Introduction

Hantaviruses are single-stranded, negative-sense RNA viruses in the Bunyavirales order. Infection occurs via inhalation of aerosolized excretions from infected rodents. These viruses are associated with both hantavirus cardiopulmonary syndrome (HCPS) caused by hantaviruses of the New World and hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses of the Old World. HCPS, also known as hantavirus pulmonary syndrome (HPS), is a febrile illness characterized by respiratory failure with diffuse interstitial edema. The illness has three distinct phases: the prodrome, cardiopulmonary phase, and the convalescent phase.[1] After a non-specific prodromal phase, patients have significant respiratory symptoms as their lungs fill with fluid. This is often associated with hemodynamic compromise with a clinical picture resembling cardiogenic shock. Treatment remains largely supportive and includes ventilator support and even extracorporeal membrane oxygenation if necessary. 

The etiologic agent causing HFRS was first described in 1978 and named after the Hantan river in South Korea. This virus caused Korean hemorrhagic fever among United Nations troops during the Korean War between 1951 and 1953. [2] HCPS was first described in 1993 after several people from the Navajo tribe developed an acute respiratory illness in the Four Corners region in the US. Patients initially presented with symptoms of fevers, chills, cough, and myalgias, however, progressed to significant respiratory distress and hemodynamic compromise. An early case-control study identified exposure to rodents as a risk factor for disease, thus a rodent-trapping operation was initiated. A genetic detection assay was used to determine that patients were infected with a novel hantavirus which was termed the Sin Nombre virus (SNV). The clinical illness became known as hantavirus cardiopulmonary syndrome. [3][4]

Etiology

Hantaviruses are enveloped RNA viruses measuring 80 to 120 nm. The genome is divided into three segments: the large (L), medium (M), and small (S) segments coding for viral transcriptase, glycoproteins of the capsule, and protein of the viral nucleocapsid respectively. At least 11 rodent-borne viruses in the Hantaviridae family are known to cause disease in humans. Infected rodents excrete virus in urine, droppings, and saliva for several weeks to months. Humans can become infected by inhaling air contaminated with the virus and more rarely via a rodent bite. Sin Nombre virus is considered to be the most important North American hantavirus as it is responsible for the majority of cases in the US and Canada. The host for this virus is the deer mouse (Peromyscus maniculatus). [5][6][7]

Viruses that cause HCPS and their respective hosts:

• Bayou virus - Oryzomys palustris
• Black Creek Canal virus - Sigmodon hispidus
• New York virus - Peromyscus leucopus
• Sin Nombre virus - Peromyscus maniculatus
• Andes virus - Oligoryzomys longicaudatus
• Choclo virus - Oligoryzomys fulvescens
• Laguna Negra virus - Calomys laucha
• Rio Mamore virus - Oligoryzomys microtis

Epidemiology

Hantavirus infections occur worldwide with HCPS caused by hantaviruses of the New World and HFRS caused by hantaviruses of the Old World. Endemics and epidemics of HCPS are associated with increased rodent populations. Sin Nombre virus is responsible for most cases of HCPS in the US and Canada. 728 cases of hantavirus disease have been reported in the US between 1993 and 2017. 95% of cases occurred in states west of the Mississippi River with most cases occurring in New Mexico and Colorado. 63% of those infected were males and the mean age of infection was 38 years. [8] 

HCPS cases have also been described in Argentina, Bolivia, Brazil, Chile, Ecuador, Paraguay, Panama, Uruguay, and Venezuela. People who get infected include those who live or work in rural areas, which is similar to the pattern seen in North America. Interestingly, Andes virus is the only hantavirus that can cause person-to-person transmission. [9]

Reported Outbreaks:

• 1993 - HCPS first identified in the Navajo tribe in the Four Corners region of the US with the causative agent being identified as Sin Nombre virus. 
• 2012 - HCPS outbreak reported at Yosemite National Park in California with a total of 10 confirmed hantavirus infections. [10]

Pathophysiology

Hantavirus infections occur via the inhalation of viral particles and subsequent deposition in terminal respiratory bronchioles. Alveolar macrophage infection is followed by viremia which results in widespread infection of the pulmonary capillary endothelium and can also disseminate to other organs via the lymphatic system. Hantavirus entry into endothelial cells is mediated by beta-3 integrins leading to dysregulation of cell migration. Furthermore, the release of proinflammatory and antiviral cytokines, including tumor necrosis factor-alpha, interleukin-1, and interferon-gamma, are suspected to lead to increased vascular permeability causing noncardiogenic pulmonary edema resulting in the cardiopulmonary phase of the disease. [9]

History and Physical

Obtaining a detailed history is critical for early diagnosis as a history of rodent exposure will trigger an evaluation for rodent-borne infections. 

Clinical Phases:

• Prodrome - After the incubation period, patients may present with fevers, chills, deep muscle aches, and shortness of breath. The disease progresses rapidly during this phase and may lead to symptoms of abdominal pain, nausea, vomiting, and diarrhea. 
• Cardiopulmonary phase - Characterized by capillary leak which leads to decreased cardiac output and a state of shock. This phase is also marked by pulmonary edema, arrhythmias, and coagulopathy. [11][12] 
• Convalescent phase - Resolution of cardiopulmonary symptoms occurs following the oliguria and diuretic phases of the disease.  

Evaluation

Serologic tests - These tests are the preferred method of diagnosis and can be used to identify acute infections (IgM) and remote infections (IgG). 

Polymerase chain reaction (PCR) - Viral ribonucleic acid (RNA) can be detected using reverse transcriptase-PCR (RT-PCR) in early infections. As viral RNA is only detected in the early days of infection, a negative test cannot rule out the disease. 

Autopsy findings - Viral antigen detection and RT-PCR can be used to diagnose hantavirus infections. 

Treatment / Management

There is currently no antiviral therapy approved for treating hantavirus infection, thus supportive care remains the mainstay of therapy. Early admission to the intensive care unit is warranted as the disease is likely to progress and mechanical ventilation, as well as extracorporeal membrane oxygenation, may be warranted in some patients. While hantavirus infection is systemic and viral nucleic acid is found in other organs on immunohistochemistry, the clinical picture is dominated by the pathology in the lung. Due to rapid fluid shifts, close attention must be paid to fluid and electrolyte balance in intensive care units. [13]

Differential Diagnosis

• Bacterial pneumonia
• Cardiogenic shock
• Phosphine toxicity
• Q fever
• Septic shock
• Severe dengue infection
• Salicylate toxicity with pulmonary edema
• Tularemia
• Viral pneumonia
• Yellow fever

Prognosis

According to the Centers for Disease Control (CDC), HCPS has a mortality rate of 38%. Chronic hantavirus infection has not been demonstrated in humans. Recovery times vary in patients and no lasting complications have been reported.

Complications

Although some patients may have a long recovery time, no lasting complications have been reported with this disease. 

Deterrence and Patient Education

There is currently no vaccine available and treatment remains largely supportive, thus emphasis should be placed on early diagnosis and disease prevention. Patients who have been diagnosed with HCPS should be treated in an intensive care unit (ICU) as early ICU care may lead to better treatment outcomes. Preventative measures include limiting contact with infected rodents by sealing up holes around the house or using mouse traps if you have an infestation.

Enhancing Healthcare Team Outcomes

Hantavirus cardiopulmonary syndrome carries a high mortality rate, thus an early multidisciplinary approach is important for early diagnosis and appropriate care in the intensive care unit. Providers should facilitate the transfer of patients admitted to rural centers to a larger tertiary care center for further management if HCPS is suspected.