Hantavirus Pulmonary Syndrome

Hantavirus Pulmonary Syndrome (HPS) is a rare but serious disease of the lungs caused by hantaviruses. These viruses are mainly spread to people through contact with the droppings, urine, or saliva of infected rodents. The disease was first identified in the United States in 1993 during an outbreak in the Four Corners region. Since then, cases have been reported in many parts of the Americas. In North America, the deer mouse (Peromyscus maniculatus) is the main source of infection, while other rodent species carry the virus in Central and South America.

HPS usually begins with flu-like symptoms such as fever, muscle pain, headache, and tiredness. After a few days, the illness can quickly worsen, causing coughing, difficulty breathing, and fluid buildup in the lungs (pulmonary edema). In severe cases, this leads to acute respiratory failure and shock. The disease is often fatal, with death rates ranging from 30% to 40%, making it one of the deadliest viral infections passed from animals to humans.

People who live in or spend time in rural or semi-rural areas are at higher risk, especially in places like farms, barns, and forests where rodents are common. In North America, there have been no confirmed cases of person-to-person spread, but rare cases of transmission between people have been reported in South America with certain types of hantavirus, such as the Andes virus.

The best way to prevent HPS is to reduce contact with rodents. This includes controlling rodent populations, storing food properly, and avoiding areas that may be infested.

There is no specific cure for HPS. Treatment focuses on supportive care, usually in an intensive care unit (ICU). Patients may need machines to help them breathe (mechanical ventilation), extra oxygen, fluids given through a vein (intravenous fluids), and medicines to keep blood pressure stable. Getting an early diagnosis and quick access to advanced medical care greatly improves the chances of survival.

Distinction Between HPS and Other Hantavirus Infections

HPS is primarily confined to the Americas. The first recognized outbreak occurred in 1993 in the Four Corners region of the United States. Since then, cases have been documented throughout North, Central, and South America. The main viral agent in the United States and Canada is the Sin Nombre virus, carried by the deer mouse (Peromyscus maniculatus). Other hantaviruses responsible for HPS in Latin America include the Andes virus in Argentina and Chile, the Juquitiba virus in Brazil, and the Laguna Negra virus in Paraguay, distinguishing it from hemorrhagic fever with renal syndrome (HFRS), which is endemic in Europe and Asia, with thousands of cases reported annually. The most important agents include the Hantaan virus, widespread in China and Korea; the Seoul virus, which has a global distribution due to its reservoir in the Norway rat (Rattus norvegicus); the Puumala virus, common in northern Europe; and the Dobrava-Belgrade virus, found in the Balkans and Eastern Europe.

While both HPS and HFRS arise from infection with hantaviruses, they are caused by different viral species:

HPS-associated hantaviruses: Sin Nombre virus, Andes virus, Laguna Negra virus, Juquitiba virus, and related strains in the Americas.
HFRS-associated hantaviruses: Hantaan virus, Seoul virus, Puumala virus, and Dobrava-Belgrade virus, predominantly in Eurasia.

The two syndromes differ fundamentally in their target organ systems and pathophysiological outcomes:

HPS primarily involves the respiratory system. Following an incubation period of one to six weeks, patients develop a prodromal phase characterized by fever, myalgia, and malaise. This rapidly progresses to pulmonary involvement marked by cough, dyspnea, and acute respiratory distress syndrome (ARDS) due to capillary leak and noncardiogenic pulmonary edema. Without prompt supportive care, mortality rates range from 30% to 50%.
HFRS chiefly affects the renal system. The disease progresses through well-defined phases: febrile, hypotensive, oliguric, diuretic, and convalescent. Patients may present with fever, headache, abdominal pain, petechiae, and signs of vascular leakage. The hallmark complication is acute kidney injury, which may necessitate dialysis. The severity of HFRS varies with viral strain, with Hantaan virus infections producing more severe illness than Puumala virus infections. Case fatality rates range from less than 1% (Puumala virus) to 15% (Hantaan virus).

Both HPS and HFRS result from a combination of endothelial dysfunction and immune-mediated injury, but the organs most affected differ. In HPS, pulmonary capillaries are the primary site of increased permeability, leading to respiratory failure. In HFRS, vascular leakage occurs predominantly in the renal vasculature, resulting in impaired kidney function. Despite differences in clinical presentation, both syndromes share the underlying mechanism of capillary leak triggered by immune responses to viral infection.

