Hantavirus Cardiopulmonary Syndrome (HCPS) 

Updated: Jun 04, 2019
Author: Sally Lynne Westcott, MD; Chief Editor: Jeter (Jay) Pritchard Taylor, III, MD 

Overview

Background

Hantavirus was first recognized as an infectious disease in the early 1950s when a cluster of 3,000 United Nation troops stationed in Korea was struck by a mysterious 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 was ever identified in the states.[6]

Hantavirus cardiopulmonary syndrome (HCPS), however, was not recognized until May of 1993, when 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.)

Hantavirus cardiopulmonary syndrome (HCPS) precaut Hantavirus cardiopulmonary syndrome (HCPS) precautions during the 1993 outbreak.

Over the next month, a highly effective collaboration ensued between the Indian Health Service, the University of New Mexico School of Medicine, and the Centers for Disease Control and Prevention, leading not only to the successful isolation of the virus, but also to the identification of the reservoir and vector for the disease, Peromyscus maniculatus (deer mouse) (see image below).

Peromyscus maniculatus - The deer mouse. Peromyscus maniculatus - The deer mouse.

Serum samples from those afflicted demonstrated evidence of Hantavirus infection and within 10 weeks of the original outbreak, researchers had successfully 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 as Hantavirus pulmonary syndrome (HPS) or, more accurately, Hantavirus cardiopulmonary syndrome (HCPS).[8]

About 20 viruses have been identified within the genus Hantavirus, family Bunyaviridae, but only 11 have been shown to cause human disease. Four of these belong to the “Old World” and cause HFRS across Europe 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.

Five of the “New World” Hantaviruses cause HCPS in North America, while a few others 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 is the cause of the vast majority of cases of HCPS in the United States (see the image below).

Geographic distribution and viral cause of Hantavi Geographic distribution and viral cause of Hantavirus cardiopulmonary syndrome (HCPS).

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

According to Native American legend, HCPS has existed in North America's southwest desert for hundreds, if not thousands, of years. Navajo oral tradition describes an illness now thought to be HCPS that struck down young healthy members of the tribe after temperate winters, and tradition also warns of the dangers of coexisting with rodents.

The earliest serologically confirmed SNV infection was in a person who developed an HCPS-like illness in July of 1959; scientists were finally able to confirm the presence of immunoglobulin G (IgG) antibodies to SNV in the victim’s serum in September of 1994.[8]

Pathophysiology

Each individual Hantavirus has its own natural host species of wild rodent as its reservoir[9] ; however, recent serologic testing of rodents has identified multiple new reservoir species. In the case of SNV, the primary reservoir is the deer mouse (see the image below). Other recently identified reservoirs include the cactus mouse (Peromyscus eremicus) and the Cherries cane rat (Zygodontomys cherriei).[10, 11]

Peromyscus maniculatus - The deer mouse. Peromyscus maniculatus - The deer mouse.

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.[12, 13]

Although generally not transmittable from person-to-person, the Andes virus of Argentina is a surprising exception to this rule.[14] One Chilean study found that sexual partners of people with Andes virus–induced HCPS had a 17.6% risk of developing infection, as opposed to 1.2% among casual household contacts.[15]

Hantavirus demonstrates similar tissue tropism in rodents and humans, but for unclear reasons, rodents typically remain symptom free; consequently, they never develop immunity and become perpetual viral shedders.[16, 17] 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.

Hantaviruses have a single-stranded, negative-sense RNA genome, part of which encodes viral glycoproteins capable of attaching to beta-3-integrin cell surface molecules found on endothelial cells and platelets.[18] Although disease severity directly correlates with viral RNA load,[17] 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.[19, 20] A 2014 study on SNV infection in rhesus macaques demonstrated a largely proinflammatory cytokine release leading to endothelial damage and subsequent HCPS-type symptomatology, suggesting a significant immune role in the disease progression.[21] Players implicated include tumor necrosis factor-alpha (TNF alpha), interleukin 1 beta (IL-1 beta), and interferon gamma (IFN-gamma), although this has yet to be clarified in humans.[22] Vascular endothelial growth factor has been implicated as a major player in the hyperpermeability found in Hantaan virus–induced HFRS.[23] . It has been shown that an immune response precedes the development of the cardiopulmonary phase of the disease, lending additional credibility to the hypothesis of an immune-mediated pathogenesis.[8]

