability in hypoxic HCPS patients. RhoA/Rho kinase inhibitors (fasudil and Y27632) dramatically reduced the permeability of ANDV-infected endothelial cells by 80% to 90%.^[10]

ANDV also persistently infects primary human vascular pericytes, which play critical roles in regulating endothelial cell permeability and immune cell recruitment. ANDV-infected pericytes secrete high levels of VEGF, and supernatants from infected pericytes increase endothelial monolayer permeability. This reveals a novel mechanism of pericyte-directed vascular barrier dysfunction contributing to HCPS.^[11]

Hantavirus-infected endothelial cells show increased Factor XII (FXII) binding and autoactivation on their surface. Incubation of FXII, prekallikrein, and high molecular weight kininogen (HK) with infected endothelial cells results in increased cleavage of HK, higher enzymatic activities of FXIIa/kallikrein, and increased liberation of bradykinin (BK).^[12] Bradykinin is an extremely potent inflammatory molecule that induces vasodilation and vascular permeability. Permeability changes could be prevented using inhibitors that block BK binding, FXIIa activity, or kallikrein activity.^[12] Successful treatment of Puumala virus-infected patients using BK antagonists (icatibant) supports the clinical relevance of this pathway.^[8]

ANDV infection alters the expression of endothelial cell-specific microRNAs (miRNAs) that regulate vascular integrity. Fourteen miRNAs were upregulated >4-fold following ANDV infection, including six associated with regulating vascular integrity. Increased expression of SPRED1 and PIK3R2 mRNAs (targets of miR-126) contributes to enhanced paracellular permeability of ANDV-infected endothelial cells.^[13]

Loss of endothelial barrier function leads to fluid extravasation into the interstitial space, resulting in pulmonary edema (in HCPS) or renal interstitial edema (in HFRS). Platelets are consumed in high numbers in response to endothelial damage, resulting in thrombocytopenia.^[2] Increased thrombopoiesis occurs during HFRS as evidenced by elevated thrombopoietin, immature platelet fraction, and mean platelet volume, but circulating platelets have reduced ex vivo function. In vivo platelet activation (elevated soluble P-selectin and soluble glycoprotein VI) is significantly increased in HFRS patients with intravascular coagulation.^[14]

Hantavirus infection induces a cytokine storm with upregulation of proinflammatory cytokines including IL-1β, IL-2, IL-6, IL-8, IL-18, TNF-α, IFN-γ, and chemokines CXCL9, CXCL10, and MIF.^[15] HCPS is characterized by a more massive upregulation of proinflammatory cytokines compared to HFRS/NE. High IL-6 levels have been associated with more severe forms of both HFRS and HCPS and with fatal outcomes of HCPS.^[15]

A 2025 study demonstrated that IL-6 trans-signaling (via soluble IL-6 receptor, sIL-6R) enhances IL-6 and CCL2 secretion, upregulates ICAM-1, and disrupts VE-cadherin-mediated cell barrier integrity in hantavirus-infected endothelial cells. HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R/sgp130 ratio, suggesting enhanced IL-6 trans-signaling potential. Plasma sgp130 levels negatively correlated with number of interventions and positively with albumin levels. Patients requiring oxygen treatment displayed a higher sIL-6R/sgp130 ratio compared to patients who did not.^[16]

Sensitized mononuclear cells infiltrate the lung, myocardial interstitium, and spleen to produce cytokines, particularly TNF-α and IFN-γ, resulting in pulmonary edema and myocarditis.^[17]

CD8+ T cells: Elevated CD8+ T cell responses correlate with disease severity and systemic organ dysfunction. Individuals with HLA-B3501 have an increased risk of developing severe HCPS, and significantly higher frequencies of Sin Nombre virus-specific CD8+ T cells (up to 44.2% of CD8+ T cells) were found in patients with severe HCPS requiring mechanical ventilation compared to moderately ill patients (up to 9.8%).^[18]

NK cells: Excessive NK cell activation with persistence of elevated numbers in peripheral blood following infection. NK cells localize to the lung during acute infection.^[15]

T regulatory cells (Treg): Treg response is downregulated in humans during hantavirus infection (in contrast to rodent reservoirs where upregulated Treg promotes viral persistence). This suppression of Treg may contribute to HCPS pathogenesis.^[8]