History of HPS Discovery

Hantavirus Pulmonary Syndrome (HPS) was first recognized as a distinct clinical entity in the spring of 1993, following a mysterious outbreak of acute respiratory illness in the Four Corners region of the southwestern United States, where the borders of Arizona, New Mexico, Colorado, and Utah meet. Previously healthy young adults presented with sudden fever, muscle aches, and rapidly progressive respiratory failure, with a high fatality rate. The unusual nature of the illness alarmed local physicians and public health authorities.

The U.S. Centers for Disease Control and Prevention (CDC), in collaboration with state health departments and local Native American health authorities, launched an intensive investigation. Within weeks, laboratory analysis revealed that the causative agent was a previously unknown hantavirus. This discovery was significant because hantaviruses had until then been primarily associated with hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe, not with severe pulmonary disease in the Americas.

By late 1993, the newly identified virus was named the Sin Nombre virus (SNV)—“nameless virus”—to avoid stigmatizing the Native American communities where cases were first detected. Researchers soon identified the deer mouse (Peromyscus maniculatus) as the principal reservoir host. Deer mice were found to carry the virus without signs of illness, shedding it in urine, feces, and saliva. This discovery established the link between rodent ecology and human disease risk, reshaping public health recommendations for rodent control and safe household cleaning practices.

The recognition of HPS in North America led to retrospective analyses of unexplained deaths, which revealed that cases had occurred before 1993 but had gone undiagnosed due to lack of awareness. Further investigations throughout the Americas uncovered additional hantavirus species responsible for similar syndromes, including the Andes virus in South America, which is unique among hantaviruses for documented person-to-person transmission.

The 1993 discovery of HPS marked a turning point in hantavirus research, broadening scientific understanding of the global diversity of these viruses.

Causes and Transmission of HPS

Hantavirus Pulmonary Syndrome (HPS) is caused by specific hantaviruses carried mainly by rodents. Transmission occurs primarily through contact with rodent excreta.

Hantavirus Species Responsible for HPS

Hantaviruses belong to the family Hantaviridae (previously classified under Bunyaviridae). These viruses are enveloped, negative-sense, single-stranded RNA viruses. Each hantavirus species is closely associated with a specific rodent host species, which acts as its natural reservoir. Importantly, hantaviruses generally do not cause illness in their rodent carriers but can produce severe disease when transmitted to humans.

In North America, the Sin Nombre virus (SNV) is the principal etiological agent of HPS. The deer mouse (Peromyscus maniculatus), widespread across much of the United States and Canada, serves as the primary reservoir host. Other hantavirus species are implicated in different geographic regions:

Andes virus in South America, especially in Argentina and Chile, is notable both for causing HPS and for its rare capacity for human-to-human transmission.
Laguna Negra virus has been reported in Paraguay.
Juquitiba virus occurs in Brazil.
Additional hantaviruses, such as the Black Creek Canal virus in Florida and the Bayou virus in Louisiana, have been linked to isolated HPS cases.

The distribution of HPS is therefore geographically patterned, reflecting the habitats and population dynamics of reservoir rodent species.

Modes of Transmission

Transmission of hantaviruses from rodents to humans occurs predominantly through inhalation of aerosolized viral particles. When rodent urine, feces, or saliva dries, viral particles can become airborne, especially when disturbed during sweeping, cleaning, or farming activities. Humans inhale these particles, allowing the virus to enter the respiratory tract.

Other less common transmission routes include:

Rodent bites, in which infected saliva introduces the virus directly into tissue.
Direct contact of contaminated rodent excreta with mucous membranes or broken skin.

Human-to-human transmission of HPS is exceptionally rare and has only been documented in outbreaks caused by the Andes virus in South America. Epidemiological investigations confirm that other hantaviruses responsible for HPS, such as Sin Nombre virus, do not spread between people.

Role of Rodents in Disease Spread

Rodents serve as the natural reservoir for hantaviruses that cause HPS. They harbor the virus chronically and shed it throughout their lifespan without manifesting disease. Virus excretion occurs through urine, feces, and saliva, continuously contaminating the environment. Humans become incidental hosts when they come into contact with contaminated material.

Rodent population dynamics significantly influence the risk of HPS outbreaks. Environmental factors such as increased rainfall, mild winters, and greater food availability (for example, mast years producing abundant seeds) can lead to surges in rodent numbers. Higher rodent density increases the probability of human–rodent interactions and thereby elevates the likelihood of virus transmission.

