Tick-Borne Encephalitis

Introduction

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, Siberian, and Far Eastern.

Transmission

TBE virus is transmitted to humans through the bite of an infected tick of the Ixodes species, primarily Ixodes ricinus (European subtype) or Ixodes persulcatus (Far Eastern and Siberian subtypes). Laboratory experiments suggest the virus can be transmitted from an infected tick to an animal within minutes. Preferred habitats for the tick species are within or near the edges of forests; they favor areas with low-growing dense brush and plant litter. Ticks act as both the vector and virus reservoir. 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; transmission from goats is most commonly reported. 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 to northern and eastern Asia. Approximately 5,000–10,000 TBE cases are reported from endemic countries each year. TBE virus transmission is highly variable by place and over time. Russia, including Siberia, has the most reported cases. The highest disease incidence in recent years has been reported from the Baltic states (Estonia, Latvia, and Lithuania), Czech Republic, and Slovenia. Other European countries with reported cases or known endemic areas are listed in Table 4.18.1. 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 extent of human and laboratory resources applied to surveillance and the vaccine coverage in the population.

During the past 30 years, the range of TBE virus transmission has expanded to new geographic areas and to higher altitudes. The overall area of recognized transmission has expanded westward and northward, and new TBE virus foci have been detected at elevations up to about 2,100 m (approximately 7,000 ft). These changes are likely due to a complex combination of factors including climatic, ecologic, human, and socioeconomic factors.

Seasonality

The main TBE virus transmission season is April–November when ticks are most active because of warmer weather in the Northern Hemisphere. Peak transmission generally occurs over multiple weeks during the warm, humid summer months, typically during June–August in European countries.

Tick-borne encephalitis among U.S. travelers

The risk for TBE for an individual traveler is greatly affected by their planned itinerary and activities. Most infections result from tick bites acquired in forested areas while participating in activities such as bicycling, birdwatching, camping, fishing, hiking, or collecting berries, flowers, or mushrooms. People with outdoor occupations (e.g., farmers, field researchers, forestry workers, military personnel training in forested areas) are also at increased risk. No U.S. traveler has been reported to have acquired TBE through ingestion of unpasteurized dairy products. TBE risk is negligible for people who remain in urban or unforested areas and who do not consume unpasteurized dairy products.

During 2000–2023, 12 cases of TBE were reported among U.S. civilian travelers. Of these, 11 cases occurred among males, and 9 were in people aged >19 years. Destinations where infections likely were acquired included China, Russia, and several countries in Europe. During 2012–2021, an additional 12 TBE cases were reported among U.S. 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.

Table 4.18.1: Country-specific risk information

Clinical presentation

Most (approximately 3 out of 4) infections are asymptomatic. The incubation period for TBE is typically 7–14 days (range, 2–28 days). Acute neuroinvasive disease (i.e., aseptic meningitis, encephalitis, or meningoencephalomyelitis) is the most recognized clinical manifestation of TBE virus infection. Relatively mild forms of disease (e.g., febrile illness) can also occur. TBE can have a monophasic or biphasic course. In patients with a biphasic disease course, the first phase is characterized by non-specific symptoms, including fever and sometimes 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 with neurologic symptoms. Clinical findings can include altered mental status, ataxia, cognitive dysfunction, cranial nerve palsies, limb paresis, meningeal signs, rigidity, seizures, or tremors. Children typically present with milder disease and disease severity increases with age. Other risk factors for more severe illness include infection with the Far Eastern subtype or being immunocompromised.

Disease outcome

Outcomes vary by clinical presentation and TBE virus subtype, although some of the reported differences could be due to access to medical care, variations in testing, or methodologic biases in published reports. The European subtype is associated with milder disease, a case-fatality ratio of <2%, and sequelae in 20%–40% of patients overall, including neurologic sequelae such as limb paresis or paralysis in ≤10%. The Far Eastern subtype is often associated with a more severe disease course, with reported case-fatality ratios of 20%–40% among neurologic disease cases. 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 non-specific febrile illness that progresses to neuroinvasive disease ≤4 weeks after arriving from an endemic area. A history of tick bite might suggest TBE diagnosis; however, approximately 30% of patients with TBE do not recall a tick bite.

