MICROBIOLOGY

• Enveloped, segmented, negative-sense RNA virus.
  • Numerous species; clinically important human pathogens cluster into New World and Old World viruses.
• Member of genus Orthohantavirus, family Hantaviridae, order Bunyavirales
  • Unlike many other bunyaviruses, hantaviruses are rodent-borne viruses associated with specific reservoirs.
  • In the U.S., geographic locales differ in viral reservoirs, which are members of the Rodentia family.
• Transmission to humans through inhalation of aerosolized saliva, urine or feces of the reservoir host.
• Hantavirus New World: known to cause hantavirus cardiopulmonary syndrome (HCPS). HCPS-causing hantaviruses are confined to the Americas.
  • Examples: found in the Americas unless otherwise stated.
    • Andes virus (ANDV)
    • Sin Nombre virus (SNV)
    • Choclo virus (CHOV), Central America
    • Carried by the New World rats and mice (family Muridae) and the subfamily Sigmodontinae, these reservoirs are primarily rural or peridomestic rather than urban.
      
      • Deer mouse
      • Cotton rat
      • Rice rat
      • White-footed mouse
• Hantaan virus, Old World: may cause hemorrhagic fever with renal syndrome (HFRS), from exposure to an infected rodent or rodent excretions, typically in rural settings. Known rodent carriers:
  • • Striped field mouse (Apodemus agrarius): Hantaan-related viruses
    • Brown or Norway rat (Rattus norvegicus, Seoul virus)
    • Bank vole (Myodes glareolus, Puumala virus)
    • Yellow-necked field mouse (Apodemus flavicollis, Dobrava virus)
  • Viruses:
    • Puumala virus (PUUV), a hantavirus carried in bank voles, may cause HFRS, primarily in Europe and western Russia.
      • Historically termed nephropathia epidemica.
    • Dobrava-Belgrade virus (DOBV) causes a more severe HFRS in the Balkans/Europe.
    • Hantaan virus: prototype (HTNV) HFRS, predominantly eastern Asia
      • Accounts for most cases in China and South Korea.
    • Saaremaa virus: Scandinavia, central Europe
    • Seoul virus: HFRS worldwide, most commonly in Asia, though present worldwide, with rare cases occurring in North America.
      • Many cases are traced to lab or pet rodents, and unlike other hantaviruses, have been described mostly in urban settings.
      • Many cases are asymptomatic or induce mild, undiagnosed disease.
• Pathogenesis in humans involves virus-induced permeability of endothelial cells of smaller vessels/capillaries that are also linked to increased innate immune and inflammatory responses.
  • Platelet dysfunction and coagulopathy also contribute.
  • HFRS hantaviruses target renal medullary capillaries, whereas HCPS hantaviruses affect the pulmonary vascular bed.
  • Why HFRS- and HCPS-causing hantaviruses differ in organ tropism and disease severity remains incompletely understood.
  • HFRS due to PUUV, in Finland, estimates are that only 15% of people who are infected receive a diagnosis[15].

CLINICAL

• Transmission occurs via inhalation following aerosolization of rodent excreta.
  • Transmission via blood products or transplanted tissues is theoretically possible but rarely documented.
  • Documented person-to-person transmission has only been described with the Andes virus.
  • The incubation period following exposure can be up to 6 weeks, making it difficult to trace the source.
• Two major syndromes in humans:
  • Hantavirus pulmonary syndrome (HPS: restricted to New World)
  • Hemorrhagic fever with renal syndrome (HFRS: Asia, Europe, rarely the Americas)
• New World: In the U.S., the most common pathogenic Hantavirus is Sin Nombre virus, a cause of acute cardiopulmonary syndrome, primarily in the western and southwestern U.S. (four-corner states, mainly Arizona, Colorado); also elsewhere (e.g., Vermont, Rhode Island, Central and South America), see CDC map.
  • April 2026 cruise ship outbreak, likely New World HCPS and Andes virus, awaiting confirmation.
    • Three deaths among 9 known infected (5/8/2026)
  • ~300 cases of HCPS are described in North and South America per year.
    • Median age 34 years (range 0-86), with 70-80% male.
      • Risk factors include forestry or agricultural workers, landscapers, construction, cleaning and rodent-infested buildings.
  • Initially manifests as an undifferentiated febrile illness, with fulminant progression to an ARDS-like picture typically in previously healthy young adults [Figure].
    
