tick-borne encephalitis (tbe, fsme) · pdf filetick-borne encephalitis (tbe, fsme) monograph...

Tick-Borne Encephalitis (TBE, FSME)

Monograph

Monograph_TBE.qxd 04.04.2007 13:08 Uhr Seite 1

1_Introduction ................................................4

2_Etiology ......................................................6

2.1. The TBE virus .......................................6

2.2. Virus transmission.................................7

2.2.1. Transmission through ticks ..............7

2.2.2. Other routes of transmission ...........7

2.3. TBE natural foci ....................................8

2.4. The vector ( Ixodes ricinus) .....................8

2.4.1. Developmental cycle .......................9

2.4.2. Seasonal t ick activity ....................10

2.4.3. Mechanism of transmission............10

2.4.4. Mixed infection of ticks ................11

2.5. Hosts .................................................11

2.6. The biotope........................................12

3_Epidemiology ............................................15

3.1. Distribution of TBE natural foci ............15

3.2. TBE incidence in man ..........................17

3.2.1. Seroprevalence .............................17

3.2.2. TBE incidence in different age groups ..................................18

3.2.3. Seasonal variations of TBE incidence ..............................18

3.2.4. Risk of contracting TBE .................18

3.2.5. Annual TBE morbidity ...................19

3.2.6. Mortality .....................................20

Content

Content

2


3

4_Clinical Description ...................................21

4.1. Clinical course and manifestations ........21

4.1.1. Stages of the disease ....................22

4.1.2. Pathogenesis ...............................26

4.1.3. Immune response .........................27

4.2. Laboratory findings .............................27

4.3. Prognosis ...........................................27

4.4. Pediatric cl inical description .................28

4.5. Mixed infections .................................28

4.6. Incidence and severity of TBE inrelation to other CNS viral diseases .......28

5_Therapy.....................................................29

6_Diagnosis ..................................................29

6.1. Laboratory diagnosis ...........................29

6.2. Differential diagnosis ..........................31

7_Prevention ................................................32

7.1. General preventive measures ................32

7.1.1. Control of t ick populations ...........33

7.1.2. Protective clothes and repellents ....33

7.2. Active immunization ............................33

References ....................................................35

Content


4

1 _ Introduction

In several European countries, tick-borne

encephalitis (TBE) is one of the most

important human infections of the central

nervous system. The disease agent, i.e.,

the TBE virus (TBEV), is transmitted

through tick bites. The virus persists in

what are called natural foci, where it circu-

lates among both vertebrate hosts (mainly

rodents) and the arthropod host (tick).The

disease occurs in Western and Central

Europe, Scandinavia, in the countries that

made up the former Soviet Union, and

Asia, corresponding to the distribution of

the ixodid tick reservoir. Most natural foci

are well described, but new TBE areas

could emerge and latent ones re-emerge.

At least 10000 cases of TBE are referred to

hospitals each year. TBE has also become

an international public health problem

because of the increasing mobility of peo-

ple traveling to risk areas. Today, the risk

of infection is especially high for all people

living in or visiting endemic areas who pur-

sue leisure activities out in nature.

The TBE virus is only rarely found in Bulga-

ria, Greece, Italy, Norway, Romania, and

Japan, with only sporadic cases reported

so far. In several European countries, no

TBE cases have occurred, among them

Great Britain, Ireland, Iceland, Belgium, the

Netherlands, Luxemburg, Spain, and Portu-

gal.

◗ The typical clinical picture of TBE is cha-

racterized by a biphasic course with non-

specific influenza-like symptoms, followed

by an asymptomatic interval and a second

stage of the disease with at least four cli-

nical manifestations of varying severity,

i.e., meningitis, meningoencephalitis,

“Even though TBE was first described as early as 1931,this dangerous form of encephalitis has been underestimated for a long time.”

(C. Kunz, MD, co-inventor of the first Western-European TBE vaccine, Vienna)

Introduction


TBE virus is common in endemic foci in

5

meningoencephalomyelitis, and meningo-

radiculoneuritis. Patients may also expe-

rience just one of these phases. Hospitali-

zation varies between days and months.

Up to 46% of patients are left with perma-

nent sequelae requiring many years of

treatment and rehabilitation.1)

◗ Diagnosis: Because the clinical symptoms

are not specific for TBE, the disease can

only be diagnosed accurately by means of

laboratory techniques. During the first

phase of the disease, the virus can be iso-

lated from the blood (PCR). Specific dia-

gnosis usually depends on detection of

specific IgM and IgG serum antibodies by

ELISA.

◗ Case definition: A confirmed case of TBE

is defined as a febrile patient with clinical

signs or symptoms of meningitis or menin-

goencephalitis, mild to moderate elevation

of cell counts in CSF, and the presence of

serum IgM and/or IgG antibodies against

the TBE virus.

◗ Therapy: No causal therapy for TBE is

known. In contrast to Lyme borreliosis,

another tick-borne disease of similar epi-

demiologic importance in Central Europe

which can be managed by administration

of antibiotics, no effective therapy exists

against TBE.

◗ Prevention: TBE can easily be prevented

by vaccination. The Austrian experience

gives clear evidence that a high vaccina-

tion coverage effectively reduces the inci-

dence of TBE.

The clinical picture of TBE was first descri-

bed in Austria in 1931 by H. Schneider.2)

Shortly afterwards, it was observed in the

Far East of the former USSR, and from

1939 onwards also in the European part of

the Soviet Union. In 1948, the virus was

isolated for the first time outside the for-

mer USSR.3) In subsequent years, TBE was

also identified in other European countries.

The name ‘tick-borne encephalitis’ refers

to the tick as the main vector of infection.

Synonyms for TBE are spring-summer-

meningoencephalitis, Central-European

encephalitis, Far-East Russian encephalitis,

Taiga encephalitis, Russian spring-summer

encephalitis, biundulating meningoence-

phalitis, diphasic milk fever, Kumlinge dis-

ease, or Schneider’s disease. In German,

the disease is referred to as ‘Frühsommer-

Meningoenzephalitis’ (FSME).

Introduction

TBE virus is common in endemic foci in

Albania France Poland

Austria Germany Romania

Belarus Greece Russia

Bosnia Hungary Serbia

Croatia Italy Slovakia

Czech Republic Latvia Slovenia

Denmark Liechtenstein Sweden

Estonia Lithuania Switzerland

Finland Norway Ukraine


6

Figure 1: Electron micrograph of TBE virus

2 _ Etiology“The different subtypes of TBE virus in Europe and Asia are antigenically closely related –

a prerequisite for the prevention of TBE with a single vaccine strain.”

(F.X. Heinz, PHD, Vienna)

E

M

C

Figure 2: Schematic representation of

TBE virus (F.X. Heinz)

Etiology

2.1. The TBE virus

The TBE virus (TBEV), like the causative agents

of yellow fever, Japanese encephalitis, and den-

gue fever, is a member of the flavivirus genus

belonging to the flaviviridae family.4) Most flavi-

viruses are what are called arthropod-borne

viruses, or arboviruses, because of their specific

route of transmission by infected ticks (e.g., TBE

virus, Louping ill virus) or mosquitoes (e.g., yel-

low fever virus, dengue viruses, West Nile virus,

and Japanese encephalitis virus).

Flaviviruses are spherical, lipid-enveloped RNA

viruses with a diameter of approximately 50nm

(Figure 1). They contain only 3 different structu-

ral proteins, i.e., proteins C (capsid), protein M

(membrane), and protein E (envelope)5, 6) (Figure

2). Protein C is the only protein component of

capsid, which encloses a positive-stranded RNA

approximately 11000 nucleotides in length.7)

This RNA codes for the three structural proteins

and a set of 7 non-structural proteins required

for virus replication in the cell.5)

The proteins E and M are incorporated in the

viral membrane. Glycoprotein E, the main com-

ponent of the viral surface (Figure 2), is respon-

sible for the formation of neutralizing antibodies

and the induction of protective immunity. By

isolating a soluble, crystallizable form of the TBE

virus protein E,8) it was possible to elucidate its

three-dimensional conformation using X-ray dif-

fraction analysis.9)

Structural analysis (Figure 3) has shown that

protein E, unlike the envelope proteins of many

other lipid-enveloped viruses, does not form spi-


7

Figure 4: Ixodes ricinus – larva, nymph fasting and replete, male replete and

fasting, female fasting and replete (A. Liebisch)

ke-like projections, but is aligned parallel to the

viral surface (Figure 2).

Antigen analyses using monoclonal antibodies

and comparisons of sequences of various virus

isolates have shown that the TBE virus is fairly

homogeneous in endemic areas of Europe

(European subtype) and is not subject to signifi-

cant antigenic variations under natural environ-

mental conditions.10, 11)

Two further subtypes (Siberian and Far Eastern)

have been identified, which predominately circu-

late in the Asian part of Russia, Northern Japan,

and Northern China. These subtypes are closely

related to the European subtype, having a

94-95% identity in their E-protein amino acid

sequences. The European strains are mainly

transmitted by Ixodes ricinus, whereas the Sibe-

rian and Far Eastern strains are transmitted

mainly by I. persulcatus. Because of their close

antigenic relationships, there is cross-protection

between the different TBE virus subtypes.12) All

subtypes are closely related both antigenically

and phylogenetically.

2.2. Virus transmission

2.2.1. Transmission throughticks

Ticks are the chief carriers (vectors)

and reservoir hosts of the TBE virus in

nature. The lack of digestive enzymes

in the tick gut favors the survival of

ingested microorganisms and may explain why

ticks transmit a greater variety of pathogens

than any other group of arthropods.13) Their

ability to feed on the blood of a variety of host

animals and to adapt to domestic animal spe-

cies, as well as their long life cycle make them

ideal vectors for a variety of pathogens (rickett-

siae, spirochetes, other bacteria, fungi, protozo-

ans, nematodes, viruses), among them the TBE

virus.

The TBE virus can be transmitted to man or

other hosts by larvae, nymphs, or adult ticks

(Figure 4).