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.

TBE virus or viral RNA sometimes can be detected during the first phase of illness. By the time neurologic symptoms are recognized, however, the virus or viral RNA is usually undetectable. Therefore, virus isolation and reverse transcription-PCR testing should not routinely be used for diagnosis. However, molecular testing might be preferred in severely immunocompromised persons. Testing for TBE is available at some State Health Departments and CDC. Contact the state or local health department or 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. Management consists of supportive care and treatment of complications.

Prevention

Personal protective measures

Travelers should avoid consuming unpasteurized dairy products and use all measures to avoid tick bites (see Mosquitoes, Ticks, and Other Arthropods chapter).

Vaccine

In 2021, the U.S. 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 U.S. travelers visiting TBE-endemic areas is very low. Based on activities, location, season, and travel duration, some people who travel abroad are at increased risk for infection (Box 4.18.1). In 2022, the Advisory Committee on Immunization Practices approved recommendations for vaccine use among people traveling or moving to a TBE-endemic area. The 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 decision 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. The risk-benefit assessment for vaccination should consider several factors (Box 4.18.2; Figure 4.18.1).

Box 4.18.1

Notes

Abbreviations: TBE, tick-borne encephalitis.

Box 4.18.2

Notes

Abbreviations: TBE, tick-borne encephalitis; TICOVAC, TBE vaccine.

Administration

Dose and primary vaccination schedule vary by age (Table 4.18.2). Each dose is administered intramuscularly. Studies have demonstrated that after a primary series and a booster dose, high seropositivity rates are maintained for at least 10 years in children and healthy adults.

Safety and adverse reactions

Although TICOVAC was only licensed in 2021 in the United States, the vaccine 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 and headache, and in adults include headache, fatigue, and myalgia. Serious adverse events are reported only rarely.

Contraindications and precautions

A severe allergic reaction to any component of TICOVAC is a contraindication to administration. Although TBE vaccine is prepared from TBE virus propagated in chick embryo fibroblast cells, the ultracentrifugation process removes all but trace amounts of chick protein, and no reports have been published related to TBE vaccine and egg allergy. However, a known severe hypersensitivity to egg or chicken protein (e.g., anaphylaxis after oral ingestion) is a contraindication to TBE vaccination. Immunocompromise and immunosuppression are precautions to vaccination because some individuals with altered immunocompetence might have reduced immune responses to TICOVAC. No studies have assessed the safety of TICOVAC in women who are pregnant or lactating.

Figure 4.18.1

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This diagram shows a decision-making flow chart for assessing U.S. travelers for tick-borne encephalitis vaccination. A healthcare professional should assess a traveler's risk for TBE virus infection based on their planned activities and itinerary:

1. All travelers to TBE-endemic countries with risk of tick exposure should take precautions to avoid tick bites.

Note: Travelers also should be advised to avoid the consumption of unpasteurized dairy products.

2. For some travelers who are at increased risk of TBE, the TBE vaccine might be indicated

Moving or traveling to a TBE-endemic area and likely to have extensive exposure to ticks based on planned outdoor activities and itinerary? Note: Persons with extensive exposure to ticks are likely to be at highest risk and could include shorter term (e.g., <1 month) travelers with daily or frequent exposure or longer-term travelers with regular (eg., a few times a month) exposure to environments that might harbor infected ticks. If yes, TBE vaccine is recommended. If no, further assess:

1. Likely extent of exposure to ticks based on planned activities and itinerary

2. Risk factors for a poorer medical outcome (e.g., older age)

3. Personal perception and tolerance of risk

TBE vaccine may be considered based on these factors.

Show Text Description

Table 4.18.2: TICOVAC tick-borne encephalitis vaccine administration schedule

Acknowledgments

The following author contributed to the previous version of this chapter: Caitlin Cossaboom.