Hantavirus Pulmonary Syndrome 

Updated: Jan 15, 2019
Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: Michael Stuart Bronze, MD 



In May 1993, an unusual cluster of deaths occurred in the southwestern United States. The deaths were characterized by a febrile prodrome that preceded acute respiratory failure and shock. Physicians from the Indian Health Service and the Centers for Disease Control and Prevention (CDC) determined that a rodent vector was responsible for the infection and identified the responsible virus as a member of the Hantavirus family.

Sin Nombre virus (SNV), as it is now known, is the primary agent responsible for Hantavirus pulmonary syndrome (HPS) and the deadliest member of the Hantavirus family. However, there are numerous other pathogenic hantaviruses. The New York virus has been identified as the cause of HPS in New York and Rhode Island, and the Bayou and Black Creek Canal viruses, found in the southeastern United States, produce a variant of the syndrome that includes a greater degree of renal failure. The more distantly related Hantaan, Seoul, Dobrava/Belgrade, and Puumala hantaviruses produce a distinct syndrome of hemorrhagic fever and renal failure (HFRS).

The hantaviruses are RNA zoonotic viruses that are generally spherical in shape, measuring 70-100 nm in diameter, and can be identified by inclusion bodies and distinctive gridlike patterns on electron microscopy. They are transmitted to humans from rodent hosts, including possibly from pet rats,[1] but, except for the Andes hantavirus, have not been shown to be capable of human-to-human transmission.

Retrospective analyses indicate that HPS has been present in North America since as early as 1959, and Hantavirus infections have now been reported in at least 32 states in the United States, as well as in Canada and South America.


The basic pathophysiological lesion of HPS, and indeed of all Hantavirus infections, is a generalized increase in capillary permeability that results from endothelial damage. This injury appears to be a consequence of the host's immunological response to viral antigens that have penetrated the endothelium by means of the cells' own integrins. The onset of clinical symptoms is correlated with the development of specific antibodies to the virus. The increased capillary permeability gives rise to widespread protein-rich edema. The particular organs affected are related to the specific species of Hantavirus. In HFRS, a large outpouring of edema fluid flows into the retroperitoneum and is associated with hemorrhage and necrosis. Individuals with HPS have edema concentrated in the pleura and lungs.

The endothelial cells appear swollen. Lung examination findings reveal an interstitial pneumonitis made up of edema fluid, mononuclear cells, and lymphocytes with polymorphonuclear leukocytes. Hyaline membranes appear along with a proliferation of type 2 alveolar lining cells. As the disease progresses, the alveolar septa become increasingly fibrotic. The spleen in patients with HPS shows infiltration of immunocompetent cells within the red pulp and the periarteriolar sheaths.

HPS can present clinically as noncardiogenic pulmonary edema. The pathophysiology of the pulmonary findings is that of a pulmonary capillary leak syndrome. The heart is not directly affected. The pulmonary capillary leak syndrome is the primary underlying pathophysiological defect responsible for both cardiopulmonary and renal dysfunction. Prerenal azotemia is due to the inadequate intravascular volume of the hypotensive patient and not to direct infection. Hantavirus particles are not found within the renal tubular cells of patients with HPS. Hypoxia also contributes to the state of shock.



United States

HPS occurs primarily in the fall, when small rodents (eg, field mice) inhabit human dwellings to protect themselves from the cold weather. In the wild, many small rodents (eg, voles, white-footed deer mice) also transmit the virus. Inhalation of infected aerosolized rodent urine or dried excreta can lead to infection with HPS. Human-to-human transmission of HPS has not been reported in the United States, nor have nosocomial infections been reported. HPS is a zoonosis and parallels the distribution of the associated rodent vectors. The climactic conditions of El Niño promote the transmission of the causative virus.


