Marc Fischer, Anne Griggs, J. Erin Staples

Infectious Agent

Tick-borne encephalitis virus (TBEV) is a single-stranded RNA virus that belongs to the genus Flavivirus and is closely related to Powassan virus. TBEV has three subtypes: European, Siberian, and Far Eastern.

Mode of Transmission

• Transmitted to humans through the bite of an infected tick of the Ixodes species, primarily I. ricinus (European subtype) or I. persulcatus (Siberian and Far Eastern subtypes). The virus is maintained in discrete areas of deciduous forest where both the tick vectors and animal hosts (mainly rodents) are found.
• Can also be acquired by ingesting unpasteurized dairy products from infected goats, sheep, or cows. TBEV transmission has also been reported through a laboratory exposure and the slaughtering of a viremic goat.
• Direct person-to-person spread of TBEV does not occur except rarely through blood transfusion or breastfeeding.

Occurrence

• TBE is endemic in temperate regions of Europe and Asia (from eastern France to northern Japan and from northern Russia to Albania) and up to about 1,400 m in altitude.
• The highest incidences are reported in Austria, Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania, Poland, Russia, Slovenia, Sweden, and Switzerland.
• European countries with no reported cases are Belgium, Ireland, Luxembourg, the Netherlands, Portugal, Spain, and the United Kingdom.
• Most cases occur during April–November, with peaks in early and late summer when ticks are active.
• The incidence and severity of disease are highest in persons >50 years of age.
• Over the last 30 years, the geographic range of TBEV and the number of reported TBE cases have increased significantly. These trends are likely due to a complex combination of changes in the ecology and climate, increased human activity in affected areas, and increased recognition.

Risk for Travelers

• The overall risk of acquiring TBE for an unvaccinated visitor to an endemic area during the TBEV transmission season has been estimated at 1 case per 10,000 person-months of exposure.
• Most TBEV infections result from tick bites acquired in forested areas through activities such as camping, hiking, fishing, bicycling; collecting mushrooms, berries, or flowers; and outdoor occupations such as forestry or military training. The risk is negligible for persons who remain in urban or unforested areas and who do not consume unpasteurized dairy products.
• Vector tick density and infection rates in TBEV-endemic foci are highly variable. For example, TBEV infection rates in I. ricinus in central Europe vary from less than 0.1% to approximately 5%, depending on geographic location and time of year, while rates of up to 40% have been reported in I. persulcatus in Siberia.
• The number of TBE cases reported from a country depends on the ecology and geographic distribution of TBEV, the intensity of diagnosis and surveillance, and the vaccine coverage in the population. Therefore, the number of human TBE cases reported from an area may not be a reliable predictor of a traveler’s risk for infection.

Clinical Presentation

• Approximately two-thirds of infections are asymptomatic.
• The median incubation period for TBE is 8 days (range 4–28 days). The incubation period for milk-borne exposure is usually shorter (3–4 days).
• Acute neuroinvasive disease is the most commonly recognized clinical manifestation of TBEV infection. However, TBE disease often presents with milder forms of the disease or a biphasic course.
  • First phase: nonspecific febrile illness with headache, myalgia, and fatigue. Usually lasts for several days and may be followed by an afebrile and relatively asymptomatic period. Up to two-thirds of patients may recover without any further illness.
  • Second phase: central nervous system involvement resulting in aseptic meningitis, encephalitis, or myelitis. Cranial nerve involvement, bulbar syndrome, and acute flaccid paralysis of the upper extremities have also been described.
• Among patients who develop central nervous system involvement, approximately 10% require intensive care and 5% need mechanical ventilation.
• Clinical course and long-term outcome varies by subtype of TBEV.
  • The European subtype is associated with milder disease, a case–fatality ratio of <2%, and neurologic sequelae in up to 30% of patients.
  • The Far Eastern subtype is often associated with a more severe disease course, including a case-fatality ratio of 20%–40% and higher rates of severe neurologic sequelae.
  • The Siberian subtype is more frequently associated with chronic or progressive disease and has a case-fatality ratio of 2%–3%.

Diagnosis

• TBE should be suspected in travelers who develop a nonspecific febrile illness that progresses to neuroinvasive disease within 4 weeks of arriving from an endemic area. Approximately 30% of TBE patients do not recall a tick bite.
• Serology is typically used for laboratory diagnosis. IgM-capture ELISA performed on serum or cerebrospinal fluid is virtually always positive during the neuroinvasive phase of the illness.
• Vaccination history, date of onset of symptoms, and information regarding other flaviviruses known to circulate in the geographic area that may cross-react in serologic assays need to be considered when interpreting results.
• During the first phase of the illness, TBEV or TBEV RNA can sometimes be detected in serum samples by virus isolation or nucleic acid amplification tests (NAAT). However, by the time neurologic symptoms are recognized, the virus or viral RNA is usually undetectable. Therefore, virus isolation and NAAT should not be used for ruling out a diagnosis of TBE.
• Health-care providers should contact their state or local health department or CDC’s Division of Vector Borne Infectious Diseases (970-221-6400) for assistance with diagnostic testing.

Treatment

There is no specific antiviral treatment for TBE; therapy consists of supportive care and management of complications.

Preventive Measures for Travelers

Personal Protection Measures

• Avoid consumption of unpasteurized dairy products.
• Use all measures to avoid tick bites (see the Protection Against Mosquitoes, Ticks, and Other Insects and Arthropods section in Chapter 2).

TBE Vaccine

• No TBE vaccines are licensed or available in the United States.
• Two safe, effective inactivated TBE vaccines are available in Europe, in adult and pediatric formulations: FSME-IMMUN (Baxter, Austria) and Encepur (Novartis, Germany). The adult formulation of FSME-IMMUN is also licensed in Canada. Two other TBE vaccines are produced in Russia, but little information has been published about their safety and efficacy.
• Immunogenicity studies suggest that the European vaccines, produced using the TBEV European subtype, should also provide cross-protection against the Far Eastern subtype.
• For both FSME-IMMUN and Encepur, the recommended primary vaccination series consists of three doses (the second given 1–3 months after the first, and the third given 9–12 months after the second (Table 5-2). Although no formal efficacy trials of these vaccines have been conducted, indirect evidence suggests that their efficacy is above 95%.
• Regardless of age, the first booster dose should be given 3 years following the primary series. Recommended intervals for subsequent booster doses vary by age and should be given every 5 years for persons <50 years of age and every 3 years for those ≥50 years of age.
• Because the primary vaccination series requires at least 9 months for completion, most travelers to TBE-endemic areas will find tick-bite prevention to be more practical than vaccination. However, an accelerated vaccination schedule has been evaluated for both European vaccines and shown to result in seroconversion rates similar to those observed with the standard vaccination schedule. For Encepur, the accelerated schedule is a three-dose primary series on days 0, 7, 21, with the first booster at 12–18 months. For FSME-IMMUN, the accelerated schedule is a three-dose primary series on days 0 and 14 and at 5–12 months; the first booster dose is administered at 3 years, according to the conventional schedule.
• Travelers anticipating high-risk exposures, such as working or camping in forested areas or farmland, adventure travel, or living in TBE-endemic countries for an extended period of time, may wish to be vaccinated in Canada or Europe.

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