AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Hantavirus pulmonary syndrome (HPS) is a rodent-borne viral infection caused by Hantaviruses and characterized by severe pulmonary illness with a high mortality rate. The Hantaviruses comprise 1 of the 5 genera of the family Bunyaviridae, with more than 250 animal viruses. Hantaviruses derive their name from the Hantaan River in South Korea near which the prototypic virus was first isolated in 1978 from a striped field mouse. Hantaviruses have been previously described to cause hemorrhagic fever with renal syndrome (HFRS, not HPS) in countries of the eastern hemisphere and worldwide as listed below.

Table 1. Hantaviruses Causing HFRS, Rodent Hosts and Geographic Distribution

Hantavirus pulmonary syndrome was first recognized in the United States in 1993 during an investigation of a cluster of sudden and unexplained deaths that occurred in rural New Mexico. Investigation by the local health officials and researchers at the Centers for Disease Control and Prevention (CDC) discovered an outbreak of HPS in the Four Corners region of the United States (ie, New Mexico, Arizona, Colorado, Utah). The outbreak was quickly linked to a Hantavirus that is now called Sin Nombre (nameless) virus. A reservoir of this virus was found in the regional deer mouse, Peromyscus maniculatus (see Image 1).

In the autumn of 1992, the weather phenomenon known as El Niño caused heavy precipitation in the Four Corners region of the United States, hypothetically resulting in the increased growth of berries, seeds, and nuts. A rapid rise in the rodent population resulted in this area. Aerosols contaminated by the infectious rodent urine and feces are thought to represent the principal vehicle for the transmission of Hantaviruses. The disease has also followed the bite of infected rodents and the consumption of food contaminated with infected rodent urine, droppings, or saliva.

Unlike viruses in the other genera of the family Bunyaviridae that are transmitted to humans by the arthropod vector, Hantaviruses have a rodent host. Each Hantavirus is adapted to a single host rodent species. Spillover of a Hantavirus to another rodent host may occur in endemic areas; however, adaptation and long-term propagation of the Hantavirus in the new host does not occur.

Hantaviruses are lipid-enveloped, negative-sense, single-stranded ribonucleic acid (RNA) viruses, 90-100 nm in diameter (see Image 2). The viral genome is trisegmented and composed of 3 fragments with sedimentation coefficients of approximately 32S, 26S, and 16S respectively. Each fragment has its own encoding function as described below.

• The small fragment encodes the viral nucleocapsid protein.
• The large fragment encodes the viral polymerase.
• The medium fragment encodes the envelope glycoproteins G1 and G2, regions of which are conserved among Hantaviruses, allowing the identification of new strains by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry.

Pathophysiology

The basic lesion in HPS is increased pulmonary capillary permeability leading to severe pulmonary edema. The pathogenesis of pulmonary edema in HPS is not well understood, although an immunologic mechanism is considered to play an important role. The lymphoblasts and the macrophages recruited to pulmonary tissue by the high viral burden may provoke a lymphokine-mediated activation of vascular endothelium, thereby increasing pulmonary capillary permeability.

In 1999, Mori and colleagues used immunohistochemical staining to enumerate cytokine-producing cells (ie, monokines, such as interleukin-1alpha [IL-1alpha], interleukin-1beta [IL-1beta], interleukin-6 [IL-6], and tumor necrosis factor-alpha [TNF-alpha]; lymphokines, such as interferon-gamma, interleukin-2 [IL-2], interleukin-4 [IL-4], and tumor necrosis factor-beta [TNF-beta]) in tissues obtained at autopsy from subjects with HPS. High numbers of cytokine-producing cells were observed in the lung and spleen tissues of HPS patients. These results suggest that local cytokine production may play an important role in the pathogenesis of HPS.

HPS patients have very high levels of viremia at the onset of pulmonary edema and then rapidly clear the virus from plasma, but pulmonary damage persists. These data suggest that the endothelial cells are not directly injured by the cytopathic effect of viral infection. In HPS, the patient's lung CD8+T cells are present in infiltrated alveolar walls. In 2004, Kilpatrick et al found significantly higher frequencies of viral-specific CD8+T cells in PBMC samples from patients with severe disease than in those with moderate disease (44, 2% and 9, 8%, respectively). These results support the hypothesis that virus-specific CD8+T cells contribute to HPS disease outcome.

