A Clear and Present Danger: Tick-borne Diseases in Europe

Paul Heyman; Christel Cochez; Agnetha Hofhuis; Joke van der Giessen; Hein Sprong; Sarah Rebecca Porter; Bertrand Losson; Claude Saegerman; Oliver Donoso-Mantke; Matthias Niedrig; Anna Papa

Disclosures

Expert Rev Anti Infect Ther. 2010;8(1):33-50. 

In This Article

Tick-borne Encephalitis

Tick-borne encephalitis virus is a medically important member of the genus flavivirus, family Flaviviridae.[146] It is classified as one species with three subtypes, namely the European subtype, the Siberian subtype and the Far Eastern subtype. Besides TBEV, three other tick-borne flaviviruses, that is, Louping ill virus, Langat virus and Powassan virus, also trigger encephalitis in mammals, but these infections are infrequent and the viruses do not cause significant outbreaks.[147,148]

The principal vector as well as reservoir of the European TBEV subtype is I. ricinus, and I. persulcatus for the other two subtypes.[149–152] Although the virus has been isolated from several other tick species,[147,153–156] in nature only the two mentioned ixodid tick species appear to play an important role in virus maintenance and contribute significantly to the epidemiology of human disease.[157,158] Horizontal TBEV transmission between ticks and their vertebrate reservoir hosts is necessary for virus endemism.[159] The duration of viremia in hosts is crucial for TBEV transmission to ticks, because the virus is mostly ingested by ticks while engorging on a viremic host.

Generally, the hosts are divided into three groups: reservoir, indicator and accidental hosts.[148] Natural reservoir hosts of TBEV, that is, animals that are sensitive to the virus, exhibiting viremia for a long period of time without becoming clinically ill and thus important for the transmission of the virus to ticks, include rodents (Clethrionomys, Apodemus, Mus, Microtus, Micromys, Pitymys, Arvicola, Glis, Sciurus and Citellus),[160] insectivores (Sorex, Talpa and Erinaceus)[160] and carnivores (Vulpes and Mustela).[151,161] Insectivores and rodents also harbor the virus during the winter. Indicator hosts are not able to transmit the virus to other vectors, either due to only brief viremia with low virus production, or due to a lack of necessary cell-based mechanisms to support nonviremic transmission during co-feeding.[162] Humans who can be infected by a bite of an infected tick, or by consumption of nonpasteurized milk from viremic lifestock, as well as large animals such as goats, cows, sheep, roe deer, dogs and pigs, are accidental hosts of TBEV. They can develop a disease with viremia, but they do not participate in virus circulation in nature and are, therefore, a dead-end of the natural TBEV cycle. In addition, seroprevalence in these large vertebrates may represent an indirect means of measuring the intensity of TBEV transmission within a geographical region, and make them valuable sentinels for epidemiological risk assessment.[147]

Although the first hints of the existence of the disease date back to Scandinavian church records from the 18th Century (Åland Islands, Finland), what is known today as tick-borne encephalitis (TBE) was first recognized and medically described by the Austrian physician H Schneider in 1931 as 'meningitis serosa epidemica' of unknown etiology.[163] A disease with similar clinical symptoms had been observed in the Far East since 1914, but has occurred more frequently since 1933, and briefly thereafter – during three successive expeditions from 1937 to 1939 – the etiologic agent was isolated in Russia and its transmission by ticks could also be demonstrated.[164] The disease was called 'Russian spring–summer encephalitis' (or Far East or taiga encephalitis), and the virus became known as Russian spring–summer encephalitis virus, now known as TBEV. In Finland, TBE was initially described as 'Kumlinge disease' in the 1940s[165] and the first European TBEV was isolated in Czechoslovakia after the Second World War in 1948,[166,167] when the incidence of clinical manifestations caused by the virus was so high that it was noticed by infectiologists in affected regions.[168] Simultaneously, the virus was also isolated from I. ricinus, suggesting the role of the tick as a vector of the disease.[149]

Today, the distribution of TBEV correlates with the ixodid tick vectors. I. ricinus occurs in most parts of Europe, and the distribution extends to the southeast (Turkey, Northern Iran and Caucasus).[169]I. persulcatus is seen in the wide area extending from eastern Europe to China and Japan.[170] Parallel occurrence of both tick species was reported in northeastern Europe and the east of Estonia and Latvia, as well as in several European regions of Russia.[152,171,172] The prevalence of TBEV-infected I. ricinus ticks varies from 0.5 to 5%, whereas in I. persulcatus in certain regions of Russia a prevalence up to 40% was recorded.[148] It should be noted that methods for measuring virus prevalence in ticks or animal reservoirs have not been standardized, and reliable tools should be introduced to translate epizootic prevalence data into infection risk for humans. TBE occurs in many parts of central Europe and Scandinavia, particularly in Austria, the Czech Republic, Estonia, Finland, Germany, Hungary, Latvia, Lithuania, Poland, Russia, Slovak Republic, Slovenia, Sweden and Switzerland, and also in northern Asia.[173–175] Furthermore, new TBE foci are emerging and latent ones are re-emerging in a number of other European countries.[176] In Russia, the highest TBE incidence is reported in Western Siberia and Ural.[154] No TBE cases have been reported, for example, in the UK, Ireland, Iceland, Belgium, The Netherlands, Luxemburg, Spain and Portugal. Bulgaria, Croatia, Denmark, France, Greece, Italy, Norway, Romania, Serbia, China and Japan are countries with only sporadic TBE occurrence. Owing to the increased mobility of people travelling to risk areas, TBE has become an international public health problem with relation to travel medicine. The risk of an infection is especially high for people living in endemic areas or visiting them for leisure activities.[176]