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.[24] Histologic and immunohistochemical evidence also suggests a concomitant Hantavirus-induced myocarditis, which contributes to myocardial structural changes and dysfunction.[25] Patients may progress quickly to cardiogenic shock with decreased cardiac output, elevated systemic vascular resistance, and lactic acidosis.[26, 27] Severe cardiac depression acts synergistically with intravascular hypovolemia caused by capillary leakage and ultimately results in precipitous cardiopulmonary collapse. In light of this, early use of vasopressors and judicious administration of fluids is recommended, as well as the prompt transfer of patients to centers with extracorporeal membrane oxygenation (ECMO) capabilities in case rescue therapy becomes necessary. The name change from Hantavirus pulmonary syndrome to Hantavirus cardiopulmonary syndrome reflects the key contribution to morbidity made by concomitant myocardial dysfunction.

Epidemiology

Frequency

United States

As of January 2017, 728 cases of Hantavirus cardiopulmonary syndrome (HCPS) had been confirmed in 36 states (see the image below). Thirty-six percent of all reported cases have resulted in death.

Hantavirus disease by state of reporting. Cumulati Hantavirus disease by state of reporting. Cumulative case count through January 2017 per state based on data collected by the Nationally Notifiable Disease Surveillance System (NNDSS). Courtesy of the Centers for Disease Control and Prevention (CDC) (https://www.cdc.gov/hantavirus/surveillance/reporting-state.html).

Most hantavirus disease cases in the United States are caused by the 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]

Geographic distribution of Hantavirus cardiopulmon Geographic distribution of Hantavirus cardiopulmonary syndrome (HCPS) and Peromyscus maniculatus.

The preponderance of cases occurs in rural locales. The prevalence of Hantavirus infection in deer mice, the host vector for Sin Nombre virus (responsible for most US cases), was 27.5-32.5%. The greatest concentration remains in the Four Corners area; the top 5 states of exposure are, in descending order, New Mexico, Colorado, Arizona, California, and Washington. National annual incidence in nonepidemic years is about 20-30 cases (see the image below); only 3 cases were reported in 2018.

Hantavirus pulmonary syndrome cases by outcome. Hantavirus pulmonary syndrome cases by outcome.

The New York virus, the Black Creek Canal virus, Seoul virus, and the Bayou virus are other rare causes of HCPS that have been confirmed in eastern and southeastern United States.[8]

Generally, outbreaks of Hantavirus occur in the spring and fall. Two US outbreaks have occurred in the past decade. An outbreak of HCPS struck campers at Yosemite National Park in summer 2012. Ten cases were confirmed in campers that slept in rodent-infested campsites; 3 of the 10 individuals died.[28] In January 2017, 24 patients were diagnosed with Seoul virus infection across 11 states; 3 people were hospitalized, and none died.[29]

International

Over 3000 cases of Hantavirus disease have been reported in the Americas collectively. Canada, primarily Alberta, reports around 10%-15% of all North American cases annually.[30] In addition, Argentina, Bolivia, Brazil, Chile, Ecuador, Panama, Paraguay, Peru, Uruguay, French Guiana, and Venezuela have all reported HCPS cases.[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, 31, 32, 15]

Mortality/Morbidity

During the 1993 outbreak in the southwestern United States, the mortality rate was approximately 80%. Increased recognition of the disease and more aggressive interventions (eg, extracorporeal membrane oxygenation (ECMO) and early mechanical ventilation) have led to a decrease in mortality, with rates now ranging from 35% to 40%, though there is wide yearly variability.[8, 33, 34] 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 named 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 infection have been white; 18%, Native American; 2%, African Americans; 1%, Asian; and 20%, Hispanic (ethnicity considered separately from race).[8, 35]

Sex

Males account for 63% 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 37 years, with a range of 6-83 years. Less than 7% of cases occur in persons younger than 17 years, and disease is very rare in those younger than 10 years. Preadolescent children infected with SNV have generally had mild illness; however, between May and November of 2009, a cluster of 5 severe pediatric cases was reported, resulting in 4 intubations and 1 case fatality.[36]

Prognosis

HCPS currently carries a case-mortality rate of 35%-40% among adults.[37, 34] Preadolescents seem to experience a milder form of the disease and have significantly lower mortality.