Frequency

United States

Through February 1, 2006, a total of 416 cases of HPS have been reported to the CDC. The vast majority of cases have occurred sporadically, although outbreaks of HPS have been reported in the United States from time to time. The first outbreak in the Four Corners region of the southwestern United States occurred in 1993 following an El Niño year. A second strong El Niño phenomenon occurred in 1997-1998, resulting in an increased prevalence of HPS 5-fold above the baseline in the Four Corners region. The disease has been reported from 31 of 50 states in the United States (see Image 3).

Since the original description of HPS due to Sin Nombre virus, cases of HPS-like disease outside the range of P maniculatus have led to the isolation of additional distinct Hantaviruses in the United States, as summarized in Table 2 below.

Table 2. HPS Virus Types, Rodent Hosts, and Distribution in the United States

HPS in the United States is largely due to infection with the Sin Nombre virus. Other Hantaviruses have been implicated in only a handful of cases in isolated locations (see Image 4).

International

Since the description of HPS in 1993, awareness and heightened surveillance has led to the discovery of several new Hantaviruses in other countries of the western hemisphere. Hantaviruses that cause HPS have their reservoir in the sigmodontine rodents that are infected asymptomatically. In 1997, Mills et al studied the prevalence of antibody to Sin Nombre virus among 3,069 small mammals of 69 species in 9 communities from the lower Sonoran desert to the Alpine tundra. An overall prevalence of 6.3% was noted in the animals captured. Seropositivity was more common in the male animals. Individual seropositivity was as follows:

• Deer mice (928) - 11%
• Brush mice (355) - 20%
• Western harvest mice (35) - 23%
• Mexican voles (24) - 12%

In 2000, Kuenzi et al found that 7 of 35 (20%) deer mice captured from 28% of the urban and suburban homes of southwestern Montana were seropositive for antibody to Sin Nombre virus. The infected mice were mostly adult males captured in the spring and fall.

Hantaviruses linked to sporadic cases or limited outbreaks of HPS in other regions of the western hemisphere are listed below with their rodent host.

Table 3. Hantavirus Types, Rodent Hosts, and Geographic Distribution in the Western Hemisphere (other than the United States)

Mortality/Morbidity

To date, 416 cases have been reported in the United States, with a mortality rate of 36%.

Race

All races are susceptible to HPS. However, 77% of all cases reported to the CDC occurred in whites, 19% in American Indians, 2% in African Americans, and 1% in Asians. Thirteen percent of cases were reported in Hispanic persons, independent of race.

Sex

To date, 63% of reported cases were in males, and 37% were in females.

Age

The age of confirmed cases ranges from 10-83 years, with a mean of 38 years.

CLINICAL

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History

• HPS begins after an incubation period averaging 2 weeks. Rodent exposure is most commonly noted to have occurred peridomestically. In a 1995 report of 70 confirmed cases of HPS, Armstrong et al reports rodent exposure to have occurred as follows:
• • Peridomestic exposure - 69%
  • Peridomestic and occupational exposure -19%
  • Peridomestic and recreational exposure - 9%
  • Occupational exposure - 4%
  • Entering and/or cleaning rodent-infested structures - 9%
• Illness starts with a prodrome of fever and severe myalgia involving the large muscles, particularly in the thigh and the lower back.
• Abdominal discomfort and gastrointestinal disturbances may be noted.
• While cough is not necessarily an early symptom, dizziness is frequently reported. Signs of viral upper respiratory tract infections, such as rhinorrhea and pharyngitis, are generally absent.
• About 4-5 days later (range of 1-10 d), the patient develops respiratory symptoms usually consisting of modest cough and dyspnea. Rapid deterioration leads to hospitalization.

Physical

• Examination may be quite unrevealing early in the disease.
• • Fever is generally present.
  • Tachycardia may be noted.
  • Tachypnea is common.
• Patients with full-blown HPS appear ill with severe ventilatory insufficiency.

