Hantavirus Cardiopulmonary Syndrome 

Hantavirus was first recognized as a disease entity in the early 1950s when a cluster of 3,000 United Nation troops stationed in Korea was infected with a mysterious viral illness. Ten to fifteen percent of those infected perished,^[1] and though the exact etiologic agent was not discovered for two decades, it was suspected that rodents served as the main epidemiologic vector. Infection was associated with fever, hypotension, renal failure, thrombocytopenia, and disseminated intravascular coagulation (DIC). The clinical syndrome became known as hemorrhagic fever with renal syndrome (HFRS), formerly Korean hemorrhagic fever, and the virus was named Hanta after the Hantaan River of Korea. Over the ensuing years, several other etiologic agents of HFRS such as the Seoul, Puumala, and Dobrava viruses, were discovered across Europe and Asia.^{[2, 3, 4]}

Though antigenic evidence of Hantavirus remains widespread among rodents across the United States,^[5] only a handful of cases of HFRS were ever identified in the states.^[6] However, in May of 1993, an unusual illness struck a Navajo tribe living on the border of New Mexico and Arizona.^[7] Those infected presented with fever, chills, myalgia, and cough, which often progressed to dyspnea, respiratory distress, and cardiovascular collapse. An alarming 80% of those infected died. (See the image below.)

Over the next month, the virus was isolated and extensive research identified Peromyscus maniculatus (deer mouse) as the reservoir and vector for the disease (see the image below).

Though clearly a distinct clinical syndrome from HFRS, serum samples from those afflicted demonstrated weak antigenic evidence of hantavirus infection. Within 10 weeks of the original outbreak, researchers at the Centers for Disease Control and Prevention (CDC) and the University of New Mexico (UNM) had developed a diagnostic test for the virus. The new virus went through a litany of names (eg, Little Water virus, Four Corners virus, Muerto Canyon virus) before finally being given the somewhat tongue-in-cheek moniker of Sin Nombre virus (in Spanish, literally the virus with no name). The clinical syndrome caused by Sin Nombre virus (SNV) became known alternatively as Hantavirus pulmonary syndrome (HPS) or, more accurately, Hantavirus cardiopulmonary syndrome (HCPS).^[8]

Numerous viruses have been identified within the genus Hantavirus, family Bunyaviridae, but only about 15 have been shown to cause human disease. Four of these belong to the Old World and cause HFRS across Europe, Russia, and Asia.^[8] China has the highest annual incidence of HFRS with somewhere between 20,000 and 100,000 cases of symptomatic HFRS reported each year. Most cases are attributable to the Seoul virus, with the Hantaan virus playing a more minor role.

At least 24 New World Hantaviruses are known. Five of these cause HCPS in North America and 6 cause disease in Central America and South America. Most New World viruses cause HCPS only; however, the Black Creek Canal virus and the Bayou virus of the southeastern United States, as well as the Andes virus of South America, have been linked to renal failure and share some similarities with HFRS. SNV is the prototypical New World Hantavirus and the cause of the vast majority of cases of HCPS in the United States (see the image below).

The SNV and the Andes virus of South America cause the most severe disease, with case fatalities somewhere between 30 and 50%.

HCPS has existed in North America's southwest desert for hundreds, if not thousands, of years. Navajo oral tradition tells of an illness similar to HCPS that struck down young healthy members of the tribe after temperate winters and warns of the dangers of coexisting with rodents. The earliest case of a serologically confirmed SNV infection was in a person who developed an HCPS-like illness in July of 1959; it was not until September of 1994 that scientists confirmed the presence of immunoglobulin G (IgG) antibodies to SNV in the victim’s serum.^[8]

A different species of wild rodent serves as the primary reservoir for each individual Hantavirus;^[9] in the case of SNV, this reservoir is the deer mouse (see the image below).

Somewhere between 5% and 20% of rodents exhibit antigenic evidence of Hantavirus infection with active viral shedding into feces, urine, and saliva. Human infection typically occurs by inhalation of aerosolized rodent waste, though occasionally disease may be contracted via a rodent bite or direct mucous membrane contact with rodent excreta. The primary risk factor for Hantavirus infection, therefore, is prolonged exposure to rodents, particularly within a closed, poorly ventilated area.^{[10, 11]} Although generally not transmittable from person-to-person, the Andes virus of Argentina is a surprising exception to this rule.^[12]

Hantavirus demonstrates similar tissue tropism in rodents and humans, though for unclear reasons, rodents typically remain symptom free; consequently, they do not develop immunity and become perpetual viral shedders.^{[13, 14]} Given that Hantavirus is typically airborne, virus first infects the lung parenchyma where it is phagocytized and transported to draining lymph nodes. From here, the virus disseminates and primarily targets vascular endothelial cells, particularly of the heart, lung, and lymphoid tissues, and in the case of HFRS, the kidney.