Experiences with HCPS at the University of New Mexico Hospital have identified several factors that resulted in a 100% mortality rate in several patients who do not receive ECMO.[38] These include the following:

  • Cardiac index less than 2.5 L/min/m2

  • Ventricular tachycardia, ventricular fibrillation, or PEA

  • Hypotension despite adequate fluid resuscitation and vasoactive pressors

Patient Education

Educate patients and their families regarding the following:

  • Prodromal symptoms of HCPS

  • Risk of transmission by contact with rodents or rodent excreta

  • Techniques to safely clean-up infested areas

  • Rodent control measures (See Deterrence/Prevention.)

 

Presentation

History

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

Following exposure, an incubation period of 2-3 weeks ensues.[32] The aerosolized virus enters the lung, is taken up by local phagocytes, and is subsequently 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 often heralds sudden deterioration and progression to the cardiopulmonary phase of disease.[39, 40]

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, resulting in life-threatening pulmonary edema.[26] Clinical deterioration is precipitous and results in bronchorrhea, shock, coagulopathy (particularly with the Andes virus), and preterminal arrhythmias, in addition to the aforementioned pulmonary edema. Mean time from onset of first symptom to cardiopulmonary failure is 5 days. See the image below.

Clinical progression of hantavirus cardiopulmonary Clinical progression of hantavirus cardiopulmonary syndrome.

Survivors of the cardiopulmonary phase frequently experience a period of oliguria and then diuresis. This is less commonly described than hantavirus hemorrhagic fever with renal syndrome (HFRS). Finally, during the convalescent period, the patient typically recovers with little or no residual deficits. Recovery can occur as early as 24-48 hours after onset of cardiopulmonary symptoms. Several months of fatigue and decreased exercise tolerance are often the only sequelae. However, some patients can have residual renal complications and may even meet criteria for chronic kidney disease.[41]

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 only clue to an 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 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 in patients with the following symptoms:

  • Sore throat

  • Rhinorrhea

  • Conjunctivitis/coryza (except Andes virus)

  • Rash (except Andes virus where petechiae are common)

  • Otalgia

Physical

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

The most frequent initial physical findings in Hantavirus cardiopulmonary syndrome (HCPS) are as follows:

  • Tachypnea

  • Fever

  • Tachycardia

Crackles or decreased breath sounds are noted in most patients on lung examination.

Abdominal tenderness is present in about 10% of patients and may be severe. One patient underwent an exploratory laparotomy before HCPS was recognized.

Petechiae are not observed despite thrombocytopenia (except Andes virus).

Hallmarks of the cardiopulmonary phase of HCPS include the following:

  • 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 (see image below). SNV causes no obvious harm to mice, and they therefore never develop immunity. Infected rodents thereby become chronic, persistent viral shedders.

Peromyscus maniculatus - The deer mouse. Peromyscus maniculatus - The deer mouse.

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 deer 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.[12, 42, 13]

Occupations at greatest risk for exposure are as follows:

  • Grain farmers

  • Agricultural workers

  • Feedlot employees

  • Field biologists

Complications

Potential acute complications of Hantavirus cardiopulmonary syndrome (HCPS) include death, cardiovascular collapse, respiratory failure, anoxic brain injury, renal failure, pulseless electrical activity (PEA), ventricular tachycardia, and ventricular fibrillation.

ECMO has its own set of significant and not infrequent complications, including massive hemorrhage, sepsis, renal failure, and limb ischemia.[43] ECMO remains a rescue therapy for patients who are deteriorating despite maximal conventional medical therapy.