Hantavirus infections occur in eastern Asia, Latin America, and North America, including Canada. However, HPS seems to be restricted to North and South America. While human-to-human transmission has not been reported in the United States, outbreaks of HPS reported from Argentina were possibly associated with human-to-human transmission.[2, 3, 4]

One report suggests clinical and pathological findings in 3 cases of severe European Puumala hantavirus infection were similar to those found in American hantavirus patients and met the case definition of HPS.[5]


Initially, HPS was thought to be uniformly lethal. Current experience indicates that HPS represents a wide spectrum of clinical disease, from mild infection in ambulatory patients to severe infection requiring mechanical ventilation. The fatality rate for the complete syndrome is approximately 50%.

Recent studies have suggested that asymptomatic Hantavirus infection may be quite common, with some populations showing up to 4% seropositivity for anti-Hantavirus antibodies.[6]


HPS has no racial predilection.


HPS has no sexual predilection; however, because of cultural sex roles, males are more likely than females to encounter small rodents in hunting and/or field exposures.


HPS is conspicuously absent among very young persons and very elderly persons. This absence may reflect their relative lack of contact with rodents in the outdoor setting. However, infections in these age groups appear to be more deadly.[7]


The small rodent vectors of Hantavirus are thought to be lifelong carriers of the virus and are not subject to symptomatic infection by the virus. The deer mouse (Peromyscus maniculatus) is the primary reservoir for SNV in the western United States. Some attention has also been given to the cactus mouse (Peromyscus eremicus) in this region. The white-footed mouse (Peromyscus leucopus) serves that role for SNV and the New York virus in the northeastern United States.[8]


The prognosis of HPS varies, although it appears to correlate with the severity of disease. It does not appear to correlate with viral load.

Mild cases of HPS are typically nonfatal, and patients can be expected to make a full recovery. Most patients who recover from near-fatal HPS do not have any residual cardiopulmonary disease, although recovery time may be substantially longer. Superinfection has been observed in more severe cases.

Patient Education

The CDC has provided patient education materials for the prevention of Hantavirus pulmonary syndrome in hikers and campers.




The incubation period of Hantavirus pulmonary syndrome (HPS) ranges from 1-4 weeks. HPS has been divided into 3 clinical phases: (1) the prodromal phase, (2) the cardiopulmonary phase, and (3) the convalescent phase.

Prodromal symptoms resemble those of many viral illnesses, including fever, headache, and myalgias. Vomiting, diarrhea, and abdominal pain are common. Because symptoms initially referable to the respiratory tract are minimal or absent, the physician may incorrectly conclude that the patient has viral gastroenteritis. Neurologic symptoms, except dizziness, are uncommon. This phase lasts 3-5 days.

The cardiopulmonary phase is initiated by dyspnea, nonproductive cough, and circulatory collapse. This stage typically lasts only 24-48 hours, although has been observed for up to 7 days. Seventy-five percent of patients with pulmonary edema require mechanical ventilation. Oliguric renal failure is uncommon. When it does occur, it is due to acute tubular necrosis (ATN), as compared to the renal tubular cell damage observed in hemorrhagic fever with renal failure syndrome (HFRS).

Resolution of the cardiopulmonary stage of HPS is heralded by the onset of significant diuresis. After this occurs, the patient improves quite rapidly (ie, convalescent phase). The chronic sequelae of HPS are minimal.

Physical Examination

Physical examination findings of Hantavirus pulmonary syndrome are typically consistent with those of sepsis, as follows:

  • Vitals reveal fever, tachycardia, and tachypnea.
  • Hypotension is seen in about one third of cases.
  • Pulmonary examination shows diffuse rales.
  • Rash is typically absent.


Sin Nombre virus (SNV) is the primary agent responsible for Hantavirus pulmonary syndrome (HPS) and is the deadliest member of the Hantavirus family. However, there are numerous other pathogenic hantaviruses. The New York virus has been identified as the cause of HPS in New York and Rhode Island, and the Bayou and Black Creek Canal viruses, found in the southeastern United States, produce a variant of the syndrome that includes a greater degree of renal failure. The more distantly related Hantaan, Seoul, Dobrava/Belgrade, and Puumala hantaviruses produce a distinct syndrome of hemorrhagic fever and renal failure (HFRS).


Renal failure due to ATN may occur.

Severe capillary pulmonary leakage may result in intractable noncardiogenic pulmonary edema and cardiorespiratory collapse and/or shock.