2.2.2. Other routes of transmission

Infection by the alimentary route resulting from

ingestion of raw milk has been reported in Slo-

vakia, Poland, and other Eastern European

countries. Recently, the family outbreaks of TBE

in Lithuania have reappeared. It is reported that

in the year 2000 4% of TBE patients were infec-

ted via unboiled milk.14) Also, in Slovakia, goats

and sheep play an important role in alimentary

TBE infections.15) Since 1974, more than 50

cases of TBE have occurred in Slovakia after the

Figure 3: Diagram showing the three-dimensional structure

of the protein E, laterial view (courtesy of Nature)

Etiology


patients had eaten cheese made from raw

sheep milk or drunk home produced raw goat

or sheep milk.15)

Laboratory infections have likewise been repor-

ted.16) Although not observed so far, man-to-

man transmission is also a theoretical possibility,

e.g., through blood transfusion from a viremic

to a healthy person.17)

2.3. TBE natural foci

A natural focus, as defined by Pawlowsky, is a

“region of distinct geographic features and ecolo-

gical settings where by way of evolution a certain

interrelationship between the species has develo-

ped, i.e. by the pathogen (microorganism) on the

one hand and its carrier (vector) on the other. The

latter transmits the pathogen from a vertebrate

host, acting as the donor of infection, to another

– recipient – host under environmental conditions

that are either conducive or adverse to further cir-

culation of the agent in such biozoonoses”.18)

The continental distribution of TBE in Europe is

statistically associated with a specific pattern of

the seasonal dynamics of Ixodes ricinus, and a

particular characteristic of the seasonal land sur-

face temperature profile.19) The development of a

TBE natural focus also depends on the coinciden-

ce of other factors (Table 1).

Circulation of the TBE virus also depends on the

population density of ticks and their hosts. Virus

prevalence in the tick population within TBE foci

is determined by the duration of viremia in hosts,

because the virus is mostly ingested by ticks whi-

le engorging on a viremic host. Virus circulation

in nature is also influenced by the percentage of

immune hosts in a particular region.

The properties of the biotope also play a role in

the development of TBE foci. In Austria, more

than 90% of all natural foci are within the 7°C

annual isotherm. Rare isolated natural foci have

been observed up to a height of 1300 meters

above sea level.21)

Climate is another determinant of tick-borne

disease dynamics. Even if the major discontinui-

ties in TBE incidence cannot be explained satis-

factorily by the recorded temperature increases,

the seasonal shifts in reported cases of TBE in

Central and North-Eastern Europe suggest that

TBE virus transmission dynamics have changed –

perhaps as a result of warmer temperatures.20)

Although the dependence of TBE on temperatu-

re is not a direct one and various factors could

be involved, an impact of climate warming on

the vertical disease distribution in Central Europe

is evident.22)

Tick activity also depends on soil humidity and

relative humidity. The critical water equilibrium

for I. ricinus is at 92% relative humidity. Without

blood feeding, individual ticks can survive at a

higher relative humidity for several months, but

they soon perish at levels below 92% relative

humidity.23)

2.4. The vector – the ixodid tick

Throughout the world, 850 tick species have

been described. Eight members of the family of

hard ticks have become notorious as carriers of

disease agents in our climate. Ixodes ricinus, the

common castor-bean tick, is the most important

and most common tick species in Europe (Figure

4) and, thus, mainly responsible for the spread

of TBE virus (Western subtype) in Europe. The

8

Factors governing the formation of TBE foci Factors governing the formation of TBE foci

• Population density and dynamics of infected ticks and their hosts

• Susceptibility of individual hosts

• Proportion of immune hosts

• Properties of the biotope

• Temperature

• Sociological changes

Table 1

Etiology


9

Far-Eastern subtype of the TBE virus is found

mainly beyond the Ural mountains;17) its primary

vector is Ixodes persulcatus.

The scientific name of I. ricinus is derived from

the replete tick’s close resemblance to a ricinus

seed or castor bean. A fasting adult female is 3-

4 mm in size, while male ticks are about 2.5

mm long.24) The body, which is variously covered

with hairs as well as warts and rings, is vastly

extensible in the female and often takes on a

light grey color after blood feeding. The female

can take in up to 100-200 times its own body

weight in blood, thus increasing its volume

approximately 120 fold.25) I. ricinus is equipped

with piercing and sucking mouth parts (chelice-

rae and hypopharynx)26) (Figure 5). The saliva of

blood-feeding ticks contains numerous bioactive

components with a broad spectrum of pharma-

cological properties, among them anti-coagu-

lants, enzymes and inhibitors, local anesthetics

and anti-inflammatory compounds, toxins and

other secretions, such as cement for anchoring

the mouth parts in the host’s skin.27)

By use of sense organs, the tick can react to

thermic, chemical, and physical stimuli, such as

vibrations or changes in temperature caused by

a passing host. The CO2 and butyric acid

discharged by the host are also thought to play

a role.28)

2.4.1. Developmental cycle

The common castor-bean tick I. ricinus spends

most of its life free-living on the ground or

among vegetation. The ticks are characterized

by a comparatively long life cycle, lasting several

years during which the infecting virus may be

maintained from one developmental stage of

the tick to the next (Figure 6). Hence, ticks act

as highly efficient reservoirs of flaviviruses. Many

tick-borne flaviviruses are transmitted vertically,

from adult to offspring, although the frequency

is too low to maintain the viruses solely in the

tick population. Instead, the survival of tick-bor-

ne flaviviruses is dependent on horizontal trans-

mission, both from an infected tick to a suscep-

tible vertebrate host and from an infected verte-

brate to uninfected ticks feeding on the ani-

mal.29)

Copulation usually takes place on a host prior to

blood feeding. Following copulation, the female

spends six to eleven days feeding on blood and

during subsequent months deposits 500 to

5000 eggs (Figure 7) in several places in the loo-

se top layer of the soil.30) Several weeks later, lar-

vae measuring 0.6-1.0 mm hatch from the

eggs. Unlike the subsequent developmental sta-

ges (nymph and imago), larvae only have three

pairs of legs, no stigmata, and no sexual open-

ings.30)

In each stage of development from larva to

nymph and imago, ticks have to feed on a ver-

tebrate host at least once before they can deve-

lop into the next stage. Male ticks do not feed

on blood, but take only a small amount of tis-

sue fluid during a short feed.31) Larvae feed on a

host for two to five days before they drop off

and molt into nymphs. These feed on a verte-

brate host again for two to seven days and

metamorphose into adults (imagos).

Figure 5: The mouthpart of Ixodes ricinus

Etiology


The duration of the developmental cycle of

one tick generation from egg to oviposition

by a fertilized female varies, according to the

literature, between six months and eight

years.32, 33) The average time in Central Europe

is thought to be two years (Figure 6), al-

though in adverse environmental conditions

each stage of development may take longer.

2.4.2. Seasonal tick activity

All developmental stages of I. ricinus hiberna-

te under leaf litter in places where the tempe-

rature may be as low as 0°C, or for short peri-

ods even lower, and where relative humidity

amounts to at least 92%. Eggs and starved

larvae perish at temperatures below –7°C.34)

Tick activity starts when the soil temperature

rises to 5-7°C in March or April and ends late in

the year35) when the average air temperature has

declined to about the same values in October or

November.

The seasonal peaks of tick activity depend on

climatic factors. In Central Europe, a two-peak

incidence curve has been observed for all devel-

opmental stages,36) with maximum activities in

May or June and September or October (Figure

8). In Northern Europe and in mountain regions,

these two peaks converge into a single maxi-

mum in the summer months. In Mediterranean

areas, maximum tick activity occurs between

November and January.23)

Wet summers and mild winters tend to increase

the tick population density. Warmer springs

(March-May) might permit an earlier onset of

questing activity, while raised temperatures

throughout the spring-autumn period (March-

September) would accelerate inter-stadial deve-

lopment.20)

Female ticks feeding in spring start to deposit

eggs in early July. The larvae hatch in the same

year, but mostly find their host in the following

spring. Larvae and nymphs feeding in spring or

early summer undergo metamorphosis and, in

the same year, appear as the next stage of deve-

lopment. The activity of the larvae of I. ricinus

usually starts one month later than that of

nymphs and adults.38)

2.4.3. Mechanism of transmission

The TBE virus in I. ricinus can be transmitted

either from one development stage to the next

(trans-stadial transmission) or from fertilized

female to egg (trans-ovarian transmission) (Fig-

ure 9). Usually, larvae and nymphs become

infected by feeding on viremic hosts. As nymphs

or imagos, they then pass on the virus to other

warm-blooded vertebrates. Ticks themselves do

not develop the disease.

The virus hibernates in ticks. Once a tick is infec-

ted, it carries the virus for life. In the period that

precedes molting, the virus multiplies in the tick

and invades nearly all its organs.39)

Female ticks usually transmit the virus to a single

host only. Male ticks feed more often and, in

this way, may infect several vertebrates.40)

After attachment to the host, twelve hours may

pass until the tick starts feeding. On humans,

ticks prefer to attach themselves to the hair-

covered portion of the head, behind the ears, to

10

Figure 6: Developmental cycle of Ixodes ricinus

moulting

moulting

nymph

fox

mouse

mouse

hedgehog

nymphnymph larva

larva

eggs

replete femaleroe deer

imago

Etiology


11

Figure 7:

Some time after copula-

tion, the female, having

expanded to 200 times

of its former volume,

deposits up to 5000

eggs before dying. The

second picture shows a

larva crawling on eggs.

the elbows and backs of knees, hands, and feet.

Owing to the anesthetizing effect of the tick’s

saliva, which contains analgesic, anti-inflamma-

tory, and coagulation-inhibiting substances, the

procedure causes no pain and often passes

unnoticed by the host.30)

The TBE virus is transferred to the host through

the saliva of an infected tick. Conversely, TBE

virus contained in host tissue enters the tick’s

intestine with blood feeding. A tick does not

need to feed for a long time to pass on the

infection – a short feed of tissue fluid by a male

tick may suffice to transmit the virus.41) Tick bites

often go unnoticed, which may be the main

reason why persons with manifest TBE frequent-

ly cannot remember having been bitten by a

tick.

