Continuing Education Activity

Hantavirus is a rare, life-threatening infection characterized by pulmonary edema, hypoxia, and hypotension. It typically results from exposure to mice feces or urine in the 1 to 3 weeks preceding symptom onset and can result in death within days. It is most common in the southwest United States and South America. Hantavirus may be preceded by vague flu-like symptoms and may be associated with hemorrhagic fever and renal syndrome (HFRS). This activity describes the clinical features, evaluation, and management of hantavirus infection and highlights the role of the inter-professional team in the management of patients with the condition.

Objectives:

• Identify the etiology of Hantavirus.

• Describe the presentation of a patient with hantavirus infection.

• Identify the management options available for hantavirus.

• Outline interprofessional team strategies for improving care coordination and communication to advance the treatment of hantavirus and improve outcomes.

Introduction

Hantavirus pulmonary syndrome (HPS), known as hantavirus, is a pulmonary syndrome characterized by pulmonary edema, hypoxia, and hypotension. It is preceded by vague flu-like symptoms or can involve hemorrhagic fever and renal syndrome (HFRS). This is commonly due to exposure to mice feces or urine within 1 to 3 weeks of symptom onset. Hantavirus is most common in the Southwest United States and South America. HFRS has a larger incidence in Asia and Europe. The virus is transmitted by inhalation of dried rodent excrement and may be transmitted by a rodent bite.[1]

Etiology

Hantavirus is a viral zoonosis that is most commonly found in the southwestern United States, South America, Europe, and Asia. It has been linked to hemorrhagic fevers, acute respiratory distress syndrome (ARDS), and renal failure. Hantavirus is an RNA virus of the family Bunyaviridae.[2] Hantaviruses were first discovered in the early 1950s in soldiers of the Korean War and named Hantaan because of the nearby Hantaan River where most cases occurred. The most common virus strain in North America is the Sin Nombre virus which is predominantly transmitted by the deer mouse (Peromyscus maniculatus) in the southwestern United States. This particular virus was found after a cluster of hantavirus cases occurred in 1993. Hantavirus was found in the United States in 1977, with at least 10 distinctive serotypes identified. Each serotype belongs to a specific rodent vector, geographic distribution, and clinical manifestation. Most hantavirus serotypes have a renal predilection.[1]

Hantavirus, like other viruses in the Bunyaviridae family, have a lipid envelope around 3 RNA segments, but they chronically infect rodents instead of the usual arthropod vectors. Hantaviruses can be wherever one can find Muridae rodents. Sigmodontinae are host to the Sin Nombre virus and are the largest group of rats and mice in the western hemisphere.[3]

Epidemiology

Cardiopulmonary syndrome is the primary form of Hantavirus syndrome in the United States. Europe and Asia more commonly have a hemorrhagic fever with renal insufficiency syndrome.

In the United States, sporadic cases of hantavirus have been seen as far east as Maine, but the vast majority of the 697 cases as of January 2017 were west of the Mississippi River. Seven states account for approximately 70% of all cases reported in the United States: with the most cases in New Mexico (109 cases), Colorado (104 cases), Arizona (77 cases), California (63 cases), Washington (47 cases), Texas (42 cases), and Montana (41 cases).

The following list of HFRS presentations contains the virus serotype, specific rodent vector, and geographic distribution.

• Hantaan virus: Apodemus agrarius, the major cause of disease in Asia
• Dobrava virus: Apodemus flavicollis, the Balkans, Slovenia, the Baltic states, and other parts of Europe
• Seoul virus: Rattus norvegicus, East Asia
• Puumala virus: Clethrionomys glareolus, Europe

The following list of Hantavirus presentations contains the virus serotype, specific rodent vector, and geographic distribution.

• Sin Nombre Virus: Peromyscus maniculatus; Canada, United States - a major cause of hantavirus in Canada and the United States
• New York Virus; Peromyscus leucopus, eastern United States
• Monongahela Virus: Peromyscus maniculatus nubiterrae, eastern United States
• Bayou Virus: Oryzomys palustris, southeastern United States
• Black Creek Canal Virus: Sigmodon hispidus, Florida, United States
• Laguna Negra: Calomys laucha, Paraguay, Bolivia - first South American hantavirus isolated
• Andes: Oligoryzomys longicaudatus, Argentina, Chile, Uruguay - only hantavirus with a person-to-person transmission reported
• Oran: O. longicaudatus; northern Argentina - regularly causes disease in cane-growing areas
• Choclo: Oligoryzomys fulvescens, Panama
• Rio Mamore: Neacomys spinosus, Peru
• Lechiguanas: Oligoryzomys flavescens, Argentina

It is suggested that around 50% of infections are due to exposure in or around the home, 10% from the workplace, and 5% during recreation.  The rest of the exposures are from mixed or unknown causes.[1]

