Hantavirus Pulmonary Syndrome

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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Table
Hantavirus Type Rodent Host Geographic Distribution
Hantaan Apodemus agrarius (striped field mouse) Far East, Russia, Northern Asia, Balkans
Dobrava Apodemus flavicollis (yellow-necked field mouse) Balkans
Seoul Rattus norvegicus (urban rats) Worldwide
Puumala Clathrionomys glariolus (bank vole) Europe, Scandinavia, Western Russia
Hantavirus Type Rodent Host Geographic Distribution
Hantaan Apodemus agrarius (striped field mouse) Far East, Russia, Northern Asia, Balkans
Dobrava Apodemus flavicollis (yellow-necked field mouse) Balkans
Seoul Rattus norvegicus (urban rats) Worldwide
Puumala Clathrionomys glariolus (bank vole) Europe, Scandinavia, Western Russia

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.

3:17 2009-4-29