Hantaviruses

Essentials of Diagnosis

• Transmitted by rodents and cause two clinical syndromes

• Hemorrhagic fever with renal syndrome (HFRS): mild to severe illness

• Hantavirus pulmonary syndrome (HPS): 40% mortality rate

General Considerations

• Hantaviruses are enveloped RNA bunyaviruses; hosts are rodents, moles, and shrews

• Hantavirus infection in humans can cause several disease syndromes

• HFRS caused by Old World hantaviruses

  • Dobrava-Belgrade virus

  • Puumala virus

  • Seoul virus and Hantaan virus in Asia and Europe; these viruses are called Old World hantaviruses

• Nephropathia epidemica (NE) is a milder form of HFRS. Puumala virus is the most prevalent pathogen and is present throughout Europe.

• HPS, also known as hantavirus cardiopulmonary syndrome, is caused mainly by Sin Nombre virus and Andes virus, the New World Hantaviruses in Americas

• A specific strain is not associated with a specific syndrome and overlap is seen between the syndromes

• Aerosols of virus-contaminated rodent urine and feces are thought to be the main vehicle for transmission to humans

• Person-to-person transmission is observed only with the Andes virus

• Occupation at highest risk for transmission of all hantaviruses include

  • Animal trappers

  • Forestry workers

  • Laboratory personnel

  • Farmers

  • Military personnel

Demographics

• A total of 728 cases of hantavirus infection have been reported in the United States since 1993

• Average case fatality rate of 36%

• Most of the cases were reported from states west of the Mississippi River

• Outbreaks of HPS associated with other hantavirus types are also reported in Central and South America as well as the Caribbean

Symptoms and Signs

• Vascular leakage is the hallmark of the disease for both syndromes

  • Kidneys are main target with variants associated with HFRS

  • Lungs are the main target with variants associated with HPS

• HFRS manifests as mild, moderate, or severe illness depending on the causative strain

  • A 2- to 3-week incubation period is followed by a protracted clinical course, typically consisting of five distinct phases

    • Febrile period

    • Hypotension

    • Oliguria

    • Diuresis

    • Convalescence phase

  • Various degrees of renal involvement are usually seen

  • Puumala virus infection is often referred to as nephropathia epidemica

    • The kidney dysfunction component appears to correlate with levels of the plasma adipokine resistin that may by internalized or diffuse (as a capillary leak syndrome) and often confused with the complications of disseminated intravascular coagulation

    • Thromboembolic phenomena are also recognized complications

  • A secondary hemophagocytic lymphohistiocytosis can be seen with HFRS

  • Pulmonary edema is not typically seen but when present usually occurs in the final stages of disease (oliguric and diuretic phase)

  • Encephalitis and pituitary involvement are rare, although a few cases are reported with Puumala virus

  • Patients may have persistent hematuria, proteinuria, or hypertension up to 35 months after infection

  • Smoking appears to exacerbate the viremia with the Puumula virus infection, and bradycardia can also be prominent

• Clinical course of HPS is divided into a febrile prodrome, a cardiopulmonary stage, oliguric and diuretic phase followed by convalescence

  • A 14- to 17-day incubation period is followed by a prodromal phase

    • Typically lasts 3–6 days

    • Associated with myalgia, malaise, abdominal pain along with nausea, vomiting, and diarrhea, headache, chills, and fever of abrupt onset

  • Cardiopulmonary phase is characterized by

    • Acute onset of pulmonary edema

    • Cough is generally present

    • Abdominal pain and symptoms as above may dominate the clinical presentation, and in severe cases, significant myocardial depression occurs

  • Acute kidney injury and myositis may occur

  • Sequelae include neuropsychological impairments in some HPS survivors

Differential Diagnosis

• Scrub typhus

• Leptospirosis

• Dengue

• Coxsackievirus

• Other respiratory infections caused by such pathogens as Legionella, Chlamydia, and Mycoplasma

• Hemoconcentration and elevation in lactate dehydrogenase, serum lactate, and hepatocellular enzymes

• Early thrombocytopenia and leukocytosis (as high as 90,000 cells/mcL in HPS) are seen in both HFRS and HPS

• In HPS, immunoblasts (activated lymphocytes with plasmacytoid features) can be seen in blood, lungs, kidneys, bone marrow, liver, and spleen

• An indirect fluorescent assay and enzyme immunoassay are available for detection of specific IgM or low-avidity IgG virus-specific antibodies

• A quantitative RT-PCR is available; however, the viremia of human hantavirus infections is short-term and, therefore, viral RNA cannot be readily detected in the blood or urine of patients unless for the more readily detected early viremia of the Andes variant

• Plaque reduction neutralization test

  • Remains a gold standard serologic assay

  • Distinguishes between the different hantavirus species, although cross reaction between Old and New World viruses exist

  • Needs to be performed in a laboratory with appropriate biosafety (level 3)

• Supportive

• Cardiorespiratory support with vasopressors is frequently needed

• Extracorporeal membrane oxygenation may be required in severe cases of HPS

• Intravenous ribavirin

  • Used in HFRS (Hantaan virus) with some success in decreasing the severity of the kidney injury

  • Its effectiveness in HPS, however, is not established

Prevention

• Eradication of rodents in houses and avoidance of exposure to rodent excreta, including forest service facilities

• There is currently no commercially available vaccine and the WHO does not recommend preventive vaccination

Prognosis

• The outcome is highly variable depending on severity of disease

• HPS is a more severe disease than HFRS, with a mortality rate of about 40%

• In Sin Nombre virus infections, the persistence of elevated IgG titers correlates with a favorable outcome