Although disease severity directly correlates with viral RNA load,^[14] considerable evidence exists that immune mechanisms rather than direct viral cytopathology are responsible for the massive vascular dysfunction and plasma leakage of HFRS and HCPS.^{[15, 16]} Likely players include tumor necrosis factor-alpha (TNF alpha), interleukin 1 beta (IL-1 beta), and interferon gamma (IFN-gamma), though this has yet to be clarified.^[17]

In the case of HCPS, capillary leak is overwhelmingly centered in the lungs leading to fulminant noncardiogenic pulmonary edema. Pathologic specimens demonstrate boggy, edematous lungs and copious tracheal and pleural fluid.^[18] Following this, patients may progress quickly to cardiogenic shock with decreased cardiac output, elevated systemic vascular resistance, and lactic acidosis.^{[19, 20]} Severe cardiac depression acts synergistically with hypovolemia caused by capillary leakage and ultimately results in precipitous cardiopulmonary collapse. The name change from Hantavirus pulmonary syndrome to Hantavirus cardiopulmonary syndrome reflects the key contribution to morbidity made by concomitant myocardial dysfunction.

Frequency

United States

As of March 2007, a total of 465 cases of Hantavirus cardiopulmonary syndrome (HCPS) had been confirmed in 33 states (see the image below).

The majority of these cases are believed to have been caused by Sin Nombre virus (SNV) and have occurred west of the Mississippi River, which corresponds to the geographic distribution of the deer mouse (see the image below).^[8]

The preponderance of cases occurs in rural locales. However, case-control studies of the original outbreak in the Four Corners region suggest that the prevalence of Hantavirus infection in deer mice in and around urban and rural homes was 27.5-32.5%. The greatest concentration remains in the Four Corners area. Northern Idaho, the Dakotas, eastern Washington, and Mono County, California, also have reported cases and could be considered hot spots. National annual incidence in nonepidemic years is about 20-30 cases (see the image below).

The New York virus, the Black Creek Canal virus, and the Bayou virus have been confirmed in at least 6 cases in the eastern and southeastern United States.^[8]

Generally, outbreaks of Hantavirus occur in the spring and fall. This appears to correspond with farming cycles when workers are exposed to field-rodents during planting and harvest periods.^[8]

International

Thirty-six cases of HCPS have been reported in Canada, primarily Alberta, and account for 10-15% of all North American cases yearly. South America is the only other reservoir of HCPS. Confirmed cases of HCPS include 404 in Argentina, 74 in Paraguay, 273 in Chile, and 168 in Brazil. Bolivia had 20 cases; Panama, 31; and Uruguay, 23.^[8] Currently, at least 4 Hantavirus species in South America are recognized to cause HCPS. One of them, the Andes virus, is unique for reports of person-to-person transmission and of an increased mortality rate in children.^{[8, 21, 22]}

Mortality/Morbidity

During the 1993 outbreak in the Southwestern United States, the mortality rate was approximately 80%. In part because of increased recognition of the disease and more aggressive interventions (eg, extracorporeal membrane oxygenation (ECMO), and early mechanical ventilation), the case-fatality rates now range from 35% to 40%.^{[23, 24, 8]} Most deaths occur within 24 hours of hospital admission.

Race

During the initial outbreak in 1993, Native Americans were almost exclusively affected and the press, somewhat disparagingly, termed the mysterious disease "Navajo flu." As cases mounted, however, it became clear that HCPS was an equal opportunity killer. To date, 78% of patients with Hantavirus have been white; 19%, Native American; 2%, African Americans; 1%, Asian; and 14%, Hispanic (ethnicity considered separately from race).^[8]

Sex

Males account for 64% of the total number of HCPS diagnoses. This may reflect a higher environmental exposure to deer mice.^[8]

Age

HCPS has a remarkable predilection for affecting relatively young, healthy adults. The mean age of patients with HCPS is 38 years, with a range of 10-83 years. Preadolescent children infected with SNV have generally suffered mild illness and have not required intubation. However, the Andes virus of Argentina and Chile carries a high risk of death in infants younger than 10 months.