Neutrophils: Attachment of hantavirus to β2 integrin receptors on neutrophils induces the release of neutrophil extracellular traps (NETs). Neutrophil activation products (myeloperoxidase and neutrophil elastase), together with IL-8, are strongly elevated in acute PUUV-HFRS and positively correlate with kidney dysfunction. These markers localize mainly in the tubulointerstitial space of the kidneys.^[19]

Plasmablasts: Significant early increase with early IgM/IgG production. Early neutralizing antibody production is broadly associated with positive prognosis in both HCPS and HFRS.^[15]

Hantaviruses have evolved multiple strategies to evade the type I interferon (IFN) response:

Glycoprotein precursor (GPC/Gn): The cytoplasmic tail of the Gn protein (GnT) from pathogenic hantaviruses binds TRAF3 and inhibits RIG-I/TBK1-directed IRF3 phosphorylation and IFN-β induction. A single residue (Y627) in the NY-1V GnT is required for this inhibition.^[20]

Nucleocapsid protein (N): ANDV NP interferes with IRF3 phosphorylation and TBK1 autophosphorylation. SNV GPC alone is sufficient for IFN antagonism, whereas ANDV requires both NP and GPC.^[21]

Non-structural protein (NSs): ANDV NSs antagonizes type I IFN induction by binding MAVS and reducing its ubiquitination, thereby suppressing downstream signaling from RIG-I and MDA5.^[15] NSs proteins from PUUV, TULV, and PHV also inhibit the RIG-I-activated IFNβ promoter.^[22]

Autophagy manipulation: Hantaan virus (HTNV) restrains innate immune responses by manipulating host autophagy flux. The Gn protein translocates to mitochondria and interacts with TUFM, recruiting LC3B and promoting mitophagy, which inhibits type I IFN responses by degrading MAVS. The NP competes with Gn for binding to LC3B and interacts with SNAP29, preventing autophagosome-lysosome fusion.^[23]

Neutralizing antibodies (NAbs) also inhibit innate type I interferon (IFN) responses of endothelial cells. This results in inhibition of upregulation of CD73 by IFN-β on endothelial cells and promotes vascular leakage.^[24]

PUUV-infected patients show altered coagulation with increased thrombin formation (prothrombin fragments F1+2), consumption of fibrinogen, and decreased natural anticoagulants (antithrombin, protein C, protein S). Cross-talk between inflammation and coagulation systems is a hallmark of acute hantavirus infection.^[3] Patients with HFRS have an increased risk for disseminated intravascular coagulation (DIC) and venous thromboembolism. Circulating extracellular vesicle tissue factor activity is transiently increased during HFRS and is significantly associated with intravascular coagulation.^[25]

In a prospective study of 106 HFRS patients, DIC was found in approximately 18.9% to 28.3% of patients (depending on scoring template used) and correlated with more severe disease.^[26] In a cohort of 395 HFRS patients, 27.30% (107/392) presented with DIC on admission, and DIC was more common in the death group. Prolonged prothrombin time (PT), low fibrinogen, and elevated total bilirubin on admission were independent risk factors for mortality.^[27]

The complement system becomes activated via the alternative pathway in the acute stage of PUUV infection. Levels of the terminal complement complex SC5b-9 are significantly increased and C3 decreased in the acute stage compared to recovery. SC5b-9 levels correlate with several clinical and laboratory parameters reflecting disease severity, including chest X-ray abnormalities.^[28]

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Hemorrhagic fever caused by hantavirus can be differentiated from other disease such as dengue, malaria and Ebola. The hantavirus cardiopulmonary syndrome can be differentiated from other diseases like histoplasmosis, coccidioidomycosis, brucellosis, tuberculosis and aspergillosis.

Hemorrhagic fever caused by hantavirus can be differentiated from other disease such as dengue, malaria and Ebola. The hantavirus cardiopulmonary syndrome can be differentiated from other diseases like histoplasmosis, coccidioidomycosis, brucellosis, tuberculosis and aspergillosis.