Causes

• A variety of Hantaviruses have been implicated in the causation of HPS. Human infection is thought to involve the inhalation of concentrated, aerosolized excreta of chronically infected rodents that shed the virus in their urine, feces, and saliva.
• Spread of Hantavirus may also occur by the following means:
• • An infected rodent bite
  • Eating food contaminated with infected rodent urine, droppings, or saliva
• Hantavirus infection for the types of Hantaviruses causing HPS in the United States is not transmitted from person to person. A person-to-person spread of HPS caused by the Andes virus has been reported in Southern Argentina.

DIFFERENTIALS

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Other Problems to be Considered

Influenza

WORKUP

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Lab Studies

• Several laboratory tests are useful in the diagnosis of HPS.
• • Thrombocytopenia is noted early in the disease.
  • Leukocytosis is noted with a left shift.
  • Abnormal lymphocytes and immunoblasts are present in the peripheral smear.
  • The hematocrit level is elevated because of the ultrafiltration of fluid into the lungs.
  • Activated partial thromboplastin time (aPTT) is prolonged.
  • Aspartate aminotransferase (AST) and lactic dehydrogenase (LDH) may be mildly elevated.
  • Arterial blood gases reveal desaturation.
• The tetrad of thrombocytopenia, leukocytosis (often with left shift), elevated hematocrit, and presence of immunoblasts in peripheral blood smear is a sensitive and specific early clue to the underlying disease. These findings in a patient with rapid onset of respiratory insufficiency should suggest the diagnosis.
• Serologic methods are useful in the diagnosis of Hantavirus infection. Most patients have both immunoglobulin M (IgM) and immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) antibodies upon admission to the hospital.
• Hantavirus can be detected in the tissue by the RT-PCR.
• Immunohistochemical staining of tissue reveals Hantaviral antigen.

Imaging Studies

• Chest radiographs usually show marked peribronchial cuffing and Kerley B lines early in the disease. Rapid progression of bilateral interstitial and alveolar infiltrates is observed in patients with full-blown HPS.

Procedures

• Catheterization of the pulmonary artery in patients with profound HPS generally shows decreased stroke volume index (SVI) and a low to low-normal cardiac index (CI). The pulmonary vascular resistance index is elevated. Increased systemic vascular resistance, along with the failure of correction of lowered CI and SVI by volume replacement, distinguishes HPS from septic shock.

Histologic Findings

Histopathology of the lungs in patients with HPS is depicted in Image 6. Under light microscopy, the lungs of these patients reveal interstitial and alveolar edema, alveolar hemorrhage, and a mononuclear interstitial pneumonitis composed of macrophages and T lymphocytes.

Unlike the acute respiratory distress syndrome (ARDS) due to other causes, no marked necrosis, polymorphonuclear leukocyte infiltration, type II pneumocyte hyperplasia, or dense hyalinization is observed.

Electron microscopy of lung tissue shows intact and somewhat swollen vascular endothelium. Inflammatory cell infiltration of capillaries, interstitium, and alveoli is evident. The cytoplasm of endothelial cells contains viral inclusions. No evidence exists of necrosis or a structural cellular defect responsible for the capillary leak.

Examination of other tissues may reveal infiltration by immunoblasts, such as in lymph nodes, spleen, liver, and blood vessels of other organs.

TREATMENT

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Medical Care

• Treatment of HPS remains supportive, requiring invasive hemodynamic monitoring with an arterial line and a pulmonary artery catheter and intensive support. Prompt treatment is of critical importance. Treatment initiated after the onset of severe respiratory distress is less likely to favorably impact the outcome.
• Mechanical ventilation may be necessary for survival during the period of severe respiratory insufficiency.
• Excessive administration of fluids should be avoided despite the fact that patients may be hemoconcentrated and hypotensive. Overzealous fluid administration may aggravate respiratory insufficiency because of increased vascular leak of fluid into the lungs.
• Early use of pressors is recommended to correct hypotension.
• Salvage therapy using extracorporeal membrane oxygenation, if available, may be considered. In a recent report, 2 subjects treated with a combination of corticosteroids and venovenous hemodiafiltration experienced rapid clinical improvement. However, the validity of this treatment is not well established.
• No specific treatment exists for HPS. Treatment with intravenous ribavirin, a guanosine analogue, conferred no survival benefit in an open-label trial. Prospective, controlled trials are underway.