Pathophysiology

Hantavirus and HFRS are Both Considered to be Immunopathologic

• Inhalation of the infectious virus results in the deposition in the alveoli or terminal bronchioles. Viremia likely is generated after infection of alveolar macrophages or other primary targets, resulting in widespread infection of the pulmonary capillary endothelium. Critical adhesive receptors, beta-3 integrins, regulate platelet activation and vascular permeability but also mediate cellular entry of hantaviruses. Invasion of the endothelium is believed to induce IFN-alpha, which is possibly the cause of the prodromal manifestations. Once the infection has progressed, immunoblasts may be seen in the peripheral blood smear. T cell clones will be hantavirus-specific. Activated macrophages, in conjunction with these immunoblasts, will migrate to the interstitium of the lung. Capillary endothelial permeability greatly increases after the secretion of TNF-alpha, IFN-gamma, and nitric oxide, which results in pulmonary edema. Soluble mediators such as TNF-alpha, IFN-gamma, and nitric oxide are suggested as etiologies of myocardial depression in this infection resulting in cardiogenic shock.
• Replication within the vascular endothelium does not have direct cytopathic effects. Instead, tissue injury appears to be due to the immune response combined with the viral replication.
• In HFRS, the main site of increased cytokine expression and endothelial adhesion molecules is the distal nephron in the peritubular area. As a result, glomerular permeability is increased, resulting in massive proteinuria and evidence of tubular dysfunction.
• Immature dendritic cells likely serve as carriers for the virus through lymphatic tissue and allow further viral replication once at the regional lymph nodes. In addition, once exposed to the endothelial cells, immune activation is induced, especially by CD8+ T cells and macrophages.
• Hantaviruses induce maturation of infected dendritic cells and elicit and profound T-cell response in the acute infection phase, dissimilar to other hemorrhagic fever viruses that inhibit dendritic cell maturation.[1]

Viral Structure

• Spherical particles, 90 to 120 nm in diameter
• Two glycoproteins and three unique negative-strand RNAs forming nucleocapsids
• Does not have matrix protein

Replication

• G1 glycoprotein interacts on the cell surface with beta integrins
• The virus is internalized via endocytosis
• Nucleocapsid released into the cytoplasm after fusion of the envelope with endosomal membranes
• mRNA and protein synthesis begins
• A 5'-capped portion of mRNA is stolen to prime synthesis of viral mRNA in the cytoplasm
• Medium length strand of viral RNA codes for the G1 and G2 proteins
• Large-length strand of viral RNA codes for the L protein (polymerase)
• Small-length strand of viral RNA codes for two non-structural proteins
• Glycoproteins are synthesized and glycosylated in the endoplasmic reticulum and then transferred to the Golgi apparatus
• Virions assembled by budding in the Golgi apparatus
• Virions released by exocytosis or cell lysis

History and Physical

Hantavirus begins with a prodromal phase of approximately 3 to 4 days of vague, flu-like symptoms. Nausea, vomiting, thrombocytopenia, dizziness, and dyspnea without a cough may help distinguish hantavirus from acute respiratory distress syndrome or other atypical and viral types of pneumonia. After the prodromal phase, there can be rapid development into hantavirus characterized by pulmonary edema, hypoxemia, tachycardia, and hypotension. This often occurs within 48 hours and rapidly turns to respiratory failure. Patients often will develop metabolic acidosis due to severe infection. Orthostatic hypotension can quickly progress to cardiogenic shock with cardiovascular decompensation. Patients with the renal disease could develop oliguria followed by diuresis. Pulmonary auscultation may demonstrate rales. Descent into the pulmonary syndrome carries a mortality rate of around 50% to 70%. [4]

Hantavirus hemorrhagic fever and renal syndrome have five distinct phases: Febrile, Hypotensive, Oliguric, Polyuric, and Convalescent. The incubation period is approximately 2 to 4 weeks and starts abruptly with a high fever, headache, vomiting, abdominal pain, and back pain often associated with blurred vision and somnolence. The high fever is typically present for 3 to 7 days and ends with conjunctival hemorrhages and palatal petechiae. Hypotension is then present for the next several hours to 2 days, with approximately one-third of HFRS deaths due to fulminant, irreversible shock during this phase. If the hemorrhagic disease becomes severe, bleeding may present as hematemesis, epistaxis, melena, hematuria, and possibly fatal intracranial hemorrhages. Oliguria will last for 3 to 7 days with a transient decrease in renal function accompanied by back or abdominal pain that may need dialysis. Approximately half of the deaths from HFRS occur during the oliguric phase. The polyuric phase is a positive prognostic sign with evidence that renal function is improving and urinary output will increase up to several liters per day. Full recovery with return to baseline clinical and laboratory markers is reached over the next 6 months without significant long-term complications.[4]

Evaluation

A chest X-ray may demonstrate bilateral pulmonary edema on the initial radiograph in about one-third of patients. Nearly all patients will have findings of interstitial edema at 48 hours after admission. Almost two-thirds of patients will develop bibasilar opacities or perihilar opacities with some degree of pleural effusions.

Thrombocytopenia may be present on blood count once admission is necessary due to the staging of the disease. Another critical laboratory finding is that of circulating immunoblasts, atypical lymphocytes, and elevated hematocrit. Once the patient needs hospitalization, a peripheral blood smear may demonstrate myelocytes, metamyelocytes, and promyelocytes with severe thrombocytopenia and hypocapnia. Hyponatremia may also be present along with slightly prolonged activated partial thromboplastin time, a decreased protein level, mildly elevated low-density lipoprotein level, and microscopic hematuria.

