Author(s): Susan Hills, Carolyn Gould, Caitlin Cossaboom

Infectious Agent

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

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 (Far Eastern and Siberian subtypes). Preferred habitats for these tick species are in or near the edges of forests with deciduous or coniferous trees and low-growing dense brush. Ticks act as both the vector and virus reservoir, and small rodents are the primary amplifying host. People also can acquire TBE by ingesting unpasteurized dairy products (e.g., milk, cheese) from infected cows, goats, or sheep. Infrequently, TBE virus transmission has been reported through laboratory exposure and slaughtering viremic animals. Direct person-to-person spread of TBE virus occurs only rarely, through blood transfusion, solid organ transplantation, or breastfeeding.

Epidemiology

TBE is focally endemic in a geographic region spreading from western and northern Europe through to northern and eastern Asia. Approximately 5,000–10,000 TBE cases are reported from endemic countries each year, with large annual fluctuations.

Russia, including Siberia, has the most reported cases. The highest disease incidence in recent years has been reported from the Baltic states (Estonia, Latvia, Lithuania), Czech Republic, and Slovenia. Other European countries with reported cases or known endemic areas include Austria, Belarus, Belgium, Bosnia, Bulgaria, Croatia, Denmark, Finland, France, Germany, Hungary, Italy, Liechtenstein, Moldova, Netherlands, Norway, Poland, Romania, Serbia, Slovakia, Sweden, Switzerland, Ukraine, and the United Kingdom. Asian countries with reported TBE cases or virus activity include China, Japan, Kazakhstan, Kyrgyzstan, Mongolia, and South Korea. The number of human TBE cases reported from an area might not be a reliable predictor of a traveler’s risk for infection because reporting of local cases depends on various factors, including the intensity of diagnosis and surveillance and the vaccine coverage in the population.

Attack Rate Among Travelers

TBE virus transmission is highly variable by place and over time, and tick population density and infection rates in TBE virus–endemic areas are not consistent. The risk for TBE virus infection for an individual traveler is greatly affected by their planned itinerary and activities. Most infections result from tick bites acquired in forested areas while bicycling, birdwatching, camping, fishing, hiking, or collecting berries, flowers, or mushrooms. People with outdoor occupations, (e.g., farmers, forestry workers, military personnel training in forested areas) are also at increased risk. The risk is negligible for people who remain in urban or unforested areas and who do not consume unpasteurized dairy products.

During 2000–2020, 11 cases of TBE were reported among US civilian travelers. Of these, 10 (91%) cases occurred among males, and most (73%) were in people >19 years old. Destinations where infections likely were acquired included China, Russia, and several countries in Europe. During 2012–2020, an additional 9 TBE cases were reported among US military personnel or their dependents residing in Germany.

Travelers at risk for TBE virus infection might also be at risk for other tickborne diseases because the same ticks that transmit TBE virus also can transmit other pathogens, including Borrelia burgdorferi (the agent for Lyme disease), Anaplasma phagocytophilum (anaplasmosis), and Babesia spp. (babesiosis); simultaneous infection with multiple organisms has been described.

Seasonality & Geographic Range

Most TBE cases occur during April–November, with peaks in early and late summer when ticks are most active. Most cases occur in areas <2,500 ft (≈750 m) in elevation. During the past 30 years, the range of TBE virus transmission appears to have expanded to new geographic areas and to higher elevations; the virus has been found at ≥5,000 ft (≈1,500 m). These trends are likely due to a complex combination of changes in diagnostics and surveillance, changes in human activities, and other socioeconomic, ecologic, and climatic factors.

Clinical Presentation

Most (≈2/3) infections are asymptomatic. The median incubation period for TBE is 8 days (range 2–28 days). Acute neuroinvasive disease is the most recognized clinical manifestation of TBE virus infection. Often, however, TBE presents with milder disease forms or a biphasic course. In patients with a biphasic disease course, the first phase is characterized by a nonspecific febrile illness sometimes accompanied by anorexia, headache, malaise, myalgia, nausea or vomiting. This phase usually lasts for several days and might be followed by an afebrile and relatively asymptomatic period. The clinical illness in the second phase reflects central nervous system involvement, specifically aseptic meningitis, encephalitis, or meningoencephalomyelitis. Clinical findings can include altered mental status, ataxia, cognitive dysfunction, cranial nerve palsies, limb paresis, meningeal signs, rigidity, seizures, and tremors.