Diagnostic Considerations

Drug-induced noncardiac pulmonary edema

An appropriate ingestion history of medications that are associated with noncardiac pulmonary edema may differentiate drug-induced noncardiac pulmonary edema from Hantavirus pulmonary syndrome (HPS).

Patients with cardiac pulmonary edema usually have a left ventricular S3 gallop rhythm and often have cardiomegaly upon physical examination, which is not the case with HPS.

Acute respiratory distress syndrome

In contrast to HPS, the distribution of the infiltrates associated with acute respiratory distress syndrome (ARDS) observed on chest radiographs is peripheral rather than central. In addition, pleural effusions are common in HPS but are not a feature of ARDS.

HPS is accompanied by perihilar cuffing, earlier appearance of interstitial edema (Kerley B lines), and pericardiac haziness (fuzzy heart sign), which are characteristic of HPS and are not found with ARDS.

Pneumonic plague

Patients with pneumonic plague are critically ill with hemoptysis, which is not a feature of HPS. Pneumonic plague occurs in the setting of an outbreak of antecedent bubonic plague. Patients with HPS are less ill and have no adenopathy suggesting preceding or concomitant pneumonic plague.

Atypical community-acquired pneumonias

Among the nonzoonotic atypical pneumonias, Legionnaires disease may resemble HPS. Levels of serum transaminases may be mildly elevated in patients with Legionnaires disease and in those with HPS. Relative bradycardia uniformly accompanies Legionnaires disease but not HPS. Gastrointestinal symptoms, particularly diarrhea, may be observed in both. Severe renal insufficiency is uncommon in HPS and is unusual in Legionnaires disease. Cardiopulmonary collapse frequently occurs in HPS and seldom complicates Legionnaires disease, except in the terminal stages.

Tularemia and Q fever are zoonotic atypical pneumonias that are in the differential diagnoses of HPS. However, the vectors are different for these zoonotic infections. Contact with sheep or parturient cats is the usual epidemiological antecedent for Q fever pneumonia. Similarly, contact with deer, rabbits, or deer flies is the usual history suggesting tularemia. Symptoms common to Q fever, tularemia, and HPS are headache and myalgias. Q fever may feature splenomegaly and relative bradycardia, which are findings not observed in HPS. Bilateral hilar adenopathy and bloody pleural effusion characterize tularemic pneumonia and are not associated with HPS.

Viral influenza

Influenza begins abruptly, with patients often recalling the exact minute and/or hour they became acutely ill. A dry nonproductive cough and a sore throat, usually accompanied by rhinorrhea, characterize influenza. These are not features of HPS. Headache and myalgias are common in both infections.



Laboratory Studies

Specific diagnosis of Hantavirus pulmonary syndrome (HPS) may be achieved by serological techniques, polymerase chain reaction (PCR), and immunohistochemistry (IHC) studies, as follows:

  • RT-PCR can help detect viral RNA in blood and tissues and is the criterion standard for diagnosis. Diagnostic sensitivities and specificities of 100% and 94%, respectively, have been reported. [9]
  • IHC can help detect viral RNA in formalin-fixed tissues with specific antibodies.
  • Most commonly, HPS is confirmed by Hantavirus immunoglobulin M (IgM)–and immunoglobulin G (IgG)–specific serology results, usually measured by performing an enzyme-linked immunoassay. Approximately one third of patients with HPS have an elevated IgM titer at the time of clinical presentation. Another one third of patients have elevated titers of IgM and IgG to Hantavirus at the time of presentation. The remaining third develop an increase in IgG titers without an increase in the IgM titer during convalescence.

