eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Hantavirus Pulmonary Syndrome

Author: Vinod K Dhawan, MD, FACP, FRCP(C), Professor, Department of Clinical Medicine, University of California at Los Angeles; Professor of Medicine, Charles R Drew University of Medicine and Science; Chief, Division of Infectious Diseases, MLK-Harbor Hospital
Coauthor(s): Veronica A Mas Casullo, MD, Assistant Professor, Department of Pediatric Infectious Diseases, Mount Sinai School of Medicine
Contributor Information and Disclosures

Updated: Aug 11, 2008

Introduction

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) in countries of the eastern hemisphere and worldwide, as listed in the table below.

Table 1. Hantaviruses That Cause HFRS, Rodent Hosts and Geographic Distribution

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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.¹ Investigation by the local health officials and researchers at the Centers for Disease Control and Prevention (CDC) discovered an outbreak of Hantavirus pulmonary syndrome 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 Media file 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 RNA viruses, 90-100 nm in diameter (see Media file 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 follows:

• 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 Hantavirus pulmonary syndrome is increased pulmonary capillary permeability that leads to severe pulmonary edema. The pathogenesis of pulmonary edema in Hantavirus pulmonary syndrome 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 [IL]-1α [IL-1α], IL-1β, IL-6, and tumor necrosis factor [TNF]-α [TNF-α], and lymphokines, such as interferon-γ, IL-2, IL-4, and TNF-beta) in tissues obtained at autopsy from subjects with Hantavirus pulmonary syndrome.² High numbers of cytokine-producing cells were observed in the lung and spleen tissues of patients with Hantavirus pulmonary syndrome. These results suggest that local cytokine production may play an important role in the pathogenesis of Hantavirus pulmonary syndrome.

Patients with Hantavirus pulmonary syndrome have very high levels of viremia at the onset of pulmonary edema and then rapidly clear the virus from plasma; however, pulmonary damage persists. These data suggest that the endothelial cells are not directly injured by the cytopathic effect of viral infection.

In Hantavirus pulmonary syndrome, 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 peripheral blood mononuclear cell (PBMC) samples from patients with severe disease than in those with moderate disease (44 [2%] and 9 [8%], respectively).³ These results support the hypothesis that virus-specific CD8+T cells contribute to Hantavirus pulmonary syndrome disease outcome. Impairment of endothelial cell's defense mechanisms against cytotoxic CD8+ T cells may be the mechanism of capillary leakage in Hantavirus pulmonary syndrome. Active suppression of immune T regulatory cells is probably involved in Hantavirus pulmonary syndrome pathogenesis.

Hantaviral antigen and particles have been noted in the cardiac endothelium and interstitial macrophages in association with atypical myocarditis in Hantavirus pulmonary syndrome. These findings support the opinion that structural changes could also be responsible for myocardial depression and shock in Hantavirus pulmonary syndrome. Hantavirus pulmonary syndrome shock is probably related to an exacerbated immune response of CD8+ T cells producing cytotoxicity on infected endothelial cells; the presence of myocarditis and myocardial depression is induced by nitric oxide.

Frequency

United States

Through March 26, 2007, a total of 465 cases of Hantavirus pulmonary syndrome have been reported in the United States. The case count started when the disease was first recognized in May 1993. The vast majority of cases have occurred sporadically, although outbreaks of Hantavirus pulmonary syndrome have been periodically reported in the United States. 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 Hantavirus pulmonary syndrome 5-fold above the baseline in the Four Corners region. The disease has been reported from 33 of 50 states in the United States, including most of the western half of the country and some eastern states as well (see Media file 3). Over half of the confirmed cases have been reported from areas outside the Four Corners area. About three fourths of patients with Hantavirus pulmonary syndrome have been residents of rural areas.

Since the original description of Hantavirus pulmonary syndrome due to Sin Nombre virus, cases of Hantavirus pulmonary syndrome–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. Hantavirus Pulmonary Syndrome Virus Types, Rodent Hosts, and Distribution in the United States

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Hantavirus pulmonary syndrome 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 Media file 4).

International

Since the description of Hantavirus pulmonary syndrome 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 asymptomatically infected. 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.⁴ 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.⁵ The infected mice were mostly adult males captured in the spring and fall.

Hantaviruses linked to sporadic cases or limited outbreaks of Hantavirus pulmonary syndrome 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)

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Mortality/Morbidity

Through March 26, 2007, 35% of the 465 cases of Hantavirus pulmonary syndrome reported in the United States have resulted in death.

Race

All races are susceptible to Hantavirus pulmonary syndrome. 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

History

• Hantavirus pulmonary syndrome (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 Hantavirus pulmonary syndrome, Armstrong et al reports rodent exposure to have occurred as follows:⁶
  • 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 GI disturbances may be noted.
• Although 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 that usually consist 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 Hantavirus pulmonary syndrome appear ill with severe ventilatory insufficiency.

Causes

• Various Hantaviruses have been implicated in the causation of Hantavirus pulmonary syndrome. 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 Hantavirus pulmonary syndrome in the United States is not transmitted from person to person. A person-to-person spread of Hantavirus pulmonary syndrome caused by the Andes virus has been reported in Southern Argentina.

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