Tickborne Encephalitis

Infectious Agent

Tickborne encephalitis (TBE) virus is a single-stranded RNA virus that belongs to the genus Flavivirus . TBE virus has 3 subtypes: European, Siberian, and Far Eastern.

Transmission

TBE virus is 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 forests. Ticks act as both vector and virus reservoir, and small rodents are the primary amplifying host. TBE can also be acquired by ingesting unpasteurized dairy products (such as milk and cheese) from infected goats, sheep, or cows. TBE virus transmission has infrequently been reported through laboratory exposure and slaughtering viremic animals. Direct person-to-person spread of TBE virus occurs only rarely, through blood transfusion or breastfeeding.

Epidemiology

TBE is endemic in focal areas of Europe and Asia, extending from eastern France to northern Japan and from northern Russia to Albania. Approximately 5,000–13,000 TBE cases are reported each year, with large annual fluctuations. Russia has the largest number of reported cases. The highest disease incidence has been reported from western Siberia, Slovenia, and the Baltic States (Estonia, Latvia, Lithuania). Other European countries with reported cases or known endemic areas include Albania, Austria, Belarus, Bosnia, Croatia, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, Norway, Poland, Romania, Serbia, Slovakia, Sweden, Switzerland, and Ukraine. Asian countries with reported TBE cases or virus activity include China, Japan, Kazakhstan, Kyrgyzstan, Mongolia, and South Korea.

Most cases occur from April through November, with peaks in early and late summer when ticks are active. The incidence and severity of disease are highest in people aged ≥50 years. Most cases occur in areas <2,500 ft (750 m). In the last 30 years, the geographic range of TBE virus appears to have expanded to new areas, and the virus has been found at altitudes up to and above 5,000 ft (1,500 m). These trends are likely due to a complex combination of changes in diagnosis and surveillance, human activities and socioeconomic factors, and ecology and climate.

The overall risk of acquiring TBE for an unvaccinated visitor to a highly endemic area during the TBE virus transmission season has been estimated at 1 case per 10,000 person-months of exposure. Most TBE virus 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 people who remain in urban or unforested areas and who do not consume unpasteurized dairy products.

Vector tick population density and infection rates in TBE virus-endemic foci are highly variable. For example, TBE virus infection rates in I. ricinus in central Europe vary from <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 TBE virus, 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. The same ticks that transmit TBE virus can also transmit other pathogens, including Borrelia burgdorferi (the agent for Lyme disease), Anaplasma phagocytophilum (anaplasmosis), and Babesia spp. (babesiosis), and simultaneous infection with multiple organisms has been described.

From 2000 through 2015, 7 cases of TBE among US travelers to Europe and China were reported. TBE is not a nationally notifiable disease in the United States, and additional cases may have occurred.

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 milkborne exposure is usually shorter (3–4 days). Acute neuroinvasive disease is the most commonly recognized clinical manifestation of TBE virus 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 recover without any further illness.
  • Second phase: central nervous system involvement resulting in aseptic meningitis, encephalitis, or myelitis. Findings include meningeal signs, altered mental status, cognitive dysfunction, ataxia, rigidity, seizures, tremors, cranial nerve palsies, and limb paresis.

Disease severity increases with age. Although TBE tends to be less severe in children, residual symptoms and neurologic deficits have been described. Clinical course and long-term outcome also vary by TBE virus subtype:

  • 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. A history of tick bite may be a clue to this diagnosis; however, 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, TBE virus or viral RNA can sometimes be detected in serum samples by virus isolation or RT-PCR. However, by the time neurologic symptoms are recognized, the virus or viral RNA is usually undetectable. Therefore, virus isolation and RT-PCR should not be used to rule out a diagnosis of TBE. Clinicians should contact their state or local health department, the CDC Viral Special Pathogens Branch (404-639-1115), or CDC Division of Vector-Borne 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.

Prevention

Personal Protection Measures

Travelers should avoid consuming unpasteurized dairy products and use all measures to avoid tick bites (see Chapter 2, Protection against Mosquitoes, Ticks, & Other Arthropods).

Vaccine

No TBE vaccines are licensed or available in the United States. Two inactivated cell culture-derived TBE vaccines are available in Europe, in adult and pediatric formulations: FSME-IMMUN (Baxter, Austria) and Encepur (Novartis, Germany). Two other inactivated TBE vaccines are available in Russia: TBE-Moscow (Chumakov Institute, Russia) and EnceVir (Microgen, Russia). Immunogenicity studies suggest that the European and Russian vaccines should provide cross-protection against all 3 TBE virus subtypes. At least 1 other TBE vaccine is produced in China, but information regarding this vaccine is not available in the English literature.

For both FSME-IMMUN and Encepur, the primary vaccination series consists of 3 doses. The specific recommended intervals between doses vary by country and vaccine (Table 3-19). Although no formal efficacy trials of these vaccines have been conducted, indirect evidence suggests that their efficacy is >95%. Vaccine failures have been reported, particularly in people aged ≥50 years.

Table 3-19. Tickborne encephalitis (TBE) vaccines licensed in Europe and Russia 1
Trade name (Manufacturer, location)Age (y)DoseRoutePrimary seriesFirst Booster (y)Subsequent Boosters (y)
FSME-IMMUN (Baxter, Austria)≥160.5 mLIM3 doses (0, 1–3 mo, 6–15 mo) 235 3
FSME-IMMUN Junior (Baxter, Austria)1–150.25 mLIM3 doses (0, 1–3 mo, 6–15 mo) 235
Encepur-Adults (Novartis, Germany)≥170.5 mLIM3 doses (0, 1–3 mo, 9–12 mo) 435 3
Encepur-Children (Novartis, Germany)1–110.25 mLIM3 doses (0, 1–3 mo, 9–12 mo) 435
EnceVir (Microgen, Russia)≥30.5 mLIM2 doses (0, 5–7 mo) 513
TBE-Moscow (Chumakov Institute, Russia)≥30.5 mLIM2 doses (0, 1–7 mo)13
Abbreviation: IM, intramuscular.
1 No TBE vaccines are licensed or available in the United States. FSME-IMMUN, FSME-IMMUN Junior, Encepur-Adults, and Encepur-Children are licensed in Europe and EnceVir and TBE-Moscow are licensed in Russia.
2 If a rapid immune response is required, the second dose can be administered 2 weeks after the first dose.
3 Booster doses recommended every 3 years for people aged ≥50 years.
4 An accelerated schedule has been used with 3 doses given on days 0, 7, and 21. After the primary series, the first booster dose is administered at 12–18 months.
5 For emergency situations, there is a rapid primary series schedule of 0 and 1–2 months.

Because the routine primary vaccination series requires ≥6 months for completion, most travelers to TBE-endemic areas will find avoiding tick bites to be more practical than vaccination. However, an accelerated vaccination schedule has been evaluated for both European vaccines, and results in seroconversion rates are similar to those observed with the standard vaccination 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 Europe.

CDC website: www.cdc.gov/vhf/tbe

Bibliography

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Authors

Marc Fischer, Ingrid B. Rabe, Pierre E. Rollin