    • Early symptoms are nonspecific.
      • Fever, headache, myalgia, GI upset, dizziness, chills
    • Then cardiopulmonary symptoms develop, 4-10 days after onset (d5 = average).
    • Thrombocytopenia is the most characteristic laboratory abnormality.
      • WBC: leukocytosis common w/ left shift, including bandemia and atypical lymphocytes.
      • DIC is associated with severe cases.
      • Hypoalbuminemia
      • Elevated CRP
    • Peripheral smear review may provide an early clue to HCPS; thrombocytopenia, myelocytes, hemoconcentration, immunoblasts, and hypocapnia strongly support the diagnosis.
    • CDC (2015 HPS case definition) surveillance definition includes compatible febrile illness with noncardiogenic pulmonary edema/ARDS plus hantavirus serology, RT-PCR, or tissue immunohistochemistry.
      • Consistent clinical illness has a temperature >38.3°C, prodromal symptoms of fever, chills, myalgia, headache, GI symptoms, PLUS one of the following features
        • Clinical description:
          • Bilateral diffuse interstitial edema OR
          • Clinical diagnosis ARDS OR
          • Radiographic evidence of noncardiogenic pulmonary edema OR
          • Unexplained respiratory illness causing death with autopsy evidence of noncardiogenic pulmonary edema without an identifiable cause OR
          • Healthcare records of HPS OR
          • Death certificate with HPS listed as a cause or significant contributing factor
        • Laboratory diagnosis:
          • Detection of hantavirus-specific immunoglobulin M or rising titers of hantavirus-specific immunoglobulin G OR
          • Detection of hantavirus-specific ribonucleic acid in clinical specimens OR
          • Detection of hantavirus antigen by immunohistochemistry in lung biopsy or autopsy tissues
    • For cases, CDC requests that this form be completed.
      • Note: CDC does not accept specimens without prior consultation; contact the local health department first.
        
        • (877) 232-3322 or (404) 639-1510
    • Rodent infestation of the home remains the leading risk factor, especially when cleaning uninhabited trailers, cabins or residences in the SW U.S.
      
      • Transmission by rodent bite (rare) or exposure to rodent urine/droppings/secretions.
    • High case fatality rate (36%).
  • As of 2023, the CDC has reported 890 cases of HPS (859) and non-HPS (31) hantavirus infections in the U.S. since 1993 (initial description).
    
    • September 2012: 9 cases described acquired within Yosemite National Park, California [https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6146a5.htm]
  • The Andes virus causes HPS in South America, the only virus documented to cause human-to-human transmission.
• Old World: nonspecific febrile prodrome, signs of endothelial and hematological dysfunction, hemorrhage, back pain, retroperitoneal fluid, hypotension, shock, DIC, oliguric renal failure. Mortality may approach 15%.
  • Renal insufficiency is observed 5-9 days after symptom onset, often accompanied by oliguria.
  • Cardiopulmonary involvement, including shock and respiratory failure, may occur in severe HFRS.
  • After recovery, some patients may have long-term hematuria or proteinuria.
    • New-onset hypertension has been described during follow-up in some cohorts.
  • Strain-dependent severity:
    • Most severe disease: Hantaan and Dobrava viruses
    • Mild-moderate disease: Puumala, Saaremaa, Seoul viruses
  • > 150,000 cases/year; Asia accounts for most cases.
  • Mortality may range from < 1% to 15%.
  • Seoul virus (U.S., Canada, 2017): CDC investigation found infection in rat colonies, and humans linked to raising rats in 11 states.
    • 26 cases of non-HPS hantavirus infection have been diagnosed in the U.S.