2.4.4. Mixed infection of ticks

The spread of mixed infections with natural

focality transmitted by ixodid ticks is a well

recognized phenomenon.42) I. ricinus ticks

coinfected by Borrelia burgdorferi, Babesia

microti, and Ehrlichia phagocytophila are com-

mon. Various combinations of pathogens simul-

taneously infecting the same ixodid tick have

been described. The main combinations are TBE

virus and Borrelia spp. or TBE virus and Coxiella

burnetii.43)

A Russian survey found that more than one-

third of all infected tick individuals were multi-

infected. Among these, more than 80% were

dually infected and 13% contained three spe-

cies of pathogens simultaneously. The prevalen-

ce of mixed infection by Borrelia and TBE virus

in adult ticks varies depending on tick species

and natural focus, reaching 5-10% in some pla-

ces.44) The presence of Borrelia in ticks has no

apparent effect on the TBE virus and vice versa,

showing that these pathogens do not interfere

with each other within the tick.44)

2.5. Hosts

The common castor-bean tick

acts as a parasite on more than

100 different species of mam-

mals, reptiles, and birds. Table

2a and b give a selection of the

most important hosts.

TBE virus infection of I. ricinus by

a host harboring the virus is only

possible during the viremic stage

in the host and if the TBE virus

titer in blood is high enough. For

most hosts, the TBE virus is apa-

thogenic, i.e., these hosts hardly

ever develop the disease.

Figure 8: Seasonal dynamics of Ixodes ricinus in a TBE natural focus37)

Etiology


An infected host develops specific antibodies to

the TBE virus and then remains immune to re-

infection for life. Under these aspects, TBE virus

circulation in nature would soon come to an

end. Thus, virus persistence in a natural focus

depends on the following conditions:

• a population of hosts with a sufficient dura-

tion of viremia and a high virus titer,

• a sufficient number of young animals suscep-

tible to infection,

• different species of hosts,

• large vertebrate hosts serving as feeding

targets for numerous ticks.

◗ Duration of viremia: In small mammals,

such as the yellow-necked field mouse, the red-

backed vole, the common vole, and the hazel

mouse, a long viremic stage (2 to 8 days) and

high virus titers are observed.39) Therefore, ticks

are most likely to become infected by feeding

on these hosts, in which the TBE virus can even

hibernate.

In large mammals (roe, goat), viremia is short-

lived, and only low virus titers are reached.

However, recent findings suggest that, with seve-

ral ticks feeding on large mammals, non-viremic

transmission of the virus to ticks may also play a

role in the virus cycle.45) During the viremic stage,

milk from goats, cows, and sheep contains the

virus and may be a source of infection for man.

Birds only pass through a very short viremic sta-

ge and play no role as reservoirs of TBE virus.

However, they often serve as hosts for the

immature stages of I. ricinus and may contribute

to the spread of infected ticks.46)

Man is only of minor importance for ticks as a

source of sustenance and infection. In the chain

of virus transmission, man is a dead-end host.

2.6. The biotope

TBE focal areas normally exist in biotopes where

I. ricinus and its hosts find optimal living condi-

tions. Infected ticks are frequently found on

forest fringes with adjacent grassland, glades,

riverside meadows and marshlands, forest plan-

tations with brushwood and shrubbery, on the

transition between deciduous and coniferous

forests, or between timber and coppic. Oak and

hornbeam as well as beech and fir woods with

rich undergrowth of weeds, ferns, elder, hazel,

and bramble bushes provide an ideal habitat for

ticks (Figure 10). Sites of infestation are fre-

quently situated on sunny slopes facing south

and having a low plant cover of shrubs and

hedges.47)

Such rural landscapes, especially when benches,

cross-country tracks, or barbecue pits are provi-

ded, attract many people so that an increased

risk of infection must be expected. It has been

shown in various studies that TBE natural foci

are usually not eliminated by cultivation of the

landscape.48) Exposure to ticks is also possible in

newly created gardens. Ticks may also be trans-

ported to homes by way of dogs, flowers, bran-

ches, or on clothing.26) Reducing the habitats of

small mammals to a few areas not suitable for

cultivation also leads to an increased circulation

of TBE virus, because the probability of virus

transmission rises with the population density of

the hosts.

Contrary to a widespread belief, ticks do not sit

on trees and jump down onto their hosts, but

rather prefer vegetation that is closer to ground

level. Larvae are usually found on grass up to a

12

Figure 9: TBE transmission cycle in a natural focus,

showing man as a dead-end host

Etiology


13

Vertebrate hosts of Ixodes ricinus which may transmit the virus – Wild animalsVertebrate hosts of Ixodes ricinus which may transmit the virus – Wild animals

Ticks may bite birds or bats, thus becoming airborne.

Many ground-dwelling animals, such as various species of mice and lizards, attract ticks.

Hosts below and above ground include mole, weasel, marten, badger, porcupine, and squirrel.

Predators and prey alike attract ticks – from insectivores, such as hedgehog or shrew, to carnivores,such as fox and hare.

Ticks also feed on larger mammals, such as wild boar, mouflon, roe deer, and red deer.

Table 2a

Etiology


level of 30 cm, nymphs on herbs and plants of

less than 1 m, and imagos on weeds or shrubs

up to 1.5 m high.39)

Keeping to the underside of foliage, ticks mostly

sit at the ends of leaves or branches next to

footpaths and the trails of wild animals, from

where they drop onto their hosts or are brushed

off by them. In adult humans, ticks tend to

attach themselves to the legs or the gluteal and

genital regions. In children, 75% of tick bites

are observed on the head. In the remaining

cases, legs and arms, the trunk, and the gluteal

and genital regions are affected.

14

Vertebrate hosts of Ixodes ricinus which may transmit the virus –Domestic animalsVertebrate hosts of Ixodes ricinus which may transmit the virus –Domestic animals

Ticks suck blood from animals, such as dog, horse, sheep, goat, cattle – and, of course, humans.

Figure 10: Typical TBE biotope

Table 2b

Etiology


15

3 _ Epidemiology“TBE is endemic in regions of 27 European countries and

every year we detect new risk areas.”

(J. Süss, PHD, Jena, 2005)

Knowledge about the distribution, persistence,

and intensity of tick-borne diseases enables us

to characterize and predict transmission foci and

to recommend preventive measures. To investi-

gate the epidemiology of TBE, several methods

can be employed:

• Describing clinical cases and their geographi-

cal localization

• Examination of ticks for the presence of the TBE

virus (by PCR)

• Serological screening of tick-exposed persons

3.1. Distribution of TBE natural foci

The distribution of the TBE virus in ticks and

vertebrate hosts covers almost the entire sou-

thern part of the nontropical Eurasian forest

belt, from Alsace-Lorraine in the west to Vladi-

vostok and the northern and eastern regions of

China in the east (Figure 11). The true extent of

TBE infections has only become clear during the

past few years. Little is known about the rate of

infection in China. In 1998, an isolated en-

demic area was identified in Hokkaido, Japan.49)

The development of new natural foci and the

stability of known endemic areas are determi-

ned by the factors listed in Table 1. The number

of infected ticks in known natural foci may vary

from year to year.

Widely differing figures are also given for TBE

virus prevalence in the tick populations in the

endemic areas of various European countries

(Table 3). Usually, questing ticks are collected by

flagging in special tick monitoring sites, and TBEV

prevalence is investigated by examining individual

ticks or tick pools. When investigations are car-

ried out on ticks removed from humans, the

TBEV prevalence can be up to ten times higher.51)

The techniques of investigating TBEV prevalence

in unfed versus partially engorged ticks are not

standardized. Therefore, the prevalence values

cannot be compared across Europe.52, 54) Because

ticks are usually infected for life, the degree of

virus prevalence increases during their develop-

ment from egg to adult arthropod. Compared to

nymphs, 3 to 5 times more adult ticks are infec-

ted with the TBE virus.33)

TBE virus prevalence in the tick population of endemic areas in several European countries

TBE virus prevalence in the tickpopulation of endemic areas in several European countries

Country Prevalence % Source

Austria >0.44 (max. 6.2) 55

Finland 0.07-2.56 56

Italy 0.05 57

Sweden 0.1-1 58, 26

Switzerland 0.10-1.36 46

Germany (high-risk areas) 0.3-5.3 52

1.7-26.6 (I. ricinus)Latvia

0-37 (I. persulcatus)51, 52

Slovakia 13.7 15

Table 3

Epidemiology


16

Table 4

Western subtype Eastern subtypeboth subtypes

Figure 11: Distribution map of the Western and Eastern subtypes of the TBE virus50)

In a number of hosts, the TBE virus prevalence is

much higher than in the tick population (Table 4).

On account of their longer life span, large mam-

mals can be repeatedly infested by infectious

ticks. Also, due to their size they often serve as

feeding targets for several ticks at a time. Either

of these factor is conducive to the transmission of

the TBE virus.

The risk of contracting TBE in the most affected

countries increased considerably between 1974

and 2003 (Figure 12). For example, in Lithuania

the incidence increased by an amazing 1033%

and in Germany by 574%. In addition to the al-

ready known risk areas, new risk areas formed in

Norway and possibly in the southern part of Swe-

den.53) Also, more and more single TBE cases have

recently been reported in non-risk areas. Along

with the shift of I. ricinus to higher altitudes, a

corresponding shift of TBE to higher altitudes has

been expected. The only exception to this in-

crease in TBE incidence is Austria, where national

vaccination campaigns have lead to consistent

immunization, reducing the number of new

infections from 600 to about 60.

The increases in the frequency of hospitalization

are based on a multitude of factors. Evidently,

various factors work alongside, and this makes

interpretation of strongly differing annual hospi-

talization and virus prevalence patterns difficult.

The warming of the climate has been discussed

TBE virus or antibody prevalence amongvertebrate hosts in TBE endemic areasTBE virus or antibody prevalence amongvertebrate hosts in TBE endemic areas

Hosts Prevalence Source

Yellow-necked field mouse 47,9% 55

Red-backed vole 29,4% 55

Fox 18,0% 30

Deer 83,0% 59

Dog 2,0-5,6% 60

Goat 44% 57

Cattle 35,5-91,0% 61, 62

Epidemiology


as one of the reasons for an increase in tick pre-

valence. Table 5 summarizes ascertained contribu-

ting factors.

3.2. TBE incidence in man

3.2.1. Seroprevalence

Data on TBE seroprevalence in the general

population and among the inhabitants of en-

demic areas are presented in Table 6. In end-

emic areas of Austria and Southern Germany,

TBE prevalence has been found to be 4-8%. In

the most severely affected areas in the east and

southeast of Austria, a prevalence of up to 14%

may be reached. Prevalence is also extremely

high in some areas of the former USSR and for-

mer Czechoslovakia. A much higher percentage

of TBE positive individuals have been observed

among risk groups such as:

• Individuals working in agriculture and forestry

• Hikers, ramblers, people engaged in outdoor

sports

• Collectors of mushrooms and berries.