Disease	Incubation period	Vector	Symptoms							Physical signs		Lab findings		Other findings	Treatment
			Fever	Cough	Rash	Joint pain	Myalgia	Diarrhea	Common hemorrhagic symptoms	Characterestic physical finding	Icterus	Plasma Creatine kinase	Confirmatory test
Leptospirosis	2 to 30 days	Rodents Domestic animals	Fever last for 4-7 days, remission for 1-2 days and then relapse	+	Present over legs Hemorrhagic rash	+	+ (Severe myalgia is characteristic of leptospirosis typically localized to the calf and lumbar areas)	+	Conjunctival hemorrhage, Hemoptysis	Conjunctival suffusion	+	Elevated	Microscopic agglutination test of urine	History of exposure to soil or water contaminated by infected rodents Recent history travel to tropical, sub tropical areas or humid areas	NSAIDs
Dengue	4 to 10 days	Aedes mosquito	Fever last for 1-2 days, remission for 1-2 days and then relapse for 1-2 days (Biphasic fever pattern)	–	Over legs and trunk pruritic rash May be hemorrhagic	+	+	–	Upper gastrointestinal bleeding	Painful lymphadenopathy	–	Normal	Serology showing positive IgM or IgG	Recent travel to South America, Africa, Southeast Asia	Supportive care Avoid aspirin and other NSAIDs
Malaria	Plasmodium falciparum: 9-14 days Plasmodium vivax: 12-18 days Plasmodium ovale: 18-40 days	Female Anopheles	Fever present daily or on alternate day or every 3 days depending on Plasmodium sps.	–	No rash	–	+	–	Bloody urine	Hepatosplenomegaly	+	Normal	Giemsa stained thick and thin blood smears	Recent travel to South America, Africa, Southeast Asia	Anti malarial regimen
Ebola	2 to 21 days.	No vector Human to human transmission Air born disease	+	+	Maculopapular non-pruritic rash with erythema Centripetal distribution	+	+	+ May be bloody in the early phase	Epistaxis Mucosal bleeding	Sudden onset of high fever with conjunctival injection and early gastrointestinal symptoms	–	Normal	RT-PCR	Recent visit to endemic area especially African countries	Isolation of the patient, supportive therapy
Influenza	1-4 days	No vector Air born disease	+	+	+/-	+	+	+	–	Fever and upper respiratory symptoms	–	Normal	Viral culture or PCR	Health care workers Patients with co-morbid conditions	Symptomatic treatment Oseltamivir or zanamivir
Yellow fever	3 to 6 days	Aedes or Haemagogus species mosquitoes	+	+	–	–	+	–	Conjunctival hemorrhage, Hemoptysis	Relative bradycardia (Faget’s sign)	+	Normal	RT-PCR, Nucleic acid amplification test, Immuno-histochemical staining	Recent travel to  Africa, South and Central America, and the Caribbean. Tropical rain forests of south America	Symptomatic treatment, Anti-inflammatory drugs
Typhoid fever	6 to 30 days	No vector Air born disease	+	–	Blanching erythematous  maculopapularlesions on the lower chest and abdomen	+	+	+	Intestinal bleeding	Rose spots	–	Normal	Blood or stool culture showing salmonella typhi sps.	Residence in endemic area Recent travel to endemic area	Fluoroquinolones, Third generation cephalosporins, Azithromycin

The hantavirus cardiopulmonary syndrome can be differentiated from other diseases like histoplasmosis, coccidioidomycosis, brucellosis, tuberculosis and aspergillosis.

