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Hantavirus Cardiopulmonary Syndrome

Author: Juliet D Caldwell, MD, Assistant Professor, Department of Emergency Medicine, Weill Medical College of Cornell University; Attending Physician, Department of Emergency Medicine, New York Presbyterian Hospital, Weill-Cornell Medical Center
Contributor Information and Disclosures

Updated: Jan 29, 2009

Introduction

Background

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 Media file 1.)

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 Media file 2).

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 Media file 3). 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

Pathophysiology

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 Media file 2). 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 Media file 4). 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 Media file 5).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 Media file 6). 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.

Clinical

History

The clinical course of Hantavirus cardiopulmonary syndrome (HCPS) advances through several sequential stages. 

Following exposure, an incubation period of about 3 weeks ensues. The aerosolized virus enters the lung, is taken up by local phagocytes, and is transported to local lymph nodes where it prepares to disseminate. The prodrome/febrile phase lasts 3-10 days and is marked by the onset of fever, chills, and myalgias, often severe, and is the likely clinical correlate to viral dissemination. It is nearly impossible to distinguish HCPS from any other nonspecific viral syndrome during this period. Disease severity progresses quickly, and patients often develop nausea, vomiting, weakness, and sometimes diarrhea and headache. Andes virus HCPS of South America differs slightly, presenting with facial flushing, fine petechiae, and conjunctivitis. Though rhinorrhea, pharyngitis, otalgia, and coryza are notably absent in most Hantavirus infections, a dry cough is common and often heralds sudden deterioration and progression to the cardiopulmonary phase of disease.²⁵

The cardiopulmonary phase lasts anywhere from 2-7 days and presents with sudden respiratory distress and, often, cardiovascular collapse within hours of arrival to the hospital. This phase of the illness correlates with massive capillary leakage into the pulmonary vascular bed. Immune response always precedes the abrupt deterioration into the cardiovascular phase of disease supporting the hypothesis of an immune-mediated pathogenesis.⁸  Clinical deterioration is precipitous and results in pulmonary edema, bronchorrhea, shock, and sometimes coagulopathy (Andes virus) and preterminal arrhythmias. Mean time from onset of first symptom to cardiopulmonary failure is 5 days.

Among survivors, recovery is nearly as rapid as decline and is often accompanied by a period of diuresis. During the convalescent period, the patient typically recovers with little or no residual deficits. Several months of fatigue and decreased exercise tolerance are often the only sequelae.

Early diagnosis is difficult because the common presenting symptoms of HCPS overlap with those of other, less ominous, viral illnesses. Risk factors for rodent exposure must be sought and are often the key to potential early diagnosis.  

• Consider diagnosis of HCPS in patients with the following:
• Fever
• Severe myalgias (often in the back and legs)  
• Exposure to mice or mouse droppings
• Other symptoms may include the following:  
• Malaise
• GI symptoms such as nausea and vomiting, diarrhea, and abdominal pain
• Headache
• Cough
• Risk factors to seek in the history include the following:
• Peridomestic rodent infestation
• Entering or disturbing seasonally closed or infrequently opened buildings
• Occupational exposure to rodents
• Risk also varies with rodent abundance and distribution, which, in turn, depends on several factors, including the following:
• Geographic region (highest incidence in the Southwest United States)
• Seasonality (increased incidence in spring and summer)
• Weather patterns (Outbreaks may follow El Nino conditions of a temperate wet winter.)
• The most common prodromal symptoms are the following:
• Fever
• Chills
• Myalgias (often in the back and legs)
• Other common prodromal symptoms include the following:
• Nausea/vomiting
• Diarrhea
• Headache
• Cough (usually nonproductive)
• Malaise
• Dizziness
• Dyspnea (usually not observed at presentation but often heralds the cardiopulmonary phase of HCPS)
• Consider another diagnosis with the following symptoms:
• Sore throat
• Rhinorrhea
• Conjunctivitis (except Andes virus)  
• Rash (except Andes virus where petechiae are common)
• Coryza
• Otalgia

Physical

Physical findings vary substantially with the stage of disease at presentation.

• Most frequent initial physical findings in Hantavirus cardiopulmonary syndrome (HCPS)
  • Tachypnea
  • Fever
  • Tachycardia
• Crackles or decreased breath sounds in most patients on lung examination
• Abdominal tenderness
  • Present in about 10% of patients
  • May be severe (One patient underwent an exploratory laparotomy before HCPS was recognized.)
• Petechiae not observed despite thrombocytopenia (except Andes virus)
• Hallmarks of the cardiopulmonary phase of HCPS
  • Hypotension
  • Respiratory distress with bilateral alveolar infiltrates on radiograph

Causes

In the United States, Hantavirus cardiopulmonary syndrome (HCPS) is primarily caused by the Sin Nombre virus (SNV) and is transmitted via inhalation of aerosolized virus from dried rodent excreta (see Background and Pathophysiology).

• The vector of SNV is the deer mouse, P maniculatus. SNV causes no obvious harm to mice, and they therefore never develop immunity. Infected rodents thereby become chronic, persistent viral shedders. 
• The incidence of HCPS closely parallels the distribution and number of infected deer mice in a geographic area.⁸ Deer mouse populations are influenced by specific environmental conditions.
• The El Nino conditions present during the 1993 Navajo outbreak increased the number of deer mice seen that year. The wet and mild conditions encouraged an unusually high population of pinons, a favorite source of food for mice. This, in turn, allowed for a 10-fold increase in the number of deer mice found that year in the Four Corners region of the United States.
• Because of horizontal viral transmission via intra-rodent aggressive behaviors such as biting, high rodent density also increases the percentage of mice infected.⁸ Thirty percent of deer mice in the Four Corners region tested positive for SNV in the 1993 outbreak.
• All agree that some type of rodent exposure, whether occupational or sporadic, is the greatest risk factor for contracting Hantavirus. Some controversy exists as to whether occupational exposure on farms or in laboratories is as great a risk factor as sporadically entering rarely opened or seasonally closed rodent-infested buildings.^10,26,11
• Occupations at greatest risk for exposure are as follows:
• Grain farmers
• Agricultural workers
• Feedlot employees
• Field biologists

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