• Ddx can be broad and depends on the geographic region and includes pneumonia, leptospirosis, sepsis with ARDS, endocarditis with pulmonary edema and influenza as examples.
  • Fever and thrombocytopenia would prompt consideration of Dengue, other arbovirus infections, severe fever with thrombocytopenia syndrome, Crimean Congo hemorrhagic fever and tick-borne infections such as Rickettsia or Ehrlichia spp.
    • Also consider viral myocarditis, leptospirosis, Legionella, Mycoplasma, Q fever, plague, F. tularensis, coccidioidomycosis, and histoplasmosis
    • Non-infectious considerations of the pulmonary-renal syndrome: Goodpasture’s, granulomatous polyangiitis, hemolytic uremic syndrome, TTP.
  • Hantavirus may also present as a gastroenteritis, enteric fever/typhoid or even an acute abdomen.
  • In pregnancy, HELLP syndrome may mimic hantavirus infection.
• Diagnosis (New World and Old World): contact a reference laboratory or local health department.
  • In the U.S., contact the state/local health department; the CDC Viral Special Pathogens Branch is available through the CDC Emergency Operations Center at 770-488-7100; CDC cannot accept specimens without prior consultation.
  • Serology: most frequently employed method.
    • Hantavirus-specific IgM or rising titers of HS IgG
      • EIA directed against the nucleocapsid antigen, which detects PUUV, HTNV and DOBV
        • Has also been used for SNV and ANDV
        • Cross-reactive EIAs may require confirmatory testing for specific hantaviruses.
  • RT-qPCR of S-segment RNA or nucleocapsid
    • Buffy coat may have a higher PCR yield than plasma.
  • Immunohistochemistry: HS antigen on tissue
  • Culture: rarely, viral isolation
• Lab criteria:
  • Hantavirus-specific IgM (+) or rising titers of IgG
  • RT-PCR
  • Hantavirus-specific antigen by immunohistochemistry

SITES OF INFECTION

• Lung: pulmonary edema, respiratory failure.
• Renal:
  • U.S./New World: may complicate shock but usually not the primary renal disease.
  • Old-world disease, Hantaan-type virus in Asia or Puumala virus in Europe: renal failure associated with hemorrhagic fever.
    • Oliguria in ~50%.
    • Proteinuria and hematuria are typical
• Cardiac: pulmonary edema in U.S. hantavirus disease can be cardiogenic, with myocardial depression contributing to shock and pulmonary edema in HCPS.
• Heme:
  • Thrombocytopenia; severe left shift with myelocytes, promyelocytes are characteristically seen on peripheral smear, important for early clinical suspicion and diagnosis.
  • HCPS: may see hemoconcentration
  • HFRS: more prone to bleeding in severe disease than HCPS.
• Ocular:
  • HFRS: blurred vision due to lens thickening

TREATMENT

FOLLOW-UP

• Mortality rates
  • • HCPS: ~35% in the U.S.; varies by virus, ~12–45%.
      • SNV ~35%, Araraquara ~44.5%, Choclo/Laguna Negra ~12–15%.
    • HFRS: PUUV and SEOV infections are usually < 1%; HTNV ~1%; DOBV may approach 10–12%.
• Thromboembolic events are reported complications, including MI and CVA.
• Persistent fatigue is described after an acute infection.
• HFRS sequelae
  • May see impaired pulmonary or renal function.
    • Proteinuria
    • New onset of hypertension
    • Pituitary/endocrine dysfunction has been described after PUUV infection.
• HCPS sequelae less well documented.
  • Pulmonary and renal impairments
  • Optic neuritis and retinal hemorrhage are described
  • Sensorineural hearing loss

PREVENTION

• Infection control:
  • Standard precautions are adequate for most hantaviruses; Andes virus is the exception, with documented person-to-person transmission, so public health consultation and enhanced precautions/contact management are appropriate after suspected Andes virus exposure.
• Avoid exposure to rodents or their droppings (at home, workplace or campsites).
  • Potentially risky activities:
    • Opening and cleaning unused buildings, such as cabins, sheds and outbuildings.
    • Household cleaning
    • Work exposure
      • Construction, pest control and utility workers
    • Campers and hikers
• Rodent control:
  • Seal holes in the home.
  • Trap rodents.
  • Keep food in containers, and clean up any food debris.
• Immunization:
  • No FDA-approved vaccines
  • Inactivated HTNV/SEOV vaccines are used in China and South Korea; protection/effectiveness data are variable.
    • China has inactivated the bivalent vaccine covering HTNV and SEOV through an expanded access program.
    • Republic of Korea: Hantavax^®, derived from mouse brain, formalin-inactivated.
      • The vaccine has variable clinical effectiveness in studies.
  • Next-generation vaccines remain investigational.