TBE disease severity increases with age with typically milder disease in children.

Disease course and outcome

Clinical course and long-term outcome vary by TBE virus subtype, although some of the reported differences could be due to access to medical care, or testing or methodologic biases in published reports.

The European subtype is associated with milder disease, a case-fatality ratio of <2%, and neurologic sequelae in ≤30% of patients. The Far Eastern subtype is often associated with a more severe disease course, including a case-fatality ratio of 20%–40% among neurologic disease cases and higher rates of severe sequelae. The Siberian subtype has a case-fatality ratio of 6%–8%, with rare reports of cases with slow or chronic progression over months.

Diagnosis

Suspect TBE in travelers who develop a nonspecific febrile illness that progresses to neuroinvasive disease ≤4 weeks after arriving from an endemic area. A history of tick bite might suggest TBE diagnosis; ≈30% of TBE patients do not recall a tick bite, however.

Serology is typically used for laboratory diagnosis. IgM-capture ELISA performed on serum or cerebrospinal fluid is almost always positive during the neuroinvasive phase of the illness. When interpreting results, consider the patient’s vaccination history, date of symptom onset, and information about other flaviviruses known to circulate in the same geographic area that might cross-react in serologic assays.

During the first phase of the illness, TBE virus or viral RNA sometimes can be detected. By the time neurologic symptoms are recognized, however, the virus or viral RNA is usually undetectable. Therefore, virus isolation and reverse transcription PCR (RT-PCR) testing should not be used to rule out TBE diagnosis and are not routinely recommended. No commercial tests are available in the United States to diagnose TBE but testing is available at some State Health Departments and the Centers for Disease Control and Prevention (CDC). Contact the state or local health department or the CDC's Arboviral Diseases Branch, Division of Vector-Borne Diseases (970-221-6400), for assistance with diagnostic testing.

Treatment

No specific antiviral treatment is available for TBE. Therapy consists of supportive care and management of complications.

Prevention

Personal Protective Measures

Travelers should avoid consuming unpasteurized dairy products and use all measures to avoid tick bites (see Sec. 4, Ch. 6, Mosquitoes, Ticks & Other Arthropods).

Vaccine

In August 2021, the US Food and Drug Administration approved Pfizer’s TICOVAC as the first TBE vaccine for use in the United States. Also marketed as FSME-IMMUN in Europe, TICOVAC is an inactivated, whole-virus vaccine with formulations for children (1–15 years) and adults (≥16 years). Five other TBE vaccines, not licensed for use in the United States, are available internationally.

Indications for Use

The risk for most US travelers visiting TBE-endemic areas is very low. Based on activities, destination, duration of travel, and season, some people who travel abroad are at increased risk for infection (Box 5-06). In February 2022, the Advisory Committee on Immunization Practices approved recommendations for vaccine use among people traveling or moving to a TBE-endemic area. Vaccine is recommended for persons who will have extensive tick exposure based on planned outdoor activities and itinerary. In addition, TBE vaccine may be considered for people traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas where ticks are likely to be found, with the decison to vaccinate based on an assessment of planned activities and itinerary, risk factors for a poor medical outcome, and personal perception and tolerance of risk (Box 5-07).

Administration

Dose and primary vaccination schedule vary by age (Table 5-21). Each dose is administered intramuscularly.

Safety & Adverse Reactions

Although TICOVAC has only recently been licensed in the United States, the current vaccine formulation has been available internationally for >20 years, and >75 million doses have been administered with no serious safety concerns identified. Adverse events reported most commonly include tenderness and pain at the injection site in ≥10% of vaccine recipients. In children and adolescents, the most common systemic symptoms include fever, headache, and restlessness; in adults, headache, fatigue, and myalgia. Serious adverse events are reported only rarely.

Contraindictions & Precautions

A severe allergic reaction to any component of TICOVAC is a contraindication to administration. Some individuals with altered immunocompetence might have reduced immune responses to TICOVAC, and immunocompromise and immunosuppression are precautions to vaccination. No studies have assessed the safety of TICOVAC in people who are pregnant or lactating.

CDC website: Tick-borne encephalitis (TBE)