Geographic and ecological overlap between human populations and rodent habitats is another determinant of disease risk. Rural dwellings, barns, grain storage areas, and wilderness cabins are frequent sites of human exposure, particularly when cleaning or occupying areas long infested by rodents.

Because no licensed vaccine for HPS currently exists, preventing encounters with rodents and their excretions is key to reducing the spread of HPS.

Symptoms and Clinical Presentation

Hantavirus Pulmonary Syndrome (HPS) begins with non-specific symptoms but can rapidly advance to severe respiratory distress. The clinical course involves an initial febrile phase followed by a critical phase marked by lung inflammation and respiratory failure.

Early Signs of HPS

The initial symptoms typically appear 1 to 5 weeks after exposure to the virus. Early signs include fever, fatigue, muscle aches, especially in large muscle groups like the thighs, hips, and back. Patients often report headaches, dizziness, and chills.

Gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain are common. These symptoms can mimic flu or other viral illnesses, making early diagnosis challenging.

Progression to Severe Respiratory Symptoms

Within a few days of initial symptoms, the disease can rapidly worsen. Patients develop cough, shortness of breath, and difficulty breathing due to fluid accumulation in the lungs (pulmonary edema).

Respiratory distress occurs because the virus damages the capillaries in the lungs, leading to increased permeability and fluid leakage. Oxygen levels drop, causing hypoxia and requiring mechanical ventilation in many cases.

Complications and Prognosis

Complications arise primarily from respiratory failure and shock due to compromised heart function. Patients may experience hypotension and multi-organ failure.

Despite advances in supportive care, HPS has a high mortality rate, approximately 35-40%. Early recognition and intensive care improve survival chances, but no specific antiviral treatment is currently available.

Key Complications	Description
Pulmonary edema	Fluid buildup in lung tissues
Respiratory failure	Inability to maintain adequate oxygen levels
Cardiogenic shock	Reduced heart output leading to tissue damage
Multi-organ dysfunction	Failure of multiple organ systems

Risk Factors and Epidemiology

Hantavirus Pulmonary Syndrome (HPS) primarily affects individuals in certain environments and regions with specific exposure risks. In North America, the Sin Nombre virus, carried by the western deer mouse (Peromyscus sonoriensis) is the most common cause of HPS, with transmission risks tied closely to rodent population dynamics.

Argentina reports an average of about 100 confirmed cases of Hantavirus Pulmonary Syndrome (HPS) each year between 2013 and 2018, with an overall case-fatality rate of roughly 18.6%. In the southern provinces, particularly in Patagonia, fatality rates can rise as high as 40%. In Chile, 786 cases were recorded between 1995 and 2012, concentrated in the southern regions, where the case-fatality rate was approximately 32%. Brazil reported 1,486 cases from 2001 to 2011, primarily in the Southeast, South, and Central-West regions. Fatality rates varied depending on the viral strain, reaching up to 44.5% in areas where the Araraquara virus circulates and around 32.5% in regions where the Juquitiba virus is found.

One distinctive feature of the Andes virus, prevalent in Argentina and Chile, is its potential for human-to-human transmission, which sets it apart from most other hantaviruses. Transmission is most often documented in close household settings. A notable outbreak occurred in Epuyén, Chubut Province, Argentina, between 2018 and 2019, when 29 laboratory-confirmed HPS cases were recorded. Several of these were secondary infections among close contacts, strengthening evidence of person-to-person spread.

HPS affects adults most commonly between the ages of 30 and 50, with the average age of onset in the United States being around 38 years. Although men are typically more affected due to occupational exposures in agriculture, forestry, construction, pest control, and janitorial work, women and children are also impacted, especially in domestic or peridomestic clusters in South America. Children are less frequently affected overall but do appear in some case clusters; in Chile, pediatric HPS cases have sometimes presented with hemorrhagic symptoms.

Populations at heightened risk include individuals living in rural or semi-rural environments, particularly where housing and storage structures are poorly sealed and allow rodent entry. People cleaning rodent-infested spaces such as barns, sheds, trailers, or cabins without proper protective equipment are also especially vulnerable. Climatic and ecological factors influence the seasonality and frequency of outbreaks.

Diagnosis of Hantavirus Pulmonary Syndrome

Diagnosis involves recognizing specific clinical features and confirming infection through laboratory tests. The process also includes ruling out other illnesses with similar symptoms to ensure accurate identification.