Disease	Geographic distribution	High risk Groups	Differentiating features		Microscopic findings
			Physical exam	Laboratory findings
Histoplasmosis	Mississippi and Ohio River valleys	Cave dwellers Soil that contains bird or bat dropping[1]	Palate and oral ulcers Splenomegaly	Pancytopenia Urine antigen testing	Yeast are typically smaller, with narrow-based budding, found intracellularly within macrophages
Coccidioidomycosis	Southwestern US region	Opportunistic infection seen in AIDS	Rash on upper body or legs[2] Night sweats	Serologic tests (enzyme immune assay) more sensitive	Characteristic spherule appearance
Aspergillosis[3]	Ubiquitous	Cystic fibrosis or asthma. tuberculosis. Immunocompromised	Wheezing Stuffiness, runny nose Hemoptysis Weight loss	Cell wall detection using galactomannan antigen detection, Beta-D-glucan detection test.	Septated hyphae with acute angle branching
Anthrax	Ubiquitous	Live stock handlers	Painless skin ulcer with a black center [4] Bloody diarrhea	Thrombocytopenia Hyponatremia ↑ BUN Hypoalbuminemia ↑ Troponin.	Nonmotile, Gram-positive, aerobic or facultatively anaerobic, endospore-forming, rod-shaped bacterium
Tuberculosis	Asia,Africa	Ill contact individuals	Night sweats Hemoptysis	Hypercalcemia Elevated alkaline phosphatase levels fluorescence microscopy (auramine-rhodamine staining)+ for baccilli.	Aerobic, non-encapsulated, non-motile, acid-fast bacillus
Listeriosis	Ubiquitous	Pregnant women [5] Adults > 65 Immunocompromised.	Pregnancy can lead to miscarriage, stillbirth, premature delivery Non-pregnant : headache, stiff neck, confusion, loss of balance, and convulsions	Elevated titers of listeriolysin O CSF analysis :Pleocytosis lymphocytes ↑CSF protein ↓ CSF glucose	flagellated, catalase-positive, facultative intracellular, anaerobic, nonsporulating, Gram-positive bacillus
Brucellosis	Mexico, South and Central America	People who take unpasteurized dairy products	Arthritis Testicular and scrotal swelling Endocarditis	Antibody production againstlipopolysaccharide and bacterial antigens Relative lymphocytosis and thrombocytopenia.	Gram-negative bacteria,non-motile, encapsulated coccobacilli.
Coxsackie A virus	−	Children attending day care[6]	Painful blisters in the mouth, palms and on the feet. Rash, appears after episode of high fever.	Clinically diagnosed	−

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Basir Gill, M.B.B.S, M.D.[2] Aditya Ganti M.B.B.S. [3]

Hantavirus infection is a zoonotic disease with a nearly global distribution, caused by viruses of the genus Orthohantavirus (family Hantaviridae).^[1] Approximately 200,000 human infections are diagnosed annually worldwide.^[2] The two major clinical syndromes are hemorrhagic fever with renal syndrome (HFRS), which is endemic in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS), also called hantavirus pulmonary syndrome (HPS), which is endemic in the Americas.^[1] A systematic review and meta-analysis of 110 studies (81,815 observations) estimated the global seroprevalence at 2.93% (95% CI 2.34%–3.67%).^[3] Many factors influence hantavirus epidemiology and transmission, including climate, environment, social development, ecology of rodent hosts, and human behaviour in endemic regions.^[1] HFRS and HCPS are reportable diseases in most countries, but reports largely reflect hospital admissions; from serosurveillance studies in Finland, only around 15% of infected people are diagnosed and reported.^[1]

In the United States, from 1993 to 2020, a total of 833 human hantavirus cases were identified, with 94.9% (745/785) occurring in states west of the Mississippi River and 45.7% (359/785) in the Four Corners region.^[4] The median age of confirmed HCPS cases is 34 years (range 0–86 years), and 70–80% of cases occur in men.^[1]

Hantavirus infections cause approximately 200,000 human cases annually worldwide.^[2][5] China accounts for the majority of global cases, with over 90% of all HFRS cases worldwide.^[6] Case fatality rates vary substantially by virus and syndrome: HFRS caused by Hantaan virus, Amur virus, and Dobrava-Belgrade virus carries CFRs of 5–15%, whereas Seoul virus causes moderate disease (CFR 1–2%) and Puumala virus and Saaremaa virus cause mild forms (CFR 1%).^[7] HCPS has higher CFRs, ranging from 12–15% for Choclo virus and Laguna Negra virus to 30–45% for Sin Nombre virus, Andes virus, Araraquara virus, and Juquitiba virus.^[1]

Region	Syndrome	Approximate Annual Cases	Case Fatality Rate	Primary Virus(es)
China	HFRS	12,800 (mean, 2004–2016)	1.3%	HTNV, SEOV
Russia	HFRS	7,300	0.4%	PUUV, DOBV, HTNV, SEOV
European Union	HFRS	3,100 (mean)	0.03%–12% (varies by virus)	PUUV, DOBV
South Korea	HFRS	300–600	1% (2011–2016)	HTNV, SEOV
Americas (total)	HCPS	~300	12%–45% (varies by virus)	SNV, ANDV, others
United States	HCPS	~26 (mean, 2008–2020)	35.4%	SNV