 

DDx

 

Workup

Laboratory Studies

Laboratory results vary with the phase of disease.

Complete blood cell count (CBC)

The CBC is the most useful test to obtain. It should be checked on arrival as well as 24 hours after presentation. In the prodromal phase, the CBC may be normal or show slight thrombocytopenia only. Changes in the CBC over time, however, can help predict prognosis and clinical course.

Platelets

Platelets may initially be normal, but a moderate and rapid decline in count usually is demonstrated, sometimes as early as the prodromal phase.[33] In patients with Hantavirus cardiopulmonary syndrome (HCPS), 98% present with a platelet count of less than 150 X 109/L. A dramatic fall sometimes heralds the cardiopulmonary phase of HCPS.[44]

White blood cell (WBC) count with peripheral blood smear

Leukocytosis and occasionally leukopenia are common. More importantly, the appearance of a marked leukocytosis (as high as 90,000 cells/microL) and the appearance of immunoblasts (circulating atypical lymphocytes) may signal the start of the cardiopulmonary phase of the disease and indicates a severe clinical course.[45] See the image below.

Hantavirus cardiopulmonary syndrome (HCPS) immunob Hantavirus cardiopulmonary syndrome (HCPS) immunoblast.

Thrombocytopenia, a left shift on peripheral smear, and an immunoblast count that exceeds 10% of the total lymphoid series has been termed the diagnostic triad of HCPS.[46] In experienced centers that see relatively high numbers of HCPS, this triad alerts practitioners to begin preparation for transfer to a center capable of aggressive critical care management and possibly ECMO.

Hematocrit (HCT)

Hemoconcentration is due to massive capillary leak and portends a poor prognosis. Hematocrits >50% in men and >48% in women may occur during the cardiopulmonary phase of HCPS and is a marker of severe disease.[47] This occurs in only 50% of cases.

Chemistries

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels are often elevated, sometimes as early as the prodromal phase of HCPS. Levels can rise to 2-5 times their reference values.

Creatinine level

SNV rarely causes renal failure; however, the Black Creek Canal, Bayou, and Andes viruses have higher rates of renal insufficiency.

Creatine phosphokinase (CPK) level

SNV rarely causes CPK elevations (again unlike the Bayou, Black Creek Canal, and Andes viruses).

Coagulation studies

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are usually within the reference range in SNV infection. However, disseminated intravascular coagulation (DIC) has been associated with a few severe cases of HCPS.

Arterial blood gases (ABGs) measurement

Progressive metabolic acidosis and severe hypoxemia mark the cardiopulmonary phase of HCPS.

Lactate level

Levels as high as 9.5 mg/dL have been recorded in severe HCPS. A lactate level greater than 4 has been associated with high mortality rates.

Serologic assays

The preferred method of diagnosis of HCPS is via serologic testing. Hantavirus-specific immunoglobulin M (IgM) can be detected early in the disease, even during the incubation phase.[40] By the time symptoms have developed, most, if not all, have developed antibodies of the IgG class. The presence of IgM antibodies or a 4-fold increase in levels of serum IgG antibodies signals an acute rather than remote infection.

State departments and the CDC use IgG and IgM mu-capture enzyme-linked immunosorbent assay (ELISA) to diagnose Hantavirus disease. Various other assays exist for Hantavirus detection but are limited in use owing to convenience and accuracy; Western blot, strip immunoblot assays, indirect immunofluorescence, compliment fixation, and hemagglutinin inhibition are some of the other available tests.[40] Hantavirus-specific ribonucleic acid amplification by polymerase chain reaction (PCR) is an extremely specific and sensitive test, but viral RNA may not be detectable after a few days of clinical illness; therefore, PCR is used primarily as a confirmatory or backup test.[16, 48]

Postmortem assays can be accomplished by using immunohistochemical tests for N-antigens or by viral RNA detection using reverse-transcription polymerase chain reaction.