OTHER INFORMATION

• Suspect hantavirus infection in patients with febrile illness plus potential rodent exposure or travel/residence in an endemic region who may have the following:
  • Residence in or travel within the preceding six weeks from an endemic region, reflecting what can be a long viral incubation period.
  • Noncardiogenic pulmonary edema
  • Renal insufficiency with proteinuria, left shift, hemoconcentration, low albumin and thrombocytopenia are lab tip-offs.
  • Andes virus (HCPS): ask about close/sexual contacts.
• Early suspicion, with concordant presentations and potential rodent exposure, should prompt diagnostic evaluation and possible transfer to a tertiary/quaternary care center.
  • In the U.S., contact the state/local health department; the CDC Viral Special Pathogens Branch is available through the CDC Emergency Operations Center at 770-488-7100; CDC cannot accept specimens without prior consultation.
• Reportable infection in most countries, but largely based on severe illness cases prompting hospitalization.

Basis for recommendation

1. Vial PA, Ferrés M, Vial C, et al. Hantavirus in humans: a review of clinical aspects and management. Lancet Infect Dis. 2023;23(9):e371-e382.  [PMID:37105214]

   Comment: Review examines both hemorrhagic fever with renal syndrome (HFRS), endemic in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS), endemic in the Americas. There remains no specific antiviral treatment. Prompt consideration of the diagnosis and transfer to institutions with higher-level critical care are important aspects of management. Case fatality rates are up to 45% for some New World hantaviruses and are usually ~1 or less for most Old World hantavirus infections, with the exception of Dobrava-related HFRS, with rates up to 12%.
   

2. Mertz GJ, Miedzinski L, Goade D, et al. Placebo-controlled, double-blind trial of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome in North America. Clin Infect Dis. 2004;39(9):1307-13.  [PMID:15494907]

   Comment: As the authors note, ribavirin was well tolerated, but it was probably ineffective in treating HCPS when severe disease in the cardiopulmonary stage occurs.
   

References

3. Koehler FC, Di Cristanziano V, Späth MR, et al. The kidney in hantavirus infection-epidemiology, virology, pathophysiology, clinical presentation, diagnosis and management. Clin Kidney J. 2022;15(7):1231-1252.  [PMID:35756741]

   Comment: Useful renal-focused review.
   

4. Ravi-Caldwell N, Iyengar P, Davies-Cole J. Notes from the Field: First Reports of Locally Transmitted Seoul Hantavirus Infection - District of Columbia, May 2018-December 2018. MMWR Morb Mortal Wkly Rep. 2022;71(9):359-360.  [PMID:35239635]

   Comment: This 30-year-old developed HLH, only the second case ever described. SEOV is present within Norwegian rats in the US. It is likely undiagnosed based on seroprevalence studies.
   

5. Martínez VP, Di Paola N, Alonso DO, et al. "Super-Spreaders" and Person-to-Person Transmission of Andes Virus in Argentina. N Engl J Med. 2020;383(23):2230-2241.  [PMID:33264545]

   Comment: ANDV with documented human-to-human spread, which to date is the first description of a hantavirus acquired by this method of transmission. Respiratory, salivary and sexual contact need to be inquired about if suspecting for contact tracing.
   

6. Brocato RL, Hooper JW. Progress on the Prevention and Treatment of Hantavirus Disease. Viruses. 2019;11(7).  [PMID:31277410]

   Comment: The treatment and vaccine strategies employed to date (primarily against HFSR) have not proven effective in trials. Charts outline the studies to date and what might be in the pipeline.
   

7. Kofman A, Eggers P, Kjemtrup A, et al. Notes from the Field: Contact Tracing Investigation after First Case of Andes Virus in the United States - Delaware, February 2018. MMWR Morb Mortal Wkly Rep. 2018;67(41):1162-1163.  [PMID:30335741]

   Comment: Case of Andes virus causing HPS. Usually only seen in South America, this Hantavirus can cause human-to-human transmission. The patient was hospitalized upon return from Chile and Argentina. No known cases were acquired in North America. Two high-risk contacts of the index patient remained asymptomatic.
   