Today, most people (90%) who will ultimately

develop the disease come to TBE endemic areas

in pursuit of recreational activities. In Central

Europe and the Baltic states, recent increases in

TBE may have arisen largely from changes in

human behavior that have brought more people

into contact with infected ticks.67) In Russia, the

rigorous treatment of TBE natural focus territory

was discontinued for environmental concerns in

the 1980s. This may partly explain the increase

in the tick population and rate of infective ticks

in this region.68)

Infection with TBE virus may also happen at

home, when infected ticks are inadvertently car-

ried in with bunches of wild flowers, Christmas

trees,28) clothes, or by dogs. Moreover, TBE virus

infections are more and more frequently repor-

ted to have occurred in the patients’ own gar-

dens, even in urban areas.

Table 582)

Figure 12: Increase (%) in TBE incidence in Europe82)

Factors augmenting theincidence, prevalence, anddistribution of vector-bornedisease

Factors augmenting theincidence, prevalence, anddistribution of vector-bornedisease

1. Increase in the human population

2. Increased population density (urbanization)

3. Migration of populations to suburban areas

4. Changing leisure habits3.+ 4.: Greater exposure to vectors, i.e., ticks

Greater exposure to animal reservoir of infections

5. Displacement of human populations as a result of conflicts; introduction of exotic diseases

6. Changes in agricultural practices

7. Increased reforestation– increased density of deer population– increased deer tick population– increased incidence of Lyme disease

and babesiosis

Epidemiology

17


3.2.2. TBE incidence in different agegroups

The lowest incidences of TBE have been found

in children less than 3 years of age, with inci-

dence rising with increasing age. The highest

incidence reported in children was in the Khaba-

rovsk region in Russia, where 26% of TBE cases

had occurred in children aged 0-14 years.69) In

Slovenia, children represented 23.5% of all con-

firmed TBE cases in the period between 1959

and 2000.70) In Austria, the 7- to 14-year-olds

used to be the age group with the greatest

annual incidence of TBE (19% of all cases).

Today, due to the Austrian vaccination program

and particularly the vaccination campaign in

schools, children between 7 and 14 years are

among the best-protected age groups (Figure

13). In Austria, most cases of TBE now occur in

older age groups.71) In Sweden, about 10% of

patients are younger than 15 years.72)

The youngest patient known thus far was a 6-

week-old infant. The oldest patient was 83 who

ultimately died, showing signs and symptoms of

meningoencephalitis.73) As for TBE prevalence in

the different age brackets, an increase with

advancing age has been observed in TBE focal

areas, although the prevalence in different end-

emic areas may vary.74)

3.2.3. Seasonal variations of TBE incidence

In many countries, two peaks of seasonal tick

activity are observed, i.e., in spring and fall. The

incidence of clinical cases of TBE lags about 4

weeks behind the seasonal tick activity (Figure

14). In some countries, including Poland, Ger-

many (Baden-Wuerttemberg), Sweden, the

Czech Republic, and recently also in Austria,

only one peak of TBE incidence has been obser-

ved, occurring in July and August.75, 76)

3.2.4. Risk of contracting TBE

Exact calculations of the risk of infection and

the resulting morbidity rates are extremely diffi-

cult to carry out, because tick bites often go

unnoticed. In areas endemic for TBE, virus trans-

mission may be estimated to occur in one of

about 3-200 tick bites, depending on the preva-

lence of TBE virus in ticks (Table 3). In the diffe-

rent TBE endemic areas, the risk of human

infection after a single tick bite varies between

1:200 and 1:1000.26)

According to estimates by Roggendorf et al. in

1989, the risk of infection in German endemic

areas was 1:900.80) It may be suspected that the

risk of infection in Germany is much higher

today. In a study of endemic areas in Sweden, the

annual incidence was found to be between 1.2%

and 2.4%, and the risk of infection following a

tick bite was estimated to be about 1:600.58)

TBE virus or antibody prevalence in thepopulation in TBE endemic areasTBE virus or antibody prevalence in thepopulation in TBE endemic areas

Country Population in endemic areas (%)

Austria 50, 55) 4-8 (14)

Slovenia 87) 4-13

Finland 89) 0.3-5

Poland 26, 65) 5-17

Norway (south) 90) 2.4

Sweden 4-22

France 26) 1-2

Estonia 26) 3-14

Germany (Baden-Württemberg) 64) 0-43

Lithuania 66) 3

Epidemiology

Table 6a

18

TBE virus or antibody prevalence of riskgroups in TBE endemic areas 46, 65)

TBE virus or antibody prevalence of riskgroups in TBE endemic areas 46, 65)

Country Prevalence (%)

Austria 41

Switzerland 4–16

Czech Republic 15–54

Table 6b


19

3.2.5. Annual TBE morbidity

Between 1997 and 2000, the average TBE inci-

dence rate in Germany with 82.2 million inhabi-

tants and 533 clinical cases was 0.17 per

100000 per year. In 2005, the TBE incidence in

Germany was 19.1 per 100000 population, and

based on preliminary data was even higher in

2006. In the German high-risk foci, the average

incidence rates were 0.29 in Bavaria and 0.87 in

Baden-Wuerttemberg. In Latvia, with 2.6 million

inhabitants and 2797 cases in the last four

years, the average annual incidence rate was

26.9 per 100000 population, placing Latvia

among the countries with the highest TBE inci-

dence world-wide.53)

Table 7 gives data on the annual morbidity of

TBE in several European countries. It is evident

that, in the past, morbidity among forestry wor-

kers in Austria was much higher than in the

general population. Since regular vaccination

campaigns have been carried out by the voca-

tional organizations involved in combating TBE,

morbidity in the most exposed groups has been

impressively reduced (see also Section 3.2.1.).

Before the annual vaccination campaign was

introduced in 1981, the incidence of TBE in

Austria was in the range of 600 cases per year.

As a result of the vaccination campaign with the

Austrian TBE vaccine, the incidence has declined

significantly, with only about 50 to 60 cases

recorded annually.86) These figures impressively

demonstrate the field effectiveness of the FSME-

Figure 13: Austria – a comparison of the TBE cases before and after the start of the national school

vaccination campaigns

Figure 13a:

Larvae and nymphs are

much smaller than the

adult female. Humans

rarely ever notice

nymphs, but they are

more frequent than

adult ticks.

Epidemiology


20

IMMUN vaccine by Baxter. At the time the cam-

paign started, it was the only TBE vaccine in

use.

3.2.6. Mortality

In very severe cases of TBE, death may occur

within the first week after onset. It has been

suggested that the Far-Eastern TBEV subtype is

more pathogenic for humans than the European

subtype, because the mortality rates in areas

where the Far-Eastern subtype is prevalent have

been reported to be significantly higher (5-20%)

than in Europe (0-3.9%).50)

However, the data of seroprevalence studies do

not support these findings. The prevalence of

antibodies to TBEV in populations living in the

endemic areas in Europe and Russia are in the

range from 1% to 20% and from 30% to

100%, respectively. This suggests that a large

proportion of mild diseases may not be diagno-

sed or may be underreported in some areas of

Russia. The apparent difference in the severity of

TBE in different areas may either reflect the true

difference in the clinical presentation or be a

result of different diagnostic criteria and patient

selection in the studies.88)Figure 14: Relationship between tick activity and incidence of CNS

disease in a TBE endemic area in Austria77, 78)

Figure 15a–c: A german TBE-patient –

he too was in need of artificial respiration

Epidemiology

Table 7

Annual morbidity from TBE in various European countriesAnnual morbidity from TBE in various European countries

Country Morbidity Source(incidence per 100000)

Austria• unvaccinated

general population 5.0 79

• forestry workers 98-100 81

Czech Republic 5.9 82, 83

Switzerland 0.4-7 84

Germany 0.2-5 52

Slovakia 0.2-1.6 15

Russia 1-6.5 85


21

4.1. Clinical course and manifestations

The typical course of TBE is diphasic in at least

two-thirds of patients.91) The incubation period is

7 days on average but may last between 2 and

28 days. The first stage, which may last for 2 to

8 days, corresponds with the viremic phase. It is

associated with non-specific systemic signs and

symptoms such as fatigue, headache, aching

back and limbs, nausea, and general malaise. In

most cases, the temperature rises to 38°C or

higher. Sometimes exceptionally high initial tem-

peratures above 40°C may occur (Figure 16).

The first stage of TBE is followed by an afebrile

interval lasting between 1 and 20 days. During

this time, patients are usually free of symptoms.

Another sudden and significant increase in tem-

perature marks the beginning of the second sta-

ge (Figure 16).

Not all individuals infected with the TBE virus go

through the entire course of the disease. In

approximately two thirds of infected individuals,

the infection remains either silent even though

viremia can be demonstrated or shows the clini-

cal picture of the initial stage of TBE (Table 8),

with symptoms subsiding without developing

into the second stage.

About one third of symptomatic patients pro-

ceed into the second stage of the disease after

the virus has spread to the CNS. 50-77% of

these patients go through the typical biphasic

course of the infection. In the remaining 23-

50%, the infection is not apparent during the

first stage and the onset of clinical illness coin-

cides with the beginning of the second phase of

the disease.

The course of infection with the Far-Eastern

variety clinically differs from the European form.

The onset of illness is more often gradual than

acute, with a prodromal phase including fever,

headache, anorexia, nausea, vomiting, and

photophobia. These symptoms are followed by

a stiff neck, sensorial changes, visual disturban-

ces, and variable neurological dysfunctions,

including paresis, paralysis, sensory loss, and

convulsions. In fatal cases, death occurs within

the first week after onset. The case-fatality rate

is approximately 20%, compared to 1-2% for

the European form,22, 93) but these figures may be

4 _ ClinicalDescription

Figure 16: Typical temperature curve in a case of TBE

after laboratory infection with the virus 24)

“With increasing age severe courses of disease accumulate,neuropsychiatric sequelae frequently persist.”