Consultations

• Infectious diseases specialist
• Pulmonary medicine specialist
• Critical care specialist

MEDICATION

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Drug therapy is not currently a component of the standard of care for this infection. No specific therapy has been found to be of benefit. Ribavirin therapy has proved inconclusive in the open-label studies. A controlled trial of ribavirin in HPS is underway.

FOLLOW-UP

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Further Inpatient Care

• Patients should be transferred to the ICU for close observation and aggressive management.

Deterrence/Prevention

• Because HPS is acquired through inhalation of the virus-laden rodent excreta, avoidance of rodent contact is of paramount importance in its prevention. Several strategies outlined below have been proposed in this regard.
• • Elimination of rodent nesting sites can be achieved through keeping food storage areas clean, keeping food properly covered, elevating garbage containers, sealing holes and cracks in dwellings to prevent entrance by rodents, and clearing the brush from around homes and outbuildings.
  • Rodent traps and rodenticides should be used to control rodent populations. Similarly, encouraging natural predators, such as nonpoisonous snakes, owls, and hawks, may reduce the rodent population.
  • Special precautions should be used while cleaning up rodent-infested areas:
    • Air out rodent-infested areas before cleaning.
    • The area should be thoroughly wet with household disinfectant or 10% bleach solution spray before sweeping, vacuuming, or stirring the dust.
    • Rubber gloves should be worn during cleaning, and hands should be properly washed afterward.
    • Workers should wear a half-face air-purifying (or negative-pressure) respirator equipped with high-efficiency particulate air (HEPA) filters when removing rodents from traps or handling rodents in the affected area.
  • Outdoor rodent exposure should be avoided. Do not disturb rodent droppings or camp near rodent burrows or areas where trash is present. If sleeping outdoors, use elevated cots. Avoid feeding or handling rodents.
• Vaccines are currently being studied for the prevention of Hantavirus infection in endemic areas. In a 1999 study of an inactivated Hantavirus vaccine by Cho and colleagues, 79% of the 64 human volunteers developed a significant Hantavirus antibody titer 30 days after vaccination. Seroconversion rates increased to 97% 1 month after the booster dose. Antibody titers declined by 1 year, but a vigorous anamnestic response occurred with revaccination in almost all subjects. However, only 50% of the subjects produced neutralizing antibodies following the booster dose 1 year later. Improved vaccination for HPS is needed.

Complications

• Acute respiratory distress syndrome (ARDS) may occur rapidly. HPS should be suspected when an otherwise healthy adult develops an ARDS-like picture without any of the known causes of ARDS.

Prognosis

• In a report of 281 patients of HPS by the CDC, a case-fatality rate of 38% was noted. If hypoxia is managed and shock is not fatal, the vascular leak reverses in a few days and the recovery is apparently complete.

Patient Education

• Patients should be educated in avoidance of rodent contact through strategies outlined under Deterrence/Prevention.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to consider the diagnosis of HPS in an appropriate epidemiologic setting
• Failure to promptly transfer patients suspected of having HPS to facilities with ICUs and ventilatory support

Special Concerns

• Diagnosis of HPS may not be considered unless an appropriate epidemiologic history of rodent exposure is solicited.

MULTIMEDIA

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Media file 1:  Deer mouse, Peromyscus maniculatus. Courtesy of the Centers for Disease Control and Prevention.
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Media file 2:  Transmission electron micrograph of Sin Nombre virus. Courtesy of the Centers for Disease Control and Prevention.
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Media file 3:  Hantavirus pulmonary syndrome cases by state of residence in the United States. Courtesy of the Centers for Disease Control and Prevention.
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Media file 4:  Distribution of Hantavirus pulmonary syndrome cases in the United States by virus type. Courtesy of the Centers for Disease Control and Prevention.
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Media file 5:  Characteristics of 281 Hantavirus pulmonary syndrome cases in the United States, February 23, 2001. Courtesy of the Centers for Disease Control and Prevention.
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Media file 6:  Histopathology of the lung in Hantavirus pulmonary syndrome. Courtesy of the Centers for Disease Control and Prevention.
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REFERENCES

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• Shope RE. A midcourse assessment of hantavirus pulmonary syndrome. Emerg Infect Dis. Jan-Feb 1999;5(1):172-4. [Medline].
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Article Last Updated: May 19, 2006