Adapted from Vial et al. 2023,^[1] Whitmer et al. 2024,^[4] and Thorp et al. 2023.^[8]

China: A mean of 12,800 HFRS cases (median 11,063; range 8,853–25,041) per year was reported from 2004 to 2016, with a CFR of 1.3% and a decline in incidence over time. A nationwide surveillance study (2008–2020) analysed 111,054 cases across 76 cities.^[1][9] Hantaan virus (HTNV) is responsible for most cases, with Seoul virus (SEOV) also circulating.^[1]

South Korea: 300–600 cases per year for the past 20 years. The CFR has decreased from 5–7% in the 1950s to 1% from 2011 to 2016.^[1]

European Union: A mean of 3,100 HFRS cases (median 2,897; range 1,831–4,249) are reported per year. Finland reported 43%, Germany 30%, and Sweden 6% of all EU cases.^[1]

Case fatality rates vary by virus and region: 0.1% in Finland (PUUV), less than 0.03% in Germany (PUUV), 0.4% in Sweden (PUUV), and 10–12% in the Balkans and southeast Europe (DOBV).^[1] DOBV has also been reported in central Europe, including Germany, Poland, Lithuania, and Czech Republic.^[1]

Russia: Approximately 7,300 HFRS cases per year, with an overall CFR of 0.4%. Puumala virus is responsible for almost all HFRS cases diagnosed in western Russia. Multiple hantavirus species circulate, including PUUV, two species of DOBV (Sochi virus and Kurkino virus), HTNV, Amur virus, and SEOV.^[1]

Overall: Approximately 300 cases of HCPS are diagnosed per year in the Americas, mainly in Argentina, Brazil, and Chile.^[1]

United States: From 1993 to 2020, 833 human hantavirus cases were identified, with 335 cases occurring from 2008 to 2020. Of all US cases, 94.9% (745/785) were detected west of the Mississippi River, with 45.7% (359/785) in the Four Corners region. From 2008 to 2020, 67.7% of New World hantavirus cases were detected between March and August.^[4] HPS cases have been reported in 30 states, including most of the western half of the country and some eastern states as well. Over half of the confirmed cases have been reported from areas outside the Four Corners area.^[10] About three-quarters of patients with HPS have been residents of rural areas.^[10]

California (1993–2020): 89 hantavirus cases were reported in California residents. Fifty-six (63%) were male, mean age was 41.5 years, and 28 (31%) were fatal. Indoor exposure was most common, and more exposures occurred in peridomestic environments than at worksites or recreational areas.^[11]

Argentina: A 9-year surveillance study (2009–2017) identified 533 HCPS cases. The Northwest region contributed the largest proportion of cases. Cases clustered predominantly during warmer months, with seasonal patterns more pronounced in tropical regions.^[12]

Seoul virus (SEOV) is the only cosmopolitan hantavirus, distributed worldwide together with its reservoir host, the brown rat (Rattus norvegicus).^[1] SEOV cases have been reported on all inhabited continents. Most SEOV infections in humans, including those acquired from laboratory or pet rats, appear to be asymptomatic or cause a mild illness that remains undiagnosed.^[1]

A 2017 multistate outbreak investigation in the United States identified SEOV infections in people and pet rats across 31 facilities in 11 US states. Seventeen people had SEOV IgM, indicating recent infection; 7 reported symptoms and 3 were hospitalized. All patients recovered. Among facilities with ≥10 rats tested, rat IgG prevalence ranged from 2% to 70% and SEOV RT-PCR positivity ranged from 0% to 70%.^[13]

A 2024 systematic review and meta-analysis of 110 studies (81,815 observations) estimated global hantavirus seroprevalence by region:^[3]

Region	Number of Studies	Pooled Seroprevalence (95% CI)
Global	110	2.93% (2.34%–3.67%)
Americas	61	2.43% (1.71%–3.46%)
Europe	33	2.98% (2.19%–4.06%)
Asia	10	6.84% (3.64%–12.50%)
Africa	6	2.21% (1.82%–2.71%)