8. Kerins JL, Koske SE, Kazmierczak J, et al. Outbreak of Seoul Virus Among Rats and Rat Owners - United States and Canada, 2017. MMWR Morb Mortal Wkly Rep. 2018;67(4):131-134.  [PMID:29393924]

   Comment: Outbreak seen in 11 states traced to rat breeding. Testing of serum samples from 183 persons in the United States and Canada identified 24 (13.1%) with Seoul virus antibodies; three (12.5%) were hospitalized, and no deaths occurred. This investigation, including cases described in a published report from Tennessee (1), identified the first known transmission of the Seoul virus from pet rats to humans in the United States and Canada.
   

9. Malinin OV, Platonov AE. Insufficient efficacy and safety of intravenous ribavirin in treatment of haemorrhagic fever with renal syndrome caused by Puumala virus. Infect Dis (Lond). 2017;49(7):514-520.  [PMID:28276794]

   Comment: An open-label trial of 73 patients to receive IV ribavirin. All patients had the Puumala virus as a cause of HFRS. Viral load kinetics were similar in both treatment groups. Significantly more patients receiving ribavirin than standard therapy experienced low hemoglobin levels (95% vs. 36%), hyperbilirubinemia (81% vs. 3%), sinus bradycardia (43% vs. 14%), and rash (19% vs. 0%). The authors conclude that there is not sufficient benefit or safety with this drug.
   

10. Latus J, Schwab M, Tacconelli E, et al. Clinical course and long-term outcome of hantavirus-associated nephropathia epidemica, Germany. Emerg Infect Dis. 2015;21(1):76-83.  [PMID:25533268]

    Comment: Among 466 identified pts in Germany, 88% had acute kidney injury. At follow-up (7-35 mo), all patients had detectable hantavirus-specific IgG; 8.5% had persistent IgM; 25% had hematuria; 23% had hypertension (new diagnosis for 67%), and 7% had proteinuria. NE-associated hypertension and proteinuria do not appear to have long-term consequences, but NE-associated hematuria may. All patients in this study had hantavirus-specific IgG up to years after the infection.
    

11. Vial PA, Valdivieso F, Ferres M, et al. High-dose intravenous methylprednisolone for hantavirus cardiopulmonary syndrome in Chile: a double-blind, randomized controlled clinical trial. Clin Infect Dis. 2013;57(7):943-51.  [PMID:23784924]

    Comment: Null RCT in the limited number of patients enrolled did not find that corticosteroids affect mortality in HCPS occurring in Chile.
    

12. Knust B, Macneil A, Rollin PE. Hantavirus pulmonary syndrome clinical findings: evaluating a surveillance case definition. Vector Borne Zoonotic Dis. 2012;12(5):393-9.  [PMID:22214273]

    Comment: Authors review existing case definitions for New World infection hantavirus. Thrombocytopenia, chest x-rays with suggestive signs, and receiving supplemental oxygenation were highly sensitive (>95%), while elevated hematocrit was highly specific (83%) in detecting HPS. Overall, the clinical scenario, including thrombocytopenia, was the most sensitive.
    

13. Huttunen NP, Mäkelä S, Pokka T, et al. Systematic literature review of symptoms, signs and severity of serologically confirmed nephropathia epidemica in paediatric and adult patients. Scand J Infect Dis. 2011;43(6-7):405-10.  [PMID:21341977]

    Comment: A thorough review of Old World hantavirus infection. Authors point out that children have milder diseases than adults and rarely require hemodialysis.
    

14. Wernly JA, Dietl CA, Tabe CE, et al. Extracorporeal membrane oxygenation support improves survival of patients with Hantavirus cardiopulmonary syndrome refractory to medical treatment. Eur J Cardiothorac Surg. 2011;40(6):1334-40.  [PMID:21900022]

    Comment: In a cohort of 51 patients who had a predicted mortality of 100%, they appeared to benefit from VA ECMO with markedly reduced mortality and complete recovery.
    