(R. Kaiser, MD, Pforzheim)

Clinical description


biased by the different

standards of medical treat-

ment available in Western

and Eastern Europe. It is

supposed that, in contrast

to the European form, the

disease caused by the Far-

Eastern variety is more

severe in children than in

adults. Neurological seque-

lae occur in 30-80% of sur-

vivors, especially residual

flaccid paralyses of the shoulder girdle and

arms. Little information is available on the viru-

lence of the recently described Siberian subtype

with respect to the course of disease in humans.

However, animal studies have demonstrated

that the limited number of Siberian subtype

strains studied have higher virulence in mice

than Far-Eastern strains.94)

4.1.1. Stages of the disease

◗ Incubation period: The incubation period

prior to the onset of the first stage in most

cases is between 7 and 14 days, but may last

from 2 to 28 days.

◗ First stage: On average, the first stage lasts

for 2 to 4 days (durations of 1 to 8 days have

rarely been observed) and corresponds with the

viremic phase. It is associated with uncharacteri-

stic flu-like symptoms (Table 8) and with an

increase in temperature to 38°C in most cases.

Sometimes, exceptionally high initial temperatu-

res may occur.

◗ Asymptomatic interval: The first stage is

followed by an asymptomatic interval lasting for

about 8 days (durations between 1 and 20 days

have been observed). During this period,

patients are usually without symptoms.

◗ Second stage: About 2 to 4 weeks after

infection, one third of patients passes into the

second stage of the disease, which is characteri-

zed by CNS involvement.95) The clinical picture is

that of meningitis, encephalitis, meningoence-

phalomyelitis, or meningoencephaloradiculitis

(Table 9). The mortality rate in adult patients in

Europe is about 1% and increases to about 3%

in patients with a severe course of TBE including

meningoencephalitis, meningoencephalomyeli-

tis, and dysfunction of the autonomic nervous

system.96) The patients have temperatures that

are often higher than temperatures associated

with other forms of viral meningitis or menin-

goencephalitis.97) The age distribution of the cli-

nical manifestations of the disease is shown in

Figure 17.

The main symptoms of meningitis are severe

headache, nausea and retching, nuchal rigidity,

and high fever (Table 10). Special attention

should be paid to the lack of meningeal symp-

toms in 10% of patients diagnosed with TBE.75)

Lack of meningeal signs in the course of TBE

does not exclude serious neurological complica-

tions.

Encephalitis is characterized by disturbances of

consciousness, ranging from somnolence to

sopor and, in rare cases, coma. Other symptoms

include restlessness, hyperkinesia of muscles of

limbs and face, lingual tremor, convulsions, ver-

tigo, and speech disorders (Table 10).

When cranial nerves are involved, mainly ocular,

facial, and pharyngeal muscles are affected. In

22

Flu-like symptoms during the first stage of TBEFlu-like symptoms during the first stage of TBE

• Fever >38.0°C

• Fatigue

• Headache

• Aching back and limbs

• Catarrhal symptoms of the upper airways

• Gastrointestinal symptoms

• Anorexia

• Nausea

Table 8



some cases, neuropsychiatric symptoms prevail,

and the patient is sent to a psychiatric ward.

The greatest extent of neurological abnormali-

ties of TBE is found in the meningoencephalo-

myelitic manifestation of the disease, which is

primarily characterized by flaccid paresis of the

extremities. Since TBE viruses have a particular

predilection for anterior horn cells of the cervical

spinal cord, paresis usually affects the upper

limbs, shoulder girdle and the head levator mus-

cles. Mono-, para- and tetraparesis may deve-

lop, including paresis of the respiratory muscles.

This clinical form of TBE closely resembles polio

virus infection. However, compared with polio-

myelitis, paresis in TBE tends to have a proximal

distribution and more often affects the upper

than the lower extremities. If the lesion spreads

to the lower portion of the brain stem, and par-

ticularly to the medulla oblongata, bulbar syn-

drome may develop, with the risk of sudden

death due to respiratory failure or circulation

disturbances. Bulbar syndrome can also be

observed in the meningoencephalitic form of

TBE without association of myelitis. It invariably

is a sign of an adverse prognosis.94)

Symptoms of polyradiculitis may occur 5 to 10

days after the remission of fever. These symp-

toms are usually accompanied by paresis of the

shoulder girdle.105) Paralysis may progress for up

to 2 weeks, followed by a moderate tendency

of improvement. Cases with paresis due to mye-

litis have only a slight tendency to regression

and are generally followed by pronounced mus-

cle atrophy. In a German study, all of the 15

patients with myelitis were left with residual

paresis.94)

23

Table 9: Different courses of severity of TBE

Figure 17: Age & clinical manifestation of TBE106)

Course of TBE as reported in publications involving large numbers of patientsCourse of TBE as reported in publications involving large numbers of patients

Meningo- Meningo- Meningo-Reference n Meningitis

encephalitis encephalomyelitis encephaloradiculitis

98 286 161 (56.3 %) 98 (34.3%) 27 (9.4%)

99 117 72 (61%) 28 (24%) 17 (15%)

100 805 398 (49%) 354 (43%) 23 (3%) 30 (4%)

101 549 393 (71.6%) 111 (20.2%) 45 (8.2%)

102 38 20 (52.6%) 12 (31.6%) 6 (15.8%)

103 100 60 (60%) 32 (32%) 3 (3%) 5 (5%)

104 120 70 (58%) 39 (33%) 11 (9%)

75 152 51 (34%) 89 (59%) 12 (8%)

91 850 400 (47%) 356 (42%) 93 (11%)

Total 3017 1625 (53.9%) 1119 (37%) 272 (9%)



24

Systemic manifestations in the second stage of TBESystemic manifestations in the second stage of TBE

*may occur in all manifestations

Symptoms

MeningomyelitisMeningitis Meningoencephalitis

Meningoencephalomyelitis

• Fever • Meningeal symptoms • Meningeal symptoms

• Headache • Lack of drive • Facial paresis

• Nausea • Increased inclination to sleep • Paresis of the upper

• Vomiting • Disturbed sleep and/or lower limbs

• Retching • Somnolence/unconsciousness • Atonic paresis in the region

• Vertigo • Nystagmus of the shoulder girdle

• Photophobia • Tremor capitis • Phrenic nerve paresis

• Nuchal rigidity • Lingual tremor • Lesions of the medulla

• Slight pharyngeal catarrh • Speech disorders oblongata and the central

• Presence of Kernig’s sign • Hyperesthesia portions of the brain stem

• Passive and intention tremor • Bulbar paralysis

• Gait ataxia • Toxic damage of the

• Hyperkinesia of the muscles liver parenchyma*

of limbs and face • Severe myocarditis*

• Transient Babinskis sign • Life-threatening conditions

• Abnormal reflexes

• Cranial nerve paralysis

• Hemiplegia

• Cerebropsychotic episodes

• Pain in arms and/or legs

• Cystoplegia

• Facial pareses

• Ophthalmoplegia

• Disorders of the autonomic

nervous system

• Hallucinations

• Mental disorders with severe psychosis



25

“TBE is a serious case of

acute central nervous system

disease, which may

result in death or long-term

neurological sequelae in

35–58% of patients.”(WHO, State of the Art of New Vaccines:

Research & Development 2003)

Prognosis

MeningomyelitisMeningitis Meningoencephalitis

Meningoencephalomyelitis

Usually full recovery. In some patients sequelae The following sequelae

In individual cases have been reported to persist have been observed:

sequelae may persist for several years, e.g., • Spinal paralysis

for several months, e.g., • Headache • Facial paresis

• Headache • Lack of concentration • Cerebellar insufficiency

• Lack of concentration • Decreased vitality • Atrophic paresis, particularly in

• Disorders of the auto- • Auton. nerv. system disorders the region of the shoulder girdle

nomic nervous system • Mood disorders In about 2 % of patients

• 19% of patients reported • Psychic handicaps the disease is lethal*.

some cognitive dysfunc- • Ophthalmoplegia

tion affecting quality of • Facial paresis

life after one year. • Hearing impairment

Lethal courses

have been observed.

*may occur in all manifestations Table 10



26

◗ Post-encephalitic syndrome: Post-menin-

goencephalitic syndrome may occur after TBE. It

impairs the quality of life, causes high costs to

health care systems with long periods of hospi-

talization and inability to work as well as long-

lasting neurological symptoms and social distress

of the patients.107) Although severe manifesta-

tions usually subside after 1 to 3 weeks, TBE

may cause long-lasting, mainly cognitive, CNS

dysfunction, and the convalescence period may

be very long.108)

According to a literature review by M. Haglund

and G. Günther in 2003, the incidence of

sequelae following TBE varies between 35%

and 58%.109) In Austria, 10% to 20% of patients

with a severe course of TBE have been reported

to develop long-term or permanent neuro-psy-

chiatric sequelae, such as a severe headache,

dizziness, lack of concentration, depression,

disorders of the autonomic nervous system, hea-

ring impairment, and mood disorders. Next in

frequency are residual pareses and atrophies in

3% to 11%. The pareses usually tend to remit,

but in rare cases muscular atrophies may persist.

In some patients, a spasmophilic tendency has

been observed for as long as 4 years following

TBE infection.110)

The post-encephalitic syndrome causes major

expenses both to the health care system and to

society, because long-term working disability

ensues. Moreover, the long-lasting sequelae

have a substantial impact on the patients’ quali-

ty of life.

◗ TBE with hemorrhagic syndrome: 8 fatal

cases of tick-borne encephalitis with an unusual

hemorrhagic syndrome were identified in 1999 in

the Novosibirsk Region. Hemorrhagic fever was

associated with the Far-Eastern TBEV subtype.12)

4.1.2. Pathogenesis

The picture of manifest TBE depends on the

virulence of the virus and the individual resi-

stance of the patient. After the bite of an infec-

ted tick, the virus usually replicates in the der-

mal cells at the site of the tick bite. This replica-

tion in Langerhans cells, as well as in neutrophi-

lic granulocytes, is unhindered because of an

immunodeficiency induced by the tick’s saliva.

