Tick-borne Encephalitis Virus

Tick-borne encephalitis virus (TBEV) is a positive-sense, single-stranded RNA virus of the genus Flavivirus. Transmission occurs primarily via Ixodes ticks found in Europe, the former Soviet Union, and Asia. The virus causes tick-borne encephalitis. Most patients are asymptomatic; however, symptomatic individuals may experience a biphasic illness. After recovering from nonspecific symptoms, patients can develop neurologic manifestations, such as meningitis, encephalitis, or meningoencephalitis. Serology or PCR can confirm the diagnosis. There is no effective antiviral therapy for TBEV infections, so management is supportive.

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Classification

RNA Viruses Flowchart Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. RNA genome viruses can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of cell membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics and Epidemiology

Basic features of tick-borne encephalitis virus (TBEV)

  • Taxonomy:
    • Family: Flaviviridae
    • Genus: Flavivirus
  • RNA virus
    • Single-stranded
    • Positive-sense
    • Linear
  • Spherical
  • Icosahedral symmetry
  • Enveloped
  • Size: approximately 50 nm
Tick-borne Encephalitis Virus Flaviviridae

Tick-borne encephalitis virus at different pHs:
A: 8.0
B: 10.0
C: 5.4

Image: “TBEV at different pH levels” by Stiasni K. License: CC BY 2.5

Clinically relevant species

Tick-borne encephalitis (TBE) is caused by 3 subtypes:

  • European
  • Siberian
  • Far Eastern

Epidemiology

TBE is the most common tick-borne CNS infection in Europe and Asia.

  • Approximately 10,000–15,000 cases reported annually 
  • Infections are most common in parts of:
    • Europe 
    • Former Soviet Union
    • Siberia
    • Asia
  • Mortality:
    • Rare in Europe: 1%–2%
    • Higher in Asia: 5%–20%

Pathogenesis

Reservoir

  • Ixodes ticks act as both the vector and the reservoir. 
  • The main hosts are small rodents.
  • Humans are accidental hosts. 

Transmission

  • Ixodes tick bites in endemic areas:
    • Ixodes ricinus (European subtype)
    • I. persulcatus (Siberian and Far Eastern subtypes)
  • Consumption of raw milk from infected
    • Goats
    • Sheep
    • Cows
Ixodes Ricinus Flaviviridae Tick-borne encephalitis virus

An adult Ixodes ricinus tick, the vector for the European subtype of tick-borne encephalitis virus

Image: “Soft tick, Ixodes Ricinus, on human skin” by Gabrielsen J. License: CC BY 3.0

Host risk factors

Outdoor recreational and occupational activities in endemic regions can increase the risk of acquiring TBEV:

  • Hunters
  • Farmers
  • Forest workers
  • Campers

Viral replication cycle

  1. Virion interacts with cell surface receptors → endocytosis
  2. ↓ pH in the endosome → fusion of viral and endosomal membranes → uncoating of the virus
  3. Viral protein synthesis occurs in the rough endoplasmic reticulum (ER). 
  4. Genomic replication occurs in invaginations of the ER → virions are repackaged and assembled.
  5. Mature virions leave the cell.
Tick-borne encephalitis Flaviviridae

Tick-borne encephalitis virus replication cycle within a cell

Image: “An overview of the TBEV life cycle” by AUTHOR. License: CC BY 4.0

Pathophysiology

  • Tick bite → TBEV is transmitted from the saliva within minutes
  • TBEV replication occurs locally in dendritic cells → transported to local lymph nodes
  • Disseminates to extraneural tissues:
    • Spleen
    • Liver
    • Bone marrow
  • Continued replication → viremia → initial phase of symptoms 
  • Eventual spread to the brain (process not understood) → inflammation → neuronal injury → 2nd phase of neurologic symptoms

Clinical Presentation

Most patients are asymptomatic. Symptomatic individuals may have a biphasic course.

  • Incubation period: 7–14 days after a tick bite
  • Initial viremic phase:
    • Fever
    • Malaise
    • Headache
    • Arthralgia
    • Myalgias
    • Nausea
  • Asymptomatic interval
  • 2nd neurologic phase:
    • Meningitis
    • Encephalitis
    • Meningoencephalitis
    • Myelitis
    • Acute flaccid paralysis

Diagnosis and Management

Diagnosis

Blood or CSF samples can be used for diagnostic testing:

  • Serology (ELISA) for IgM antibodies
    • Appear 0–6 days after onset
    • May be detected if neurologic symptoms are present
  • PCR for viral RNA

Supporting evaluation:

  • CSF studies:
    • Pleocytosis
      • Neutrophil predominance (early in the disease)
      • Lymphocyte predominance (later in the disease)
    • Normal glucose
    • Normal or slight ↑ protein
  • Leukopenia
  • Thrombocytopenia
  • Transaminitis (rare)

Management

There is no specific drug therapy. Management is supportive.