Adapted from Tortosa et al. 2024.^[3]

An inverse correlation of seroprevalence rates and disease severity has been observed: in the USA, Chile, and Argentina where the disease is severe, seroprevalence is low (0.1–2.2%), whereas in Paraguay and Panama, where HCPS is milder, 17–40% and 33%, respectively, are seropositive.^[1]

A systematic review and meta-analysis of 42 studies (total workforce of 15,043 individuals) found elevated seroprevalence in occupational groups with high rodent exposure:^[14]

Occupational Group	Pooled Seroprevalence (95% CI)	Odds Ratio vs. Reference (95% CI)
Farmers	3.7% (2.2%–6.2%)	1.875 (1.438–2.445)
Forestry workers	3.8% (2.6%–5.7%)	2.892 (2.079–4.023)

Adapted from Riccò et al. 2021.^[14]

Other high-risk occupations include military troops (especially those with extended outdoor training), construction and demolition workers, and laboratory workers handling rodents.^[1][5]

HCPS cases occur mainly in spring and summer in the Americas.^[1] In the United States, 67.7% of New World hantavirus cases from 2008 to 2020 were detected between March and August.^[4] In Chile, abrupt, localised increases in Oligoryzomys longicaudatus populations (known as ratadas), following blooming and seeding of bamboo species, lead to increased Andes virus infections in rodents and humans.^[1]

HFRS in China exhibits a dual seasonal pattern dependent on the dominant hantavirus genotype. Hantaan virus-dominant areas (Type I) show one spike every year in the autumn-winter season. Seoul virus-dominant areas (Type II) show one spike in spring. Mixed-type areas (Type III) show dual peaks.^[9] In Northern Europe, 3- to 4-year cycles of Myodes glareolus (bank vole) populations drive cyclical Puumala virus epidemics, linked to tree-seed production following warm summers and autumns.^[15]

Hantavirus outbreaks are strongly influenced by ecological and climatic factors that drive rodent population dynamics and human-rodent contact.^[1]

Temperature and rainfall are key climatic variables controlling the interannual cycles of hantavirus outbreaks. A 54-year study (1960–2013) from Central China revealed that 8-year cycles of Hantaan virus outbreaks are driven by the confluence of cyclic dynamics of striped field mouse (Apodemus agrarius) populations and climate variability. Outbreaks occur only when climatic conditions are favorable for both rodent population growth and virus transmission.^[2]

El Niño-Southern Oscillation (ENSO): In the Americas, El Niño-associated increased rainfall leads to increased vegetation, higher deer mouse densities, and more frequent Sin Nombre virus transmission. The 1997–1998 ENSO resulted in a 5-fold increase in HCPS caseload above baseline in the Four Corners states in 1998–1999.^[16]

Northwestern Argentina: A significant association between HCPS incidence and lagged rainfall and temperature with a delay of 2 to 6 months has been demonstrated.^[17]

Future projections: Spatiotemporal modelling of HFRS in China (2005–2098) under 27 climate scenarios predicts that annual HFRS cases will increase significantly in 62 of 356 cities in mainland China. Rattus norvegicus regions are predicted to be the most active, surpassing Apodemus and mixed regions. Eighty cities are identified as at severe risk level, including 22 new cities primarily located in East China after 2020.^[18]

Unrecognised cases exceed reported cases for Puumala, Seoul, and Choclo viruses.^[1] HFRS and HCPS are reportable diseases in most countries, but reports largely reflect hospital admissions. From serosurveillance studies in Finland, only around 15% of infected people are diagnosed and reported.^[1] Seropositive individuals have been identified in areas without known pathogenic hantaviruses, meaning these individuals might have been infected during travel or by unrecognised local viruses.^[1] The actual incidence of hantavirus infections in Africa is not well known due to limited availability of diagnostic tests and the potential for cross-reactive antibodies from other infections in the region.^[19]

HCPS (global): The median age for people with HCPS is 34 years (range 0–86 years).^[1]

United States (first 100 cases): The average age of case-patients was 34.9 years, and 8 were children or adolescents aged ≤16 years.^[20]