Furthermore, the TBE virus does not only use

Langerhans cells and granulocytes for replication

but also as vehicles to reach regional lymph

nodes via lymph capillaries.133) Thus, the virus

spreads via the lymphatic system and, a few

days later, reaches the bloodstream (viremia). It

then invades other susceptible organs or tissues,

especially the reticuloendothelial system (thy-

mus, spleen, liver), where massive virus replica-

tion takes place. Only after this stage is it possi-

ble for the virus to reach the central nervous

system. Because the capillary endothelium is not

easily infected, high virus production rates in the

primarily affected organs are a prerequisite for

the virus to cross the blood-brain barrier. Once

these endothelial cells have been invaded from

the lumen, the virus replicates and enters the

central nervous system by seeding through the

capillary endothelium into the brain tissue. The

TBE virus may also spread along nerve fibers.

This route may be especially relevant in labora-

tory infections by aerosols. After infecting the

neuroepithelial cells of the nasal mucous mem-

brane, the virus directly enters the brain via the


Figure 18: Atrophic shoulder

following TBE (R. Kaiser)


fila olfactoria. Considering the short incubation

period and the often extremely severe course of

such infections, this route of entry seems likely.41)

However, in arthropod-borne infections, neural

spread of the virus is of little importance.

Histopathological studies from lethal human

cases revealed neuronal and glial destruction,

spongiform focal necrosis, inflammation and

perivascular infiltration, cellular nodule forma-

tion, and edema. Residual pathological lesions

are characterized by neuronal loss and microglial

scarring.112) Detection of viral RNA during the

encephalitic stage of disease in cerebrospinal flu-

id (CSF) is difficult, which indicates that the main

pathogenic mechanism may be due to inflamma-

tory mediators, even if TBEV may be concealed

in the neurons without leaking into the CSF.

4.1.3. Immune response

A TBEV infection confers life-long protection,

and there is no known human case of sympto-

matic re-infection.

4.2. Laboratory findings

◗ Blood count: The typical changes in blood

count in TBE are as follows: With the onset of

the meningoencephalitic stage, the leukopenia

observed during both the first stage of the disea-

se and the asymptomatic interval disappears. It is

followed by transient leukocytosis, with leukocyte

counts that are considerably higher than in other

forms of viral meningitis (6600–14600/mm3).

Usually, leukocytosis changes into leukopenia

before the blood count returns to normal. The

blood sedimentation rate may be as high as

100mm/h.1) The frequency and extent of abnor-

mal values do not correlate with the diagnosis or

prognosis of TBE.91) Elevated C-reactive protein is

detected in more than 80% of patients.91)

◗ Cerebrospinal fluid: Pleocytosis, mainly of

lymphocytes, is observed in the CSF, reaching

maximum values of 5000/mm3 cells. Frequently,

cell counts of several hundred mm3 as well as

protein values between 50-200mg/dl are obser-

ved. Usually, it takes 4 to 6 weeks for the CSF

lab parameter values to normalize, but in indivi-

dual cases elevated values may persist for seve-

ral months.1)

4.3. Prognosis

Hospitalization is usually required for about 3

weeks, even though in severe cases it may last

up to several years. With increasing patient age,

especially in persons over 60, TBE is more likely

to take a severe course, leading to paralysis and

sometimes resulting in death.32) With the excep-

tion of CSF cell counts, which may indicate the

intensity of CNS infection and correlate with the

severity of the disease, the results of laboratory

examinations seem to have little predictive value

with regard to prognosis.75) Similarly, TBE antibo-

dy concentrations as detected by ELISA do not

correlate with the outcome of the infection,

whereas the neutralizing antibody titer – to-

gether with the CNS cell count – seems to be

more predictive of the clinical outcome. At the

onset of the disease, the presence of low con-

centrations of neutralizing antibodies in serum

and a high cell count in CSF might indicate an

unfavorable course of TBE.113)

27

Figure 19: MRT of a

5-year-old girl with

TBE. T2 sequence

shows significant

changes within both

thalami and the right

nucleus lentiformis

without enhance-

ment by contrast

medium (W. Zenz,

2003)



Figure 20: In Austria, a significantnumber of cases of viral encephali-tis can now be avoided.

4.4. Pediatric clinical description

TBE in children can run a severe course and may

lead to permanent sequelae. In children and juve-

niles, meningitis is the predominant form of the

disease, which is why the infection usually takes a

milder course with better prognosis than in adults.

Retrospective studies have shown TBE infection to

occur in infants as young as 3 months.132) A higher

incidence of TBE was reported in boys (ratio 7:3),

who more often show signs of focal encephali-

tis.108) There is a clear tendency for a more severe

course of TBE above the age of 7 years.114) Severe

cases have been reported even in young children115)

with permanent neurological sequelae, mild or

severe, such as headache, behavioral disorders, sei-

zures, and pareses.69) The most common symptoms

and signs of acute TBE in children are raised body

temperature (38°C), headache and meningeal

signs, fatigue and vomiting.70, 114) Cizman also

reports an unusually high rate of children aged 0–

15 years who were hospitalized (n=133) due to

severe TBE virus infection in Slovenia between

1993 and 1998 (Table 11).108) Symptoms of seque-

lae in children are headaches, sleep and concentra-

tion disturbances, vertigo, fatigue, and epileptic

disorders.1)

4.5. Mixed infections

Co-infections involving various combinations of

pathogens have frequently been described, and

some tend to be particularly severe. Diseases

caused by mixed TBE virus-Borrelia infections have

already been reported in several countries of Cen-

tral Europe.42) Co-infection with Borrelia burgdorf-

eri is reported in about 15% of patients on the

basis of seropositive results in serum and/or CSF.75)

In the majority of patients with concomitant infec-

tion, the clinical features at presentation were

characteristic of, or consistent with, TBE.116) It is

suggested that in confirmed cases of TBE in

patients with acute lymphocytic meningitis or

meningoencephalitis originating in TBE and Lyme

borreliosis endemic regions, an additional infec-

tion with Borrelia should be considered.116) If pre-

sent, borreliosis can be successfully treated with

antibiotics. There is some information in the litera-

ture that co-infection with B. burgdorferi sensu

lato might contribute to a more severe course of

TBE.96, 117) Similar findings of mixed infections have

been described in children, most commonly TBE

and Lyme borreliosis.114) Double infections occur

more frequently in areas where I. persulcatus ticks

are abundant.118) A study from the Czech Republic

demonstrated that TBE-human granulocytic ehrli-

chiosis (HGE) co-infections can also be encounte-

red in Central Europe.119)

4.6. Incidence and severity of TBE inrelation to other CNS viral diseases

According to a study conducted in 1958, the pro-

portion of TBE in the total number of CNS viral

diseases in Austria was 56% (Figure 19).120) Before

the start of the vaccination program, it was the

most important and most frequent disease of this

type in adults, with several hundred cases repor-

ted every year.

In Switzerland, TBE ranked fourth among viral

infections of the central and peripheral nervous

system in 1981, with only picorna, mumps, and

Varicella zoster infections being more frequent. In

some cantons, TBE was even the most frequent

cause of CNS diseases.121) In Germany,

TBE accounts for up to 50% of all

viral diseases,122) and in Lithuania,

TBE accounts for more than half

(53%) of all CNS infections.

28

56%


Hospitalized children in Sloveniaaged 0–15 years 1, 108)

Table 11

Hospitalized children in Sloveniaaged 0–15 years 1, 108)

48.5% had aseptic meningitis

48.5% had meningoencephalitis

3.0% had meningoencephalomyelitis

5.2% were admitted to the intensive care unit


29

5 _ Therapy“The bad news: You cannot abstain from TBE and therapeutic

possibilities are poor. But there is good news regarding prevention.”

(M. Kunze, MD, Vienna)

6 _ Diagnosis“It will only be possible to clearly identify the endemic TBE areas in Europe

when every case of meningitis is tested for a pathogen.”

(A. Mickiene, MD, Kaunas)

The diagnosis of TBE rests on the following pil-

lars:112)

• Epidemiological information: stay in a TBE risk

area, facultative history of a tick bite

• Clinical data: uncharacteristic and usually not

sufficient for diagnosis

• Demonstration of TBE-specific IgM and IgG

antibodies in serum (adequate evidence of

infection) and CSF

6.1. Laboratory diagnosis

Because of the nonspecific clinical features of

TBE, the definite diagnosis must be established

in the laboratory. The laboratory results have no

influence on the therapy of TBE and mainly ser-

ve to differentiate a TBE virus infection from

other causes of meningoencephalitis, which may

require special treatment.

The method of choice is the demonstration of

specific IgM and IgG serum antibodies by enzy-

me-linked immunosorbent assay (ELISA).124) As

the symptoms affecting the CNS are not usually

observed until 2 to 4 weeks after the tick bite,

the antibody test is almost invariably positive at

the time of admission to hospital. Soon after

infection, IgM antibodies are more specific,

Therapy | Diagnosis

No specific therapy for TBE is known so far.

Since there is no specific treatment targeting the

virus itself, symptomatic treatment of patients

with TBE is required. Strict bed rest for at least

10 days is imperative. In many Austrian hospi-

tals, encephalitis patients are referred to intensi-

ve care units for continuous surveillance as a

precaution. Only when their temperature is

down to normal and neurological symptoms

have subsided may the patient start to leave bed

briefly for washing and using the toilet. For

another 1 to 2 weeks, predominant bed rest is

recommended to avoid complications. Mainte-

nance of the water and electrolyte balances,

sufficient caloric intake, and the administration

of analgesics, vitamins, and antipyretics are the

most important lines in the clinical management

of patients. Physiotherapy of paralyzed limbs is

essential to prevent muscular atrophy.

Man is the dead-end host in the natural trans-

mission cycle of TBE. As man-to-man transmis-

sion of the virus has never been observed, there

is no need to isolate TBE patients.


while later, IgG antibodies are more reactive

(Figure 21). A recent infection can be establis-

hed by the qualitative determination of IgM.

Specific IgG antibodies and rheumatoid factors

do not interfere with the test. However, in cases

of other flavivirus contacts (e.g., vaccinations

against yellow fever or Japanese encephalitis;

dengue virus infections) the performance of a

neutralization assay (e.g., RFFIT, rapid fluore-

scent focus inhibition test) is necessary for asses-

sing immunity due to the interference of flavivi-

rus cross-reactive antibodies in ELISA and

hemagglutination inhibition test.123)

The high cross-reactivity rate of yellow fever and

TBE antibody-positive sera in dengue virus anti-

body assays should be taken into account in the

interpretation of laboratory tests for the diagno-

sis of flavivirus infections and when undertaking

seroepidemiological surveys.124) Neutralization

tests, such as the RFFIT, require handling infec-

tious virus, which makes the test cumbersome,

costly, and only available in highly specialized

virus laboratories. IgG antibodies are detected

by qualitative methods, e.g., they establish the

prevalence of TBE in the population or in a

group of patients or follow seroconversion after

active immunization and control of humoral

immune status.