Prevention

  • Use insect repellent.
  • Wear protective clothing.
  • Pasteurize milk.
  • A vaccine is available in endemic areas (not in the United States).

Comparison of Similar Flavivirus Species

Table: Features and diseases of several Flavivirus species
OrganismTick-borne encephalitis virusJapanese encephalitis virusSt. Louis encephalitis virusWest Nile virus
CharacteristicsThe structural features are almost identical.
Region
  • Europe
  • Siberia
  • Asia
  • Asia
  • Western Pacific
North America
  • Africa
  • Middle East
  • Europe
  • South Asia
  • Australia
  • North America
TransmissionTickMosquitoMosquitoMosquito
Clinical
  • Most are asymptomatic.
  • Initially nonspecific symptoms
  • Neurologic phase:
    • Meningitis
    • Encephalitis
    • Meningoencephalitis
  • Nonspecific febrile illness
  • Meningitis
  • Encephalitis
  • Acute flaccid paralysis
  • Guillain-Barré syndrome
  • Most are asymptomatic.
  • Nonspecific febrile illness
  • Meningitis
  • Encephalitis
  • Meningoencephalitis
  • Most are asymptomatic.
  • West Nile fever
  • Neuroinvasive disease:
    • Meningitis
    • Encephalitis
    • Acute flaccid paralysis
Diagnosis
  • Serology
  • PCR
SerologySerology
  • Serology
  • PCR
ManagementSupportiveSupportiveSupportiveSupportive
Prevention
  • Tick avoidance measures
  • Vaccination (in endemic areas)
  • Mosquito avoidance measures
  • Vaccination
Mosquito avoidance measuresMosquito avoidance measures

Differential Diagnosis

  • Bacterial meningitis: acute infection of the meninges. Patients with bacterial meningitis present with headache, fever, nuchal rigidity, and rapid clinical deterioration. Lumbar puncture is performed to make the diagnosis. Unlike with viral meningitis, CSF studies will show a turbid fluid, low glucose, and high WBC count with neutrophil predominance. Gram stain and culture will determine the causative bacteria. Treatment includes antibiotics and corticosteroids. 
  • Lyme disease: tick-borne infection caused by the gram-negative spirochete Borrelia burgdorferi. The presentation of Lyme disease can vary depending on the stage of the disease and may include the characteristic erythema migrans rash, which is not seen in TBE. Neurologic, cardiac, ocular, and joint manifestations are also common in later stages. The diagnosis relies on clinical findings and tick exposure and is supported by serologic testing. Antibiotics are used for treatment. 
  • Ehrlichiosis and anaplasmosis: tick-borne infections caused by Ehrlichia chaffeensis and Anaplasmosis phagocytophilum, respectively. Symptoms of ehrlichiosis and anaplasmosis include fever, headache, and malaise. Meningoencephalitis can also occur with severe disease. The diagnosis is made using PCR. Treatment of both diseases is with doxycycline.
  • Babesiosis: tick-borne infection caused by Babesia. Patients with babesiosis can be asymptomatic or develop fever, fatigue, malaise, and arthralgias. Asplenic, immunocompromised, and elderly patients are at risk for severe disease, which causes neurologic symptoms, hemolytic anemia, thrombocytopenia, hepatosplenomegaly, renal failure, and death. Diagnosis is confirmed with a peripheral blood smear, serologic testing, and PCR. Management includes antimicrobials such as atovaquone plus azithromycin.
  • Tularemia: infection caused by Francisella tularensis. The presentation of tularemia depends on the type of exposure and can include ulcerations, nonspecific systemic symptoms, ocular disease, lymphadenitis, pneumonia, mediastinitis, or meningitis. Diagnosis is made with cultures, serology, and PCR testing. Antibiotics are used for treatment.

References:

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  12. Petersen, L.R. (2019). Arthropod-borne encephalitides. In Mitty J. (Ed.), UpToDate. Retrieved May 4, 2021, from https://www.uptodate.com/contents/arthropod-borne-encephalitides
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