Imaging Studies

Radiography

At presentation, approximately one third of patients show radiographic evidence of pulmonary edema. Within 48 hours, virtually all patients demonstrate edema and two thirds have progressed to severe bilateral airspace disease. Although chest radiograph findings on presentation are often normal, onset of the cardiopulmonary phase brings about a characteristic radiologic evolution (see the image below).[49]

Chest radiographic progression of Hantavirus cardi Chest radiographic progression of Hantavirus cardiopulmonary syndrome (HCPS).

Mild interstitial pulmonary edema progresses to severe multilobar, bilateral alveolar edema in a basilar or perihilar pattern.

Pleural effusions are common.

Heart size is normal (barring concomitant heart disease).

Echocardiography

Occasionally, echocardiography is useful to distinguish cardiogenic pulmonary edema from the noncardiogenic edema typically seen in HCPS.

Global cardiac dysfunction does occur in the later stages of HCPS.

Electrocardiography

Although no specific ECG findings suggest Hantavirus disease, some patients may present with ischemic-like ECGs with ST-segment changes in regional distributions, a phenomenon attributed to Hantavirus-induced myocarditis.[50]

MRI

Although not routinely recommended, MRI can be useful in the diagnosis and follow-up of patients with Hantavirus-induced myocarditis.[51]

Procedures

A flow-directed pulmonary artery catheterization (PAC), or Swan-Ganz catheter, can be a useful tool to aid in resuscitative fluid management of HCPS. As HCPS demonstrates a characteristic hemodynamic profile, it can also offer valuable diagnostic and prognostic information. A low pulmonary artery occlusion pressure (consistent with a pulmonary capillary leak) and a low cardiac index characterize early HCPS.

Advanced HCPS yields a severe drop in cardiac index and an increased systemic vascular resistance index (SVRI).

A cardiac index of less than 2 L/min/m2 (one marker used to predict a 100% mortality without further intervention) has been used successfully as criteria to initiate rescue ECMO therapy.[43]

 

Treatment

Prehospital Care

Prehospital care of Hantavirus cardiopulmonary syndrome (HCPS) is supportive.

  • Early but judicious use of fluid resuscitation with crystalloids is indicated.

  • Administer oxygen by nasal cannula, Venturi, or nonrebreather mask.

  • Intubation is warranted for severe respiratory distress.

  • Rapid transfer to a tertiary care center with ICU and ECMO capabilities is indicated if the diagnosis is suspected.

  • Standard respiratory precautions for infectious agents should be followed.

Emergency Department Care

The ED physician's main challenge is to recognize HCPS and to admit for close observation. Given the possibility for rapid deterioration, early implementation of hemodynamic support is critical and is associated with increased survival. In cases of advanced HCPS, skilled resuscitation with judicious use of fluids and early institution of pressors, as well as transfer to an ICU, are paramount.[52] The general approach to a patient presenting with early HCPS symptoms remains the same as with any acutely ill patient with some special considerations: Resuscitate the patient in the familiar ABC fashion. Administer oxygen by facemask or nonrebreather mask.

Intubate patients with respiratory failure. It is unusual for patients to die solely from respiratory failure in centers equipped with sophisticated ventilatory support.[53, 38] Patients’ hemodynamic statuses may deteriorate after intubation secondary to preload dependence and loss of adrenergic drive; cardiac arrest at time of intubation is not uncommon and ECMO preparations, if available, should be underway.[34]

Fluid resuscitation with crystalloids is indicated for any sign of hemodynamic compromise. Because of massive capillary leakage, administer fluids judiciously and use vasoactive infusions early and liberally. Dobutamine is the preferred inotrope, with dopamine or norepinephrine[34] added to maintain blood pressure. Patients with HCPS may require large doses of vasopressors to maintain a stable blood pressure.

If possible, avoid placing central lines in the right subclavian, the right internal jugular, and one femoral vein. These veins are used for venous access for ECMO.

Broad-spectrum antibiotics are indicated for most patients presenting with respiratory distress and fever. Use strict universal precautions.

Consultations

Patients with suspected or confirmed Hantavirus cardiopulmonary syndrome (HCPS) require ICU admission. Consult a medical intensivist early.