While courses and symptoms are quite similar in the early stage of disease, TBE caused by viruses of the different subtypes may vary not only in the frequency of development of certain disease forms, but also in the severity of each form. Siberian and Far Eastern TBEV subtypes can be the cause of chronic disease.[177,178] For the Far Eastern TBEV subtype, the frequency of focal encephalitic symptoms is 31–64%, meningeal forms amount to nearly 26%, febrile forms 14–16% and biphasic forms 3–8%. Complete recovery occurs in 25% of all cases.[179] The current increase in the proportion of patients with a febrile form is likely to be associated with the improved diagnostics based mainly on serology.[180,181] The case–fatality rate is up to 35%.[182] Chronic disease develops in less than 0.5% of cases. The Siberian subtype is associated with focal encephalitic forms in 5% of incidents, meningeal forms in nearly 47%, febrile forms in 40% and biphasic forms in approximately 21%. Complete recovery occurs in 80% of all cases. The case–fatality rate is nearly 2%.[179] Nevertheless, patients infected with the Siberian subtype have a tendency to develop chronic or extremely prolonged infections accompanied by diverse neurological and/or neuropsychiatric symptoms.[183] In contrast to the forms mentioned previously, infections caused by European strains typically take a biphasic course in 72–87% of patients.[184–186] After a short incubation period (usually 7–14 days, with extremes of 4–28 days), the first (viremic) phase presents as an uncharacteristic influenza-like illness lasting 2–4 days (range: 1–8 days) with fever, malaise, headache, myalgia, gastrointestinal symptoms, leukocytopenia, thrombocytopenia and elevated liver enzymes as frequent symptoms. This is often followed by a symptom-free interval of approximately 1 week (range: 1–33 days) before the second phase. Seroconversion without prominent morbidity is common. The second phase of TBE occurs in 20–30% of infected patients[187] and is marked by four clinical features of different severity (meningitis, meningoencephalitis, meningoencephalomyelitis or meningoencephaloradiculitis) and the appearance of specific antibodies in the serum and cerebrospinal fluid. This is usually the time when patients with high fever and severe headache seek medical advice. Neurological symptoms at this stage principally do not differ from other forms of acute viral meningoencephalitis.[188] The fatality rate in adult patients is less than 2%. However, severe courses of TBE infection with higher mortality and long-lasting sequelae often affecting the patient's quality of life have been correlated with increased age.[188,189] Further factors associated with severe forms are severity of illness in the viremic phase and low neutralizing antibody titers at onset of disease.[190] Direct viral infection of neurons is considered to be the major cause of neurological disease, because viral infections cause apoptosis of neurons in vivo or in vitro. Although critical for controlling viral infection in the CNS, the host immune response has been implicated in contributing to neuropathy.[191] In addition, recent studies have demonstrated that inflammatory responses in the CNS have immune-pathological effects.[192] Finally, it should be noted that due to differences in seroprevalence rates in Europe and Russia, the higher morbidity of eastern TBE forms could, at least partly, be the result of the selective notification of mainly severe cases.[151]

Since there is no specific treatment for TBE available to date, and the administration of hyperimmunoglobulin for a passive postexposure prophylaxis is highly questionable and is no longer recommended due to concerns about antibody-dependent enhancement of infection,[185,193,194] active immunization should always be recommended for people living in or travelling to TBE-endemic areas. In Europe, two vaccines are available that are based on European TBEV strains: FSME-IMMUN (Baxter Bioscience, Orth an der Donau, Austria) with strain Neudoerfl, and Encepur (Novartis Vaccines and Diagnostics, Marburg, Germany) with strain K23. Since their introduction, both European vaccines have undergone several modifications and are manufactured by the same steps during the production process.[195] Viral antigens are propagated in chick embryo cells, filtered and inactivated by formaldehyde, and purified by ultracentrifugation. During the formulation, the antigens are adsorbed onto aluminium hydroxide and stabilized with human albumin (FSME-IMMUN) or sucrose (Encepur). Thiomersal was removed from both vaccine formulations in the 1990s to fulfill high safety and tolerability standards. The large envelope protein E induces the production of neutralizing antibodies important for the protective immunity. Due to the highly conserved structure of this antigen, broad cross-protection by the vaccines could be shown against TBEV of all three subtypes.[196] The conventional immunization schedules for primary immunization are similar for both vaccines, with three intramuscular doses given on 0, 21–90 days and 9–12 months. Thus, both vaccines induce antibody concentrations that are believed to be protective in over 90% of children and adults.[188] Thus far, the protective amount of antibodies is not clearly defined and standardized for both vaccines. Besides vaccines for adults, both European vaccine manufacturers offer pediatric vaccine formulations containing half the dose of viral antigen of the adult ones to improve tolerability in children. Data regarding the persistence of postimmunization antibodies led the manufacturers to change their recommendations.[195] Regular boosters are recommended every 5 years for individuals 49 years of age or less (except for the first booster after 3 years). In individuals 49 years of age or more, a 3-year-booster interval is recommended due to the significant gradual decline of postimmunization antibodies.

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