California (1993–2020): Mean age was 41.5 years.^[11]

HCPS: 70–80% of cases occur in men.^[1]

HFRS: The male-to-female ratio is 2.6:1.^[1]

United States (first 100 cases): 54% were male.^[20]

California (1993–2020): 63% were male.^[11]

PUUV infection: The male/female ratio is 1.67 in Finland and 1.52 in Sweden.^[15]

United States (first 100 cases): 63% were Caucasian, 35% were Native American, and 2% were African American.^[20]

Of cases with known ethnicity, 19% of HPS cases have been reported among Hispanics (ethnicity considered separately from race).^[10]

Ethnicity has been shown to affect the clinical course of ANDV and LANV infection, suggesting that human genetic composition can influence the severity of hantavirus infections.^[1]

HCPS: Acquired in rural settings by residents (80%) or visitors (20%) of endemic areas.^[1]

HFRS: Most cases occur in rural settings, in farmers, military troops, and other people who spend extended time outdoors.^[1]

Seoul virus: In contrast to other HFRS-causing hantaviruses, SEOV cases are mainly seen in urban settings, where wild rats are prevalent.^[1]

Of total US HPS cases reported from 1993 to 2020, 94.9% occurred in states west of the Mississippi River.^[4]

HPS cases have been reported in 30 states, including most of the western half of the country and some eastern states as well. Over half of the confirmed cases have been reported from areas outside the Four Corners area.^[10]

About three-quarters of patients with HPS have been residents of rural areas.^[10]

The proportion of cases in children varies by region. For HFRS, children and adolescents represent 1.7% of the cases in China, 6.0% in Finland, 9.7% in Russia, and 6.9% in Germany. In 2019, the incidence in Europe was less than 0.5 cases per 100,000 in children aged 14 years or younger, representing 1.3% of all cases in Europe. For HCPS, 18.6% of the cases in Chile, 8% in the USA, 10% in Brazil, and 9% in Argentina occur in children younger than 16 years. HCPS caused by ANDV occurs in children aged younger than 10 years and in adolescents, whereas SNV infection in children is largely limited to adolescents. The gender distribution in children (1:1) is different than in adults (4:1 male:female). The prodromal and cardiopulmonary phases, and laboratory findings in children are similar to those in adults.^[1]

Among 719 HPS patients in the United States (1993–2018), 22 (3.0%) were aged ≤12 years, 47 (6.5%) were 13 to 18 years old, and the remaining 650 (90.4%) were adults. Overall mortality was 35.4% and did not differ between age groups (P = .8). However, the time between symptom onset and death differed by age group, with children living a median of 2 days (interquartile range [IQR] 2 to 3), adolescents 4 days (IQR 3 to 5), and adults 5 days (IQR 4 to 8; P = .001). The mean highest hematocrit and median highest creatinine level were significantly associated with mortality in those 0 to 18 years old but not in adults.^[8]

Risk factors for hantavirus infection include:^[1][5]

Forestry or agricultural work

Weeding, construction, and demolition activities

Cleaning previously unused homes, cellars, storage areas, or stables

Actions that raise dust in rodent-contaminated environments

Peridomestic rodent presence

Outdoor military training

Smoking (reported as a risk factor for contracting Puumala virus infection and for more severe disease)^[1]

Condition of housing (whether there are holes allowing rodents to enter)^[15]

Use of rodent traps instead of poison in rodent control^[15]

Woodcutting and house warming with firewood^[15]

Pet rat ownership or breeding (for Seoul virus)^[13]

Residence in open developed areas and arid climates in the western United States^[21]

Andes virus is the only hantavirus known to be transmitted from person to person.^[1] In 2018–2019, a person-to-person transmission outbreak affected 34 patients in Argentina, 11 of whom died. A prospective study in Chile followed 476 household contacts of 76 confirmed ANDV cases for 5 weeks and found 16 additional patients, with a secondary attack rate of 3.4%.^[1]

Host human leukocyte antigen (HLA) type appears to influence the severity of hantavirus disease:

Puumala virus (PUUV): Individuals with HLA-B08 and HLA-DRB10301 alleles are likely to have a severe form of PUUV infection, whereas those with HLA-B27 are likely to have a benign clinical course. Other genetic factors related to the tumor necrosis factor (TNF) gene and the C4A component of the complement system may also be involved.^[22]