Diagnosis can be made by immunofluorescent or immunoblot assay. ELISA utilizing IgM is preferred. Virus isolation, however, is not useful due to the low yield despite demonstrating easy detectability by quantitative polymerase chain reaction (PCR).[1]

Treatment / Management

Hantavirus 

• Symptom intensity often drives patients to seek medical attention, but lack of significant findings necessitating admission often results in supportive care for discharge. 
• Despite appropriate treatment in intensive care units (ICU), around one-third of patients will die in the first 48 hours after admission. 
• Almost half of the patients admitted with hantavirus will not require mechanical ventilation via intubation if appropriately managed with judicious fluids and close monitoring. 
• Treatment is providing supportive measures. 
• Ribavirin has been proposed as a treatment option with possibly some benefit to inhaled ribavirin, but overall is ineffective in hantavirus. 
• Respiratory failure can be severe, with around 40% of cases requiring mechanical ventilation. Extracorporeal membrane oxygenation (ECMO) is a possible treatment strategy for those patients not improving with mechanical ventilation. Still, it is complicated by a lack of controlled trials, follow-up data, and iatrogenic complications. 
• Fluid balance with goals of maintaining normal-high filling pressures for cardiac output and minimizing pulmonary edema will likely be difficult. 
• Inotropic agents such as dobutamine are encouraged early. 
• Death is often associated with disseminated intravascular coagulation, which includes frank hemorrhage and drastic leukocytosis. 
• Should patients improve in the first few days, there is a good probability of extubation within the first week, and often there are no major long-term complications. 
• Subjective complaints of dyspnea, fatigue, and myalgias may occur.

HFRS

• Similar treatment strategies apply to HFRS with regards to supportive care. 
• Hemodialysis may be utilized during the oliguric phase due to transient renal function insufficiency. 
• Clinical studies in China suggest that giving the patient ribavirin in the first 5 days after symptom onset has significant mortality reduction.[4][5][6][7]

Differential Diagnosis

Acute Respiratory Distress Syndrome (ARDS) 

• Acute onset of dyspnea with bilateral chest X-ray non-cardiogenic infiltrates and PaO2/FiO2 less than 300
• Difficult to delineate ARDS from Hantavirus 
• Must look for inciting factors
• Management is similar

Mycobacterial Pneumonia

• If the patient requires mechanical ventilation and bronchoalveolar lavage obtained, other presenting pathogens may guide antibiotic therapy.
• Broad-spectrum antibiotic treatment not shown to change outcomes of Hantavirus for better or worse

Influenza Pneumonia

• Influenza PCR helpful for ruling-in influenza pneumonia instead of Hantavirus

Viral Hemorrhagic Fevers

• Specific PCRs necessary to diagnose a single etiology
• Treatment still supportive care in the ICU

Staging

By the time a patient requires hospitalization, transformation into the second stage of the disease (cardiopulmonary compromise or hemorrhagic fever with renal insufficiency) has already developed. A cough and vomiting may dominate the clinical presentation at this point. Orthostatic hypotension, tachycardia, and tachypnea will likely all be present. The first significant abnormal laboratory test, which is also the most useful, is platelet count.  Thrombocytopenia or decreasing platelet count warrants admission to the hospital for further evaluation.

Hematuria has been noted as a marker of kidney injury but has not been correlated with thrombocytopenia.[8][9][10]

Prognosis

Despite appropriate treatment in the ICU, around one-third of patients will die in the first 48 hours after admission. Almost half of the patients admitted with Hantavirus will not require mechanical ventilation via intubation if appropriately managed with judicious fluids and close monitoring.

Should patients improve within the first few days, there is a good probability of extubation within the first week, and often there are no major long-term complications. However, subjective complaints of dyspnea, fatigue, and myalgias may occur.

Higher titers of antibodies neutralizing the viral nucleocapsid immune complexes correlate with a higher likelihood of survival.

Complications

Significant long-term complications of Hantavirus or HFRS are rare; however, short-term complications, including death, have a high incidence.[1]

Deterrence and Patient Education

A vaccine that was, but is no longer, produced in Asia demonstrates protective immunity but requires frequent booster administration for effect. There is no vaccine utilized in Europe or the United States outside of clinical trials.

Pearls and Other Issues

Hantavirus does not affect children as dramatically as it does adults.[11]

Enhancing Healthcare Team Outcomes

Hantavirus is a lethal infection, and despite optimal treatment, mortality rates are high. Because the infection can involve many organs, it is best managed by an interprofessional team that includes an infectious disease expert, ICU nurses, a hematologist, nephrologist, pulmonologist, and a neurologist. The key is to prevent the infection in the first place.

Prevention is best approached by minimizing human-rodent contact. Pest control and removal of mice from living areas are key. Ventilating homes and allowing natural light into the area for neutralization of the virus by ultraviolet light may prevent the spread of the infection. Minimize food available for rodents. When disposing of dead rodents, carefully handle them using air filtration and gloves.