Clinical Evaluation

Initial evaluation centers on identifying patients with a compatible history of illness and potential exposure to rodent-infested environments. The early or prodromal phase of HPS typically includes fever, chills, myalgia (muscle aches), headache, and gastrointestinal symptoms such as nausea, vomiting, or abdominal pain. Within several days, the illness progresses to the cardiopulmonary phase, characterized by cough, dyspnea (shortness of breath), tachypnea (rapid breathing), and hypoxemia (low blood oxygen levels). Hypotension (low blood pressure) and signs of shock may develop rapidly as pulmonary edema worsens.

Physical examination often reveals tachycardia (rapid heart rate), bilateral crackles in the lungs due to fluid accumulation, and evidence of impaired oxygen exchange. Recognition of this biphasic illness pattern, moving from generalized symptoms to sudden respiratory compromise, is a critical diagnostic clue. Clinicians must also elicit a thorough exposure history, including activities such as farming, cleaning barns or cabins, or camping in areas known to harbor hantavirus-carrying rodents.

Laboratory Testing

Laboratory confirmation of hantavirus infection is essential to establish a definitive diagnosis. The following diagnostic methods are commonly employed:

Serologic testing: Detection of hantavirus-specific antibodies remains the primary diagnostic tool. Enzyme-linked immunosorbent assays (ELISA) are widely used to identify IgM antibodies (indicating recent infection) and IgG antibodies (indicating prior or ongoing infection).
Molecular assays: Reverse transcription polymerase chain reaction (RT-PCR) can detect hantavirus RNA in blood or tissue samples during the early phase of illness, allowing direct identification of the viral genome.
Routine laboratory findings: Patients frequently present with thrombocytopenia (low platelet count), hemoconcentration (increased concentration of red blood cells due to plasma leakage), and elevated hematocrit levels. Leukocytosis (elevated white blood cell count) with a left shift is also common.
Radiographic imaging: Chest radiographs typically demonstrate bilateral interstitial infiltrates or diffuse pulmonary edema, findings consistent with capillary leak syndrome, a hallmark of HPS pathophysiology.

Advanced laboratory testing is often conducted at reference or specialized public health laboratories, given the rarity and severity of the disease.

Differential Diagnosis

The clinical features of HPS overlap with many infectious and non-infectious conditions, making differential diagnosis an essential step. Early in the disease course, HPS can resemble influenza, atypical pneumonia, bacterial sepsis, or leptospirosis. Other viral hemorrhagic fevers, such as those caused by arenaviruses or filoviruses, may also present with overlapping symptoms in endemic areas.

During the cardiopulmonary phase, HPS may be mistaken for acute respiratory distress syndrome (ARDS), cardiogenic pulmonary edema, or severe community-acquired pneumonia. Unlike these conditions, however, HPS typically progresses with unusual rapidity in previously healthy individuals who report rodent exposure.

Distinguishing HPS relies on integrating epidemiologic clues (such as rodent contact in endemic regions) with laboratory evidence of hantavirus infection and recognition of its characteristic clinical progression.

Treatment and Medical Management

Management of Hantavirus Pulmonary Syndrome (HPS) focuses on rapid diagnosis, early intervention, and intensive supportive care, as no specific antiviral therapy has been approved. The primary goals of treatment are to maintain adequate oxygen delivery to the body, stabilize cardiovascular function, and carefully regulate fluid balance to prevent worsening of pulmonary complications. Outcomes are significantly improved when patients are identified early and transferred to facilities with advanced critical care resources.

Supportive Care Strategies

Supportive care represents the cornerstone of HPS management. Because the disease can progress quickly from mild symptoms to life-threatening respiratory distress, close monitoring and early intervention are critical. Oxygen therapy is commonly used to maintain blood oxygen levels, helping to reduce the risk of hypoxemia (low oxygen in the blood) and respiratory failure.

Intravenous fluid therapy is administered with caution. While fluids are necessary to maintain blood pressure and organ perfusion, excessive fluid administration can worsen pulmonary edema (fluid buildup in the lungs), which is a hallmark of the cardiopulmonary phase of HPS. Medications such as vasopressors may be required to support blood pressure and cardiac output when hypotension (dangerously low blood pressure) develops.

Other aspects of supportive management include the use of antipyretics to control fever, analgesics for pain relief, and continuous monitoring of vital signs to detect early evidence of shock or organ dysfunction. Laboratory and imaging studies may be employed to track the progression of pulmonary and cardiovascular compromise.