The following are other laboratory results that may aid in diagnosis:

  • Complete blood count (CBC) may show leukocytosis with a left shift, thrombocytopenia, and an elevated hematocrit due to hemoconcentration.
  • Peripheral blood smear may show atypical lymphocytes and/or immunoblasts, which have a high predictive value.
  • Hepatic panel may show mild transaminitis, but with a markedly elevated lactate dehydrogenase levels.
  • Coagulation studies may show mildly elevated activated partial thromboplastin time with a normal fibrinogen level. If the fibrinogen level is decreased, disseminated intravascular coagulation (DIC) should be considered.
  • Basic metabolic panel usually shows a baseline BUN and creatinine and a low bicarbonate level.
  • Urinalysis shows proteinuria in about 50% of cases.
  • Creatine kinase levels are elevated in 50% of cases.
  • Arterial blood gas analysis may reveal hypoxemia related to respiratory failure. Development of lactic acidosis and rapid respiratory deterioration usually portend death within 1-2 days.

The serum albumin level is decreased in almost all patients with Hantavirus pulmonary syndrome (HPS). Although this depression represents an acute-phase reactant that may be observed in many types of infections, the presence of severe hypoalbuminemia in a previously healthy patient with an acute onset of respiratory distress should suggest HPS.

Isolation of Hantavirus in tissue culture is not clinically available because of the technical difficulty of achieving this and because of issues related to biosafety.

Imaging Studies

Chest Radiography

The chest radiograph typically shows a pattern of noncardiac pulmonary edema. Perihilar haziness ("shaggy heart sign") is characteristic of HPS. Almost all patients with HPS have interstitial edema due to pulmonary capillary leak, which manifests radiologically as peribronchial cuffing or Kerley B lines. Pleural effusions are also common.

The chest radiograph typically does not show new cardiomegaly or mediastinal widening.

Other Tests

Patients with HPS often have a normal pulmonary wedge pressure, decreased cardiac index, and elevated systemic vascular resistance. However, these studies are not necessary for the diagnosis.

Histologic Findings

The histologic findings of HPS are nonspecific and correlate with the pathophysiology of the disease. Histology of lung tissue reveals capillaritis, pulmonary capillary leak syndrome, or both. Hemorrhage is typically not observed. In patients with severe and/or prolonged hypotension, the kidneys may develop histological findings suggestive of ATN.



Approach Considerations

Currently, treatment for Hantavirus pulmonary syndrome (HPS) is primarily supportive in nature. The attending physician must pay careful attention to acid-base disturbances and fluid balance, as well as respiratory status. HPS is a nationally reportable condition, and the state health department should be contacted immediately for instructions on reporting and submitting samples.

Medical Care

The nucleoside analogue ribavirin has been shown to be effective in a related disease, hemorrhagic fever with renal failure syndrome (HFRS), which is also caused by the Hantaviruses. Ribavirin has also been shown to be effective against HPS in animal studies. However, a meta-analysis of only two small trials showed no mortality benefit for HPS in humans. Additional studies are underway.[10]

Extracorporeal membrane oxygenation (ECMO) has been used successfully in several patients.[11] ECMO was most effective when initiated prior to the development of hemodynamic instability and major coagulopathy.[12]

Some experts have suggested that VEGF antagonists may be effective for hantaviral infections based on the observed up-regulation of VEGF during infection. However, this has not been studied clinically.[13]

Treatment with corticosteroids has not been shown to affect mortality.[14]


An infectious disease specialist should be consulted for every patient considered to have HPS or a zoonotic infectious disease, and a pulmonologist and critical care specialist should be involved intubation and mechanical ventilation may be required. 


 Some suggestion has also been made to reduce physical activity.


Caution patients against having contact with rodents or aerosolized rodent urine or excreta. Dead rodents should not be handled without taking proper precautions and wearing protection. Make dwellings rodent-proof; follow cleanliness and maintenance procedures such that dwellings do not attract small rodents.

Currently, there are no widely available vaccines against Hantavirus infection, although a controversial inactivated Hantavirus vaccine has been used in Korea with some effect.[15]

Long-Term Monitoring

Continue monitoring patients with mild Hantavirus pulmonary syndrome (HPS) in an outpatient setting until they are completely well.

Patients with mild HPS often complain of substernal discomfort. In patients with such symptoms, perform an ECG and/or cardiac enzyme test to help exclude myocardial infarction. Substernal discomfort that is oppressive in character is common in patients recovering from HPS. Although a cardiac explanation for the chest pain is suggested by its sternal location, myocardial infarction is not a complication of HPS.