In the past, antibody identification relied on four

tests, i.e., the hemagglutination inhibition, com-

plement fixation, plaque reduction neutraliza-

tion, and indirect fluorescent antibody (IFA)

tests. Positive identification using these IgM-

and IgG- based assays requires a four-fold in-

crease in titer between acute and convalescent

serum samples. The sensitivity and specificity of

new assays, e.g. IIFT (indirect immunofluore-

scence test), ELISA, and immunoblot test

systems, are considerably higher than those of

tests used in the past, and cross-reactivity with

related flaviviruses is significantly reduced.125)

In the viremic phase of the initial stage of the

disease before seroconversion, TBE virus can

also be identified by reverse-transcriptase poly-

merase chain reaction (RT-PCR), by electron-

microscopy, or by cultivation. In fatal cases, the

virus can be isolated or detected by RT-PCR from

the brain and other organs.123) Electron micro-

scopy and cultivation are not suitable as routine

diagnostic tools. In contrast to many other flavi-

viruses, the PCR method is not very useful for

the laboratory diagnosis of TBE in clinical practi-

ce.123)

The overall prevalence of TBE can be established

serologically, since the infection leads to

immunity for life and the presence of antibodies

to the TBE virus in the patient’s blood.

30

fever

lgG ablgM ab

viremianeurological symptoms

IgM antibodies in CSF

Diagnosis: VIS, PCR – serological tests

>

>

therapy

Figure 21:

Biphasic course

of a TBE virus

infection

(F.X. Heinz, 2005)

4–14 d.incubation period

2–3 d.interval

~ 3 weeksphase 2

2–5 d.phase 1

Diagnosis


31

6.2. Differential diagnosis

Fever, headache and meningism associated with

signs of inflammation in serum (leukocytosis,

elevation of the sedimentation rate and of C-

reactive protein), and predominance of neutro-

philic cells over lymphocytes in the CSF are main

findings in patients with TBE, but are also highly

indicative of bacterial meningitis. Consequently,

most patients are treated with antibiotics – at

least until the TBE serology is found to be positi-

ve.123)

Thus, many viral and bacterial infections have to

be considered in the differential diagnosis of

TBE (Table 12). Lyme disease (lyme borreliosis)

has been recognized as the most frequent vec-

tor-borne disease in mild climate areas and has

to be included in the differential diagnosis of

TBE. Its causative agent, the Borrelia burgdorferi

sensu lato complex (B. burgdorferi sensu stricto,

B. garinii and B. afzelii), is transmitted by ticks

and other arthropods. In our part of the world,

the incidence of lyme borreliosis is higher than

that of TBE. Contrary to TBE, the various stages

and the manifestations of lyme borreliosis occur

facultatively; transitions may be indistinct. High-

dose administration of penicillin, cephalosporin,

macrolide, or doxycycline is the therapy of choi-

ce.126)

Acute human granulocytic ehrlichiosis (HGE) is

an emerging tick-borne disease, which should

now be included in the differential diagnosis of

febrile illnesses occurring after a tick bite in

Europe. HGE is caused by Ehrlichia phagocyto-

phila (anaplasma), gramnegative intracellular

bacteria infecting white blood cells. Comparing

the clinical signs and laboratory findings of adult

patients with proven acute HGE with that of

patients in the initial phase of TBE shows that

the duration of fever in the initial phase of TBE

is shorter (median 4 days vs. 7 days in patients

with acute HGE). Clinical signs, including chills,

myalgia, and arthralgia, and laboratory findings,

e.g., elevated values for lactate dehydrogenase

and C-reactive protein, suggest a diagnosis of

acute HGE rather than the initial phase of

TBE.127)

Differential diagnosis of TBEDifferential diagnosis of TBE

Clinical Picture

• Lyme disease

• Acute human granulocytic ehrlichiosis

• Poliomyelitis

• Coxsackie virus infection

• ECHO virus infection

• Parotitis

• Measles

• Herpes virus infection

• Lymphocytic choriomeningitis

• Japanese B encephalitis

• St. Louis encephalitis

• Eastern and Western equine encephalitis

• Adenovirus infection

• West Nile Fever

• Louping Ill virus infection

• Tuberculous meningitis

• Leptospiral meningitis

• Tularaemia

• Q-fever

• Tick typhus

• Tick paralysis caused by salivary toxin of ticks

• Bacterial meningitis caused by common

pathogens

Table 12: Differential diagnosis of TBE

Diagnosis


Elimination of TBE by controlling all vectors is

not possible, and no effective or practicable

tools are available for interrupting the virus cycle

in nature. Prevention is the only effective means

to combat the disease.

7.1. General preventive measures

• Avoiding tick-infested areas whenever possible

• Wearing light-colored clothing that shows

ticks easily and covers arms and legs. Wearing

long-sleeved shirts, tight at the wrists, long

pants tight at the ankles and tucked into

socks, and shoes covering the entire foot.

• Applying diethyltoluamide (e.g., DEET) to skin

and permethrin to clothing. Dot apply per-

methrin to clothing while being worn and

allow the clothing to dry thoroughly before

wearing.

• Performing daily checks of skin for ticks.

Check children 2-3 times a day. Check under

waist bands, sock tops, under arms, and any

other moist areas.

• Removing ticks by using fine-tipped tweezers

(Figure 22). Grasp the tick firmly and as close-

ly to the skin as possible. Using a steady

motion, pull the tick’s body away from the

skin without rotation. If parts of the tick

remain stuck in the skin, they should be remo-

ved as soon as possible. Suffocating the tick

with oil, cream etc. may induce injection of

more infectious material into the body – so do

not use petroleum jelly, burning matches,

cigarette ends, nail polish, or the like.

7.1.1. Control of tick populations

Ticks being the chief vector of TBE virus, past

efforts to fight TBE concentrated on the control

of tick populations in TBE endemic areas. In for-

mer Czechoslovakia and the USSR, large-scale

control measures using tetrachlorvinphos, DDT,

or Hexachlor did not produce the desired effect.

32

7 _ Prevention“Vaccination is recommended for everyone, children and adults alike,

residing in – or traveling to – endemic areas.”

(I. Mutz, MD, Leoben, ISW-TBE 2004)

Prevention

Figure 22: Removing a tick


Prevention

33

As the virus persists not only in ticks, but also in

wild animals, such measures are of no use in the

elimination or even control of the disease.

7.1.2. Protective clothes and repellents

As ticks attach to any spot on the host, and

from there try to reach an uncovered part of the

skin, adequate clothing may help to make

access to the skin more difficult for ticks. Protec-

tive clothes must be completely closed to be

really effective, but this may be found intolera-

ble by people spending their leisure time or holi-

days in endemic areas in the warm season.

In former Czechoslovakia, forestry workers were

given protective clothes impregnated with DDT

and were regularly disinfested after work.128)

However, these preparations afford protection

for a few hours only. Moreover, there have been

reports from the former USSR of ticks becoming

resistant to repellents.34)

All these preventive measures directed at ticks

have offered only limited protection. It was reali-

zed quite early that a vaccine was required for

protection against the causative agent itself, i.e.,

the TBE virus.

7.2. Active immunization

Currently, no causal treatment is known for TBE.

However, TBE can be successfully prevented by

active immunization. Prevention by special clo-

thing and tick repellents has proven not reliable

enough, and the registration of TBE-specific

hyperimmunoglobulin for post-exposure prophy-

laxis has been suspended due to concerns about

antibody-dependent enhancement of infec-

tion.130)

Baxter offers the most widely used TBE vaccine

in Europe, FSME-IMMUN 0.5 ml for adults from

16 years of age and FSME-IMMUN 0.25 ml

Junior for children and adolescents from 1 to

below 16 years (Table 13). FSME-IMMUN has

been registered in Austria since 1979 and has

been widely used for many years in more than

20 European countries. More than 85 million

doses have been administered since then.

Residents of and travelers to TBE endemic areas,

who are at risk of tick bites, are advised to recei-

ve TBE vaccination.80, 82) The Austrian example

Table 14

Vaccination coverage in Austria 2004*Vaccination coverage in Austria 2004*

Age Vaccination coverage (%)

1-12 81

13-19 95

20-29 93

30-39 90

40-49 87

50-59 87

60-69 83

70-79 79

80+ 68

*) Fessel-GfK Austria 2005


34

shows that containment of TBE is feasible by

mass vaccination. In the pre-vaccination era,

Austria had a very high recorded morbidity of

TBE – probably the highest in Europe at the

time. In high-risk areas, the average annual inci-

dence in the population exposed to ticks in their

working environment was 0.9 per 1000.131)

A mass vaccination campaign was started in

1982 and has since continued annually. The vac-

cination coverage of the total Austrian popula-

tion is high and reached 86% in 2001. In the

highest risk areas, it was as high as 95% (Table

14). 66% of the total population adhere to the

recommended vaccination schedule, including

regular booster vaccinations. The vaccination

program for school children has proven to be

particularly effective. TBE infection in this age

group has decreased to a very low rate of 2.3%

of the total recorded cases (Figure 13).86)

The increased vaccination coverage has resulted

in a marked decline of the morbidity of TBE in

Austria. This development is unparalleled in

Europe, with vaccination coverage still low in

most countries. The incidence of TBE can only

be lowered by an increasing vaccination covera-

ge and is not fully controlled until general vacci-

nation is undertaken. 86)

For more information on FSME, see the FSME-

IMMUN Product Monograph and attached

SmPCs.