15. Makary P, Kanerva M, Ollgren J, et al. Disease burden of Puumala virus infections, 1995-2008. Epidemiol Infect. 2010;138(10):1484-92.  [PMID:20109263]

    Comment: A detailed view of PUUV in Finland finds that only ~ 15% infected are diagnosed. More details include that the majority are male among 22,681 cases reported (average annual incidence 31/100,000 population), 85% were in persons aged 20-64 years. 13 deaths appeared to be directly due to PUUV infection (case-fatality proportion 0.08%). 590 cases (3%) were registered as occupational disease, of which most were related to farming and forestry.
    

16. Figueiredo LT, Moreli ML, de-Sousa RL, et al. Hantavirus pulmonary syndrome, central plateau, southeastern, and southern Brazil. Emerg Infect Dis. 2009;15(4):561-7.  [PMID:19331732]

    Comment: Cases in Brazil far more common than in U.S. Report of >800 cases, mortality rate is 39%.
    

17. Ye C, Prescott J, Nofchissey R, et al. Neutralizing antibodies and Sin Nombre virus RNA after recovery from hantavirus cardiopulmonary syndrome. Emerg Infect Dis. 2004;10(3):478-82.  [PMID:15109416]

    Comment: This paper shows that high titer neutralizing antibodies found at admission is a favorable prognostic sign. The authors examined the duration and titer of anti-Hantavirus antibodies and found that they were long-lasting; this finding may have significance for using the plasma from convalescent patients for treating patients with HPS. Sin Nombre virus RNA was not detectable after convalescence, indicating that the virus would not be transmitted during such procedures. However, standard procedures for cleaning such plasma of infectious viruses would be followed in this setting.
    

18. Mills JN, Corneli A, Young JC, et al. Hantavirus pulmonary syndrome--United States: updated recommendations for risk reduction. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2002;51(RR-9):1-12.  [PMID:12194506]

    Comment: Since no vaccine or drug is available for prophylaxis or treatment, CDC published these recommendations to reduce or prevent the risk of infection in the U.S. Most important for residents of endemic areas are 1) reducing rodent shelter and food sources inside and outside the home and 2) preventing rodents from entering the home by rodent-proofing. This article also provides a very valuable summary of the clinical and epidemiological aspects of the disease.
    

19. Koster F, Foucar K, Hjelle B, et al. Rapid presumptive diagnosis of hantavirus cardiopulmonary syndrome by peripheral blood smear review. Am J Clin Pathol. 2001;116(5):665-72.  [PMID:11710682]

    Comment: On examination of a peripheral blood smear, the presence of 4 of 5 findings (thrombocytopenia, myelocytosis, hemoconcentration, lack of significant toxic granulation in neutrophils, and more than 10% of lymphocytes with immunoblastic morphologic features) had sensitivity for HCPS of 96% and a specificity of 99% and missed no patients with HCPS who required intensive care.
    

20. Centers for Disease Control and Prevention (CDC). Hantavirus pulmonary syndrome--Vermont, 2000. MMWR Morb Mortal Wkly Rep. 2001;50(28):603-5.  [PMID:11476530]

    Comment: This report is an excellent review of the epidemiology, and description of a new site presumably endemic for Hantavirus infection east of the Mississippi, although cases have been described as having been transmitted in Rhode Island and New York.
    

21. Ramos MM, Overturf GD, Crowley MR, et al. Infection with Sin Nombre hantavirus: clinical presentation and outcome in children and adolescents. Pediatrics. 2001;108(2):E27.  [PMID:11483837]

    Comment: Nice summary of the clinical aspects of hantavirus infection in the pediatric population in the U.S.
    

22. Centers for Disease Control and Prevention (CDC). Update: outbreak of hantavirus infection--southwestern United States, 1993. MMWR Morb Mortal Wkly Rep. 1993;42(23):441-3.  [PMID:8502218]

    Comment: Report of the investigation of the original Hantavirus outbreak (later called Sin Nombre virus) in the United States.
    

23. CDC. Reported Cases of Hantavirus Disease [accessed 5/10/26, last updated 4/23/2026].

    Comment:
    CDC page with links to reported cases and epidemiological data. Has not been updated in case counts since 2023, perhaps reflecting reduced efforts by the CDC since 2025.
    
    
    

Media

Severe HPS

Characteristic radiograph resembling ARDS.

Source: CDC

http://www.cdc.gov/hantavirus/technical/hps/clinical-manifestation.html#radiologic