Potential Antiviral Therapies

At present, there are no U.S. Food and Drug Administration (FDA)-approved antiviral agents for the treatment of HPS. The broad-spectrum antiviral drug ribavirin has been evaluated in both animal studies and limited human clinical settings. While ribavirin has demonstrated efficacy against some Old World hantaviruses that cause hemorrhagic fever with renal syndrome (HFRS), its effectiveness in HPS remains unproven. Clinical trials have shown limited or no benefit, and as a result, ribavirin is not widely recommended for routine management of HPS.

Experimental research continues on antiviral candidates that directly target hantavirus replication, as well as on immunotherapeutic approaches such as monoclonal antibodies. However, these remain investigational and are typically only available in the context of controlled clinical studies. As such, antiviral therapy does not form a standard part of HPS treatment protocols.

Hospitalization and Intensive Care

Hospital admission is considered essential for all confirmed or strongly suspected cases of HPS due to the unpredictable and rapid progression of the disease. Most patients require care in an intensive care unit (ICU), where specialized monitoring and advanced life-support measures can be provided.

Mechanical ventilation (use of a breathing machine) is often required in cases of acute respiratory failure, which occurs when fluid-filled lungs prevent adequate oxygen exchange. In addition, extracorporeal membrane oxygenation (ECMO)—a technique in which blood is oxygenated outside the body and returned to the patient—has been used in some centers for the most severe cases, though availability is limited.

Continuous hemodynamic monitoring allows clinicians to detect and treat shock, maintain cardiovascular stability, and manage multi-organ dysfunction. Fluid therapy in the ICU is carefully balanced: while sufficient fluids are needed to preserve circulation, overhydration must be avoided to reduce the risk of worsening pulmonary edema.

Prevention and Public Health Measures

Effective prevention of hantavirus pulmonary syndrome requires targeted actions to reduce rodent contact, raise awareness, and ensure safe practices in healthcare settings. These steps help minimize the risk of virus transmission to humans.

Rodent Control and Exposure Prevention

Rodents serve as the natural reservoirs of hantaviruses, and transmission to humans occurs primarily through inhalation of airborne particles from rodent urine, droppings, or saliva. Preventive measures are aimed at minimizing opportunities for contact with infected rodents or their excreta:

Seal holes, cracks, and gaps in homes, workplaces, and storage buildings to block rodent entry.
Store food, water, and waste in tightly sealed, rodent-proof containers to reduce attraction.
Ventilate enclosed spaces such as cabins, attics, or sheds before cleaning to disperse potentially contaminated dust.
Clean areas contaminated with rodent droppings using gloves and disinfectant solutions; avoid sweeping or vacuuming, which can aerosolize viral particles.
Maintain outdoor areas by removing nests, brush, and debris that provide rodent shelter.
Inspect seasonal dwellings, campsites, barns, and outbuildings in endemic areas before use.

These strategies form the foundation of public health campaigns in endemic regions, as direct control of rodent populations is considered the most effective means of reducing hantavirus exposure.

Educational Campaigns

Public health agencies often conduct educational campaigns focused on risk factors and preventive measures. Targeted messages emphasize avoiding contact with rodents and their urine, droppings, or nesting materials.

Materials such as posters, brochures, and digital content explain safe cleaning techniques and highlight symptoms for early detection. Campaigns also promote awareness in high-risk communities, like rural or forested regions.

Educational efforts incorporate language and cultural considerations to improve reach and effectiveness. Collaboration with local schools and workplaces ensures broader dissemination of information.

Guidelines for Healthcare Workers

Healthcare workers are at risk of exposure when managing patients with suspected or confirmed HPS. To minimize occupational hazards, public health agencies and hospital infection control committees recommend strict adherence to protective measures:

Use personal protective equipment (PPE), including gloves, gowns, masks, and eye protection, when handling patients or contaminated materials.
Isolate patients with suspected HPS promptly to limit nosocomial transmission risks.
Collect and transport clinical specimens following established biosafety and biohazard protocols.
Employ standard precautions for aerosol-generating procedures, with heightened respiratory protection where appropriate.
Participate in training sessions to reinforce knowledge of hantavirus epidemiology, clinical presentation, and safe handling of specimens.
Maintain clear communication between laboratory staff, clinicians, and public health authorities to ensure coordinated response and surveillance.

By combining personal protection, rigorous adherence to infection control standards, and professional training, healthcare systems reduce the likelihood of secondary transmission and improve patient safety.