Sin Nombre virus (SNV): Individuals with HLA-B3501 have an increased risk of developing severe HCPS. Significantly higher frequencies of SNV-specific CD8+ T cells (up to 44.2% of CD8+ T cells) were found in patients with severe HPS requiring mechanical ventilation compared with moderately ill patients (up to 9.8% of CD8+ T cells).^[23]

Hantaan virus (HTNV) and Seoul virus (SEOV): In a Chinese Han population, HLA-DRB10401-0411, HLA-DRB11001, and DRB11305 alleles were more frequent in moderate HTNV-infected HFRS, whereas DRB11101-1105 was more frequently observed in severe HTNV-infected HFRS. The DRB50101-0201 allele may play a protective role in moderate HFRS caused by both HTNV and SEOV.^[24]

A genetic predisposition related to HLA type is considered important for the severity of both HFRS and HCPS, although results across studies have been discordant, even involving the same species of hantavirus.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2], Usama Talib, BSc, MD [3]

The most potent risk factor in the development of hantavirus infection is exposure to rodent excreta and close contact with hantavirus-infected humans.^[1][2]

The most potent risk factor in the development of hantavirus infection risk factors is exposure to rodent excreta and close contact with hantavirus-infected humans. Other risk factors include:^[1][2]

• Pest control department workers
• Construction workers
• Unhygienic environment leading to mice growth
• Unattended dumpsters
• Homeless
• Forest adventures
• Hunting
• Hiking
• Field exposures
• Living in endemic areas
• Camping
• Rural areas
• Spring and Summer
• Cleaning of uninhabited buildings
• Cleaning of the attics
• Rodent infested environment

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2], Aditya Ganti M.B.B.S. [3]

If hantavirus infection left untreated, it may result in multi-organ failure and death. Possible complications include, acute encephalomyelitis, Pituitary hemorrhage, Glomerulonephritis, Pulmonary edema, acute respiratory distress syndrome, Disseminated intravascular coagulation, Thrombocytopenia, and shock. Its prognosis depends on the extent of the diseases. The hantavirus cardiopulmonary syndrome (HCPS) has 38% mortality rate but, hemorrhagic fever with renal syndrome (HFRS) has a better prognosis with 1 to 15% mortality rate.^[1][2][3]

• Within 24 hours of initial evaluation, most patients develop some degree of hypotension and progressive evidence of pulmonary edema and hypoxia, usually requiring mechanical ventilation.
• The patients with fatal infections appear to have severe myocardial depression which can progress to sinus bradycardia with subsequent electromechanical dissociation, ventricular tachycardia or fibrillation.
• Hemodynamic compromise occurs a median of 5 days after symptom onset–usually dramatically within the first day of hospitalization.
• In contrast to HFRS, overt hemorrhage occurs rarely in HPS, although hemorrhage is occasionally seen in association with disseminated intravascular coagulation.
• If left untreated hantavirus infection may cause multiple organ failure and death.

Complications that can develop as a result of Hantavirus infection depends on the type of infection and can be summarized in the following table.^[4]

Type of hantavirus infection	Complications
Hemorrhagic fever with renal syndrome (HFRS)	Acute encephalomyelitis Bleeding Multiorgan dysfunction Pituitary hemorrhage Glomerulonephritis Pulmonary edema Acute respiratory distress syndrome Disseminated intravascular coagulation
Hantavirus cardiopulmonary syndrome (HCPS)	Renal insufficiency Thrombocytopenia Bleeding Myalgia Vomiting Diarrhea Shock

The overall prognosis of hantavirus infection depends on the clinical syndrome. The hantavirus cardiopulmonary syndrome (HCPS) has 38% mortality rate. Hemorrhagic fever with renal syndrome (HFRS) has better prognosis than hantavirus cardiopulmonary syndrome (HCPS). Depending upon which virus is causing the HFRS, death occurs in less than 1% to as many as 15% of patients. Fatality ranges from 5-15% for HFRS caused by Hantaan virus, and it is less than 1% for disease caused by Puumala virus.^[1][2][3]

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