If applicable, consult the ECMO team early. ECMO has been used with reported success in a number of institutions and has been shown to improve the likelihood of survival.[43, 54] ECMO has been implemented in patients with criteria predictive of 100% mortality with a reported success of achieving a 66% survival rate.[55] An important criterion for implementation of this rescue therapy has been demonstration of severely depressed myocardial function. Vascular surgery consult is typically needed for ECMO catheter placement.

Prevention

The best way to prevent HCPS is to avoid all exposure to rodents, especially deer mice, and their excreta.

Tips on rodent-proofing homes indoors and outdoor may be found at All About Hantaviruses - Prevention Indoors and Outdoors.

Never sweep or vacuum rodent-infested areas as this further aerosolizes the virus. Instead, wet the area thoroughly with disinfectant before cleaning, wearing rubber gloves. Other tips on cleaning infested areas may be viewed at All About Hantaviruses - Clean Up Infested Areas, Using Safety Precautions.

Homes with heavy infestations or homes of patients with confirmed HCPS require special precautions for cleaning. Contact the local health department for guidance. CDC recommendations may be found at All About Hantaviruses - Special Precautions for Homes of Persons with Confirmed Hantavirus Infection or Buildings with Heavy Rodent Infestations.

Persons who frequently handle or are exposed to rodents (eg, mammalogists, pest-control workers) in affected areas are probably at higher risk for Hantavirus infection than the general public because of their frequency of exposure. Therefore, enhanced precautions are warranted to protect them against Hantavirus infection. These precautions may be found at All About Hantaviruses - Precautions for Workers in Affected Areas Who are Regularly Exposed to Rodents.

Vaccines

Presently, no vaccines are approved for use against Hantaviruses in the United States. However, researchers are exploring the efficacy and safety of killed-virus vaccines as well as DNA vector derived antigen vaccines with some promising results in human and animal models.[33, 56, 57, 58, 59]

China and Korea offer a killed-virus vaccine for Hantaan virus and Seoul virus, but cost precludes widespread usage in many affected areas. A study of inactivated hantavirus vaccine (IHV) in Korea has demonstrated that it is moderately effective in endemic areas among high-risk individuals.[60]

Although indirect evidence exists to suggest a role for passive immunization, no regimen has yet been developed. Interestingly, patients who present with high titers of neutralizing antibodies to Sin Nombre virus (SNV) tend to exhibit milder disease than those who present with low titers of neutralizing antibodies. Patients with low titers more often died or required extracorporeal membrane oxygen salvage therapy.[61]  Additionally, administration of antisera harvested from those who survived HCPS appears to mitigate the severity of disease in actively infected individuals.[62]  Given these findings, further study is warranted.

Further Inpatient Care

Ventilator management

High positive end-expiratory pressure (PEEP) and high fraction of inspired oxygen (FIO2) are often useful.

Pressure-controlled ventilation and inverse inspiration/expiration (I/E) ratio ventilation are beneficial in select cases.

Hemodynamic management

Careful hemodynamic management optimizes survival.

Maintain mean arterial pressure greater than 70 mm Hg through a measured use of fluids and pressors.

Pulmonary artery catheterization may be used to avoid fluid overload: Maintain PAOP at 12 mm Hg or below.

Use vasoactive infusions early and liberally. (See Medication.)

Extracorporeal membrane oxygenation (ECMO)

The University of New Mexico Hospital (located in southeast corner of the four corners region) performed extensive research from 1994-2010 to determine the usefulness of ECMO rescue therapy in Hantavirus cardiopulmonary syndrome (HCPS). Given its investigational status, only patients with a projected 100% mortality rate and with clinical and laboratory evidence of HCPS were eligible to receive ECMO. Qualified patients had to demonstrate a cardiac index of less than 2 L/min, a PaO2/FIO2 ratio of less than 60, as well as refractory shock not responsive to standard medical therapy. Remarkably, among the 51 patients who qualified, approximately two thirds survived to recover completely.[43, 55]  The cardiovascular collapse of HCPS is profound but uniquely brief; rescue bridging with ECMO yields complete recovery in many previously believed to be irrecoverable.

