Pediatric 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. ^{[1, 2, 3, 4, 5]} 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.

Old World Hantaviruses have been previously described to cause hemorrhagic fever with renal syndrome (HFRS). The clinical presentation of HFRS varies from subclinical, mild, and moderate to severe, depending in part on the causative agent of the disease. ^[6] Old World Hantaviruses cause human infection 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 (Open Table in a new window)

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 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.

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.

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.

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. ^[7] 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). ^[8] 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

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.

Most hantavirus infections are caused by Sin Nombre virus, but cases of HPS caused by Bayou, Black Creek Canal, Monongahela, and New York viruses have been reported, and cases of domestically acquired hemorrhagic fever and renal syndrome caused by Seoul virus have also occurred. Rarely, hantavirus infections result in mild illness that does not progress to HPS.

According to CDC a total of 637 cases of Hantavirus Pulmonary Syndrome have been reported in the United States through December 31, 2013, Of these, 606 cases occurred from 1993-onward, following the initial identification of HPS, whereas 31 cases were retrospectively identified. Cases have been reported in 34 states. More than 95% of reported cases have occurred in states west of the Mississippi River. About three-quarters of patients with HPS have been residents of rural areas.

Most recently in summer of 2012, an outbreak of hantavirus infections occurred among visitors staying overnight in a signature tent cabin at Yosemite National Park in California, USA. Of 10 cases 8 experienced hantavirus pulmonary syndrome, of whom 5 required intensive care with ventilatory support and 3 died. Rodent nests and tunnels were observed in the foam insulation of the cabin walls. Antibodies reactive to Sin Nombre virus were detected in 10 (14%) of 73 captured deer mice. All signature tent cabins were closed and subsequently dismantled to control the outbreak. ^[9]

Cases have been reported in 34 states. See map below.

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 (Open Table in a new window)

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.

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. 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.

Outside of North America, numerous individual cases and small clusters of HPS cases have been reported in Argentina, Bolivia, Brazil, Chile, Ecuador, Paraguay, Panama and Uruguay and Venezuela. Large outbreaks have been rare and have usually been associated with human disturbance and land-use changes or with unusual environmental events such as increased rainfall or periodic bamboo flowering.

In Colombia, Costa Rica and Mexico, rodents carrying viruses similar to Sin Nombre virus found in the United States have been found, but these particular hantaviruses have not been associated with disease in humans.

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) (Open Table in a new window)

 

Mortality/Morbidity

Through December 31, 2013, 36% of the 637 cases of Hantavirus pulmonary syndrome reported in the United States have resulted in death.

Race

All races are susceptible to Hantavirus pulmonary syndrome. In the United States, Whites currently account for 78% of all cases. American Indians account for about 18% of cases, African Americans for 2% of cases, and Asians for 1% of cases. About 20% of HPS cases have been reported among Hispanics (ethnicity considered separately from race).

Sex

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

Age

The mean age of confirmed case patients is 37 years (range, 6-83 y).