ECMO therapy appears to improve survival in a select group of patients with severe disease; an early effort should be made to transfer patients suspected of having HCPS to facilities capable of ECMO.[43, 34, 37, 55]  It is possible that earlier institution of ECMO could yield even greater survival benefits.

Patients with prolonged cardiac arrest or prolonged cerebral hypoxia are not candidates for ECMO.

Transfer

Most cases of HCPS occur in rural communities where facilities equipped for aggressive intensive care are often lacking. Given the precipitous nature of this disease, consider the following:

  • Transport early: A patient who subsequently does not require aggressive therapies at a tertiary care center is preferable to a patient who deteriorates suddenly and dies en route.

  • Transport quickly: Use the fastest and best-equipped transport, whether it be fixed-wing aircraft, rotor, or ground transportation, depending on proximity.

  • Transport to the highest level of care center possible: Again, anticipate the possible need for intensive care and possibly ECMO.

  • Prepare for clinical decline en route: Anticipate the need for fluids and vasopressors.

 

Medication

Medication Summary

Currently, no Food and Drug Administration-approved antiviral drugs, vaccines, or immunotherapeutic agents are available for Hantavirus cardiopulmonary syndrome (HCPS). Although ribavirin, a nucleoside analogue, has shown a statistically significant 7-fold reduction in mortality when initiated early in the treatment of hemorrhagic fever with renal syndrome (HFRS),[63] there is limited data regarding its use for HCPS. One double-blind, placebo-controlled study and one nonrandomized trial showed no survival benefit of ribavirin in the treatment of HCPS,[64, 65] though questions remain regarding study design and lack of power. A meta-analysis of ribavirin in human and animal subjects showed no mortality benefit in humans with HCPS, although the animal studies did show a statistically significant increase in survival. The analysis was hindered by the small number of available studies.[66] As of now, no evidence exists to support an off-label use of ribavirin in the treatment of HCPS.

Based on a study involving 60 Chilean patients with HCPS, glucocorticoids are not recommended as treatment for HCPS.[67]

Some indirect evidence supports the use of neutralizing antibodies, or passive immunotherapy, for HCPS. Bharadwaj et al found that patients who had higher titers of neutralizing antibodies suffered milder disease.[61] Studies addressing the role of passive immunotherapy for treatment or postexposure prophylaxis of HCPS have not yet been published.

Liberal employment of high-dose vasopressors and inotropes, as well as standard administration of antibiotics, is strongly encouraged. (See Emergency Department Care.)

Inotropes

Class Summary

Used in the implementation of hemodynamic support.

Dopamine (Intropin)

Stimulates beta1- and alpha1-adrenergic and dopaminergic receptors in a dose-dependent fashion; stimulates release of norepinephrine. Lower doses (2-5 mcg/kg/min) mainly stimulate dopamine receptors, producing renal and mesenteric vasodilation. Doses between 5 and 10 mcg/kg/min predominantly stimulate beta1-receptors, causing increased chronotropy, inotropy, and cardiac output. Doses >10 mcg/kg/min stimulate alpha1-receptors, causing marked vasoconstriction. After initiating therapy, dose may be increased by 1-4 mcg/kg/min q5min until optimal response.

Dobutamine (Dobutrex)

Stimulates alpha1-, beta1-, and beta 2-adrenergic receptors; has potent inotropic effects with minimal chronotropic effect; causes vasodilation; is vasopressor of choice in HCPS.

Norepinephrine (Levophed)

Stimulates alpha1- and beta 1-adrenergic receptors; increases inotropy and chronotropy; is potent vasoconstrictor.

Epinephrine (Adrenalin, EpiPen)

Stimulates alpha1-, alpha2-, beta1-, and beta2-adrenergic receptors, increasing cardiac muscle contractility and heart rate as well as vasoconstriction. As a result, increases systemic BP and coronary blood flow.

Antivirals

Class Summary

These agents inhibit or reduce severity of some viral infections but have no demonstrable effect in HCPS as of yet.

Ribavirin (Virazole)

Proven effective in HFRS caused by Old World Hantaviruses; no demonstrated benefit in HCPS.