Prevention

Table 13

Pharmaceutical composition of FSME-IMMUN vaccinesPharmaceutical composition of FSME-IMMUN vaccines

FSME-IMMUN 0.5ml FSME IMMUN 0.25ml Junior

Active substance: formaldehyde-inactivated, 2.4 µg (target) 1.2 µg (target)

sucrose gradient purified, TBE virus antigen 2–2.75 µg (range) 1-1.375 µg (range)

Adjuvant: aluminum hydroxide, hydrated 0.35 mg Al3+ 0.17 mg Al3+

Stabilizer: human serum albumin 0.5 mg 0.25 mg

Buffer system

• Sodium chloride 3.45 mg 1.725 mg

• Na2HPO4.2H2O 0.22 mg 0.11 mg

• KH2PO4 0.045 mg 0.0225 mg

Sucrose Max. 15 mg Max. 7.5 mg

Formaldehyde Max. 5 µg Max. 2.5 µg

Protamine sulfate Trace Trace

Neomycin and gentamicin Trace Trace

Water for injection Ad 0.5 ml Ad 0.25 ml


35

References

1) Haglund M, Göran G: Tick-borne encephalitis-pathogenesis,clinical course and longterm follow-up. Vaccine 2003, 21:S1/11–18.

2) Schneider H: Über epidemische akute “Meningitis serosa”.Wiener klin. Wschr. 1931; 44: 350–352.

3) Gallia F, Rampas J, Hollender L: Laboratorni infekce encefali-tickym virem. Cas. Lek. Ces. 1949; 88: 224–229.

4) Virus Taxonomy. Seventh Report of the International Com-mittee on Taxonomy of Viruses 2000.

5) Chambers TJ, Hahn CS, Galler R, Rice CM: Flavivirus genomeorganization, expression and replication. Annu. Rev. Micro-biol 1990; 44: 649–688.

6) Heinz FX: Molecular aspects of TBE virus research. Vaccine2003, 21: S1/3–S1/10.

7) Mandl CW, Heinz FX, Stöckl E, Kunz Ch: Genome sequenceof tick-borne encephalitis virus (Western subtype) and com-parative analysis of nonstructural proteins with other flavivi-ruses. Virology 1989; 173: 291–301.

8) Heinz FX, Mandl CW, Holzmann H, Kunz C, Harris BA, Rey R,et al.: The flavivirusenvelope protein E: Isolation of a solubledimeric form from tick-borne encephalitis virus and its cry-stallization. J. Virol. 1991; 65: 5579–5583.

9) Rey FA, Heinz FX, Mandl Ch, Kunz Ch, Harrison Stephen C:The envelope glycoprotein from tick-borne encephalitis virusat 2A resolution. Nature 1995; 375: 291–298.

10) Ecker M, Allison SL, Meixner T, Heinz FX: Sequence analysisand genetic classification of tick-borne viruses from Europeand Asia. J. Gen. Virol. 1999; 80: 179–185.

11) Holzmann H, Vorobyova MS, Landyzhenskaya IP, Ferenczi E,Kundi M, Kunz C, et al.: Molecular epidemiology of tick-bor-ne encephalitis virus: cross-protection between European andFar-Eastern subtypes. Vaccine 1992; 10: 345–349.

12) N Chiba et al., Vaccine 17: (1532-1539, 1999)13) Sonenshine DE: Biology of ticks. 1991. vol.1 Oxford Universi-

ty Press.14) Vaisviliene D, Kilciauskiene V, Zygutiene M, Asokliene L,

Caplinskas S: TBE in Lithuania: epidemiological aspects andlaboratory diagnosis. Int J Med Microbiol. 2002 Jun; 291Suppl 33: 181.

15) Labuda M, Eleckova E, Lickova M, Sabo A: Tick-borne ence-phalitis virus foci in Slovakia. Int J Med Microbiol. 2002 Jun;291 Suppl 33: 43–7.

16) Bodemann HH, Pausch J, Schmitz H, Hoppe-Seyler G: DieZeckenenzephalitis (FSME) als Labor-Infektion. Med. Welt1977; 28: 1779–1781.

17) Blessing J: Epidemiologie und Diagnose der Frühsommer-Meningoenzephalitis. Med. Welt 1981; 32: 1345–1347.

18) Blaskovic D: Epidemiologische und immunologische Proble-me bei der Zeckenenzephalitis. Wiener klin. Wschr. 1958; 70:742–749.

19) Randolph S: Quantitative ecology of ticks as a basis for trans-mission models of tick-borne pathogens. Vector Borne Zoo-notic Dis. 2002 Winter; 2 (4): 209–15.

20) Randolph S: Evidence that climate change has caused ‘emer-gence’ of tick-borne diseases in Europe? Int J Med Microbiol.2004 Apr; 293 Suppl 37: 5–15.

21) Kunz Ch: Tick-borne encephalitis in Europe. Acta Leiden.1992; 60: 1–14.

22) Zeman P, Bene C: A tick-borne encephalitis ceiling in CentralEurope has moved upwards during the last 30 years: possi-ble impact of global warming? Int J Med Microbiol. 2004Apr; 293 Suppl 37: 48–54.

23) Krippel E, Nosek J: Das Vorkommen der Zecke Ixodes ricinusL. in verschiedenen Waldgesellschaften der Westkarpaten.Beitrage zur Geoökologie der Zentraleuropäischen Zecken-Enzephalitis. Berlin: Springer-Verlag, 1978: 48–59.

24) Radda AC, Kunz C: Die Frühsommer-Meningoenzephalitis inMitteleuropa. Kinderarzt 1983; 14: 714–724.

25) Liebisch A: Der Holzbock – die unbekannte Gefahr. Zeckenbei Tier und Mensch. Pirsch 1976; 7: 364–367.

26) Süss J: Epidemiology and ecology of TBE relevant to the pro-

duction of effective vaccines. Vaccine 2003, 21: S1/19–35.27) Sauer JR, McSwain JL, Bowman AS, Essenberg RC: Tick Sali-

vary gland physiology. Annu. Rev. Entomol. 1995; 40: 245–267.

28) Hopf HC: Neurologische Komplikationen nach Zeckenkont-akt. Deut. Aerztebl. 1980; 77: 2063–2066.

29) Nuttall PA, Labuda M: Dynamics of infection in tick vectorsand at the tick-host interface. Adv Virus Res. 2003; 60: 233–72.

30) Rufli T, Mumcuoglu Y: Dermatologische Entomologie. Diepraktisch-medizinische Bedeutung von Milben und Insektenin der Schweiz und in ihren angrenzenden Regionen. 18. Ixo-didae, Schildzecken. 19. Argasidae, Lederzecken. Schweiz.Rundsch. Med. 1981; 70: 362–385.

31) Kunz C: Die Prophylaxe der Frühsommer-Meningoenzephali-tis (FSME) in der dermatologischen Praxis. Schrifttum u. Pra-xis 1974b; 5: 55–58.

32) Radda AC: Die Frühsommer-Meningoenzephalitis in Öster-reich. Beitrage zur Geoökologie der Zentraleuropäischen Zek-ken-Encephalitis. Berlin: Springer-Verlag, 1978: 42–47.

33) Gresikova M, Kozuch O, Nosek J: Die Rolle von Ixodes ricinusals Vektor des Zeckenenzephalitisvirus in verschiedenenmitteleuropäischen Naturherden. Zbl. Bakt. Parasit. 1968;207: 423–429.

34) Hoffmann G: Zecken und ihre hygienische Bedeutung. Pro-bleme der Insekten- und Zeckenbekämpfung: Ökologische,medizinische und rechtliche Aspekte. Berlin: Schmidt-Verlag,1978a: 13–21.

35) Riedl H, Sixl W, Nosek J: Studien zur Synökologie des Früh-sommer-Meningo-Enzephalitis(FSME)-Virus in Österreich(Übersichtsreferat und regionale Untersuchungen). Z. ges.Hyg. 1973; 19: 733–737.

36) Kriz B, Benes C, Danielova V, Daniel M: Socio-economic con-ditions and other anthropogenic factors influencing tick-bor-ne encephalitis incidence in the Czech Republic. Int J MedMicrobiol. 2004 Apr; 293 Suppl 37: 63–8.

37) Radda A, Kunz C, Loew J, Neumann A, Pretzmann G, ZukriglK: Beitrag zur Kenntnis der Syn-Ökologie des Virus der Zen-traleuropäischen Enzephalitis. Zbl. Bakt. Parasit. 1967: 202:273–296.

38) Cerny V: The role of mammals in natural foci of tick-borneencephalitis in Central Europe. Folia Parasitol. 1975; 22: 271–273.

39) Liebisch A: Zur Überträgerökologie der Zeckenenzephalitis inder Bundesrepublik Deutschland. In: H. JUSATZ (ed.) Beiträgezur Geoökologie der Zentraleuropäischen Zecken-Enzephali-tis. Berlin: Springer-Verlag, 1978: 20–29.

40) Jellinger K: The Histopathology of Tick-Borne Encephalitis. In:Kunz C, editor. Tick-Borne Encephalitis. Wien: Facultas,1981: 59–75.

41) Hofmann H: Die unspezifische Abwehr bei neurostropenArbovirusinfektionen. Zbl. Bakt. Hyg. 1973; 223 (I. Abt. Orig.A): 143–163.

42) Korenberg EI: Problems in the study and prophylaxis of mixedinfections transmitted by ixodid ticks. Int J Med Microbiol.2004 Apr; 293 Suppl 37: 80–5.

43) Alekseev AN, Dubinina HV, Jushkova OV: First report on thecoexistence and compatibility of seven tick-borne pathogensin unfed adult Ixodes persulcatus Schulze (Acarina: Ixodidae).Int J Med Microbiol. 2004 Apr; 293 Suppl 37: 104–8.

44) Korenberg EI: Relationships between the agents of transmis-sible diseases in mix-infectid ixodid ticks. Parazitologiya 1999,32: 273–289.

45) Labuda M, Nuttall PA, Kozuch O, Eleckova E, Williams T, Zuf-fova E, et al: Non-viremic transmission of tick-borne ence-phalitis virus: a mechanism for arbovirus survival in nature.Experientia 1993; 49: 802–805.

46) Matile H, Ferrari E, Aeschlimann A, Wyler R: Die Verbreitungder Zecken-Enzephalitis in der Schweiz. Ein Versuch zurErstellung eines Katasters der Naturherde aufgrund einerseroepidemiologischen Untersuchung des Forstpersonals im

REFERENCES


36

therapy

Mittelland. Schweiz. med. Wschr. 1981; 111: 1262–1269.47) Jusatz HJ, Wellmer H: Die Gefährdung von Freizeiten und

Erholung durch eine Virus-Infektion nach Zeckenbiss. Arbeits-,Soz.-, Prävent.-Med. 1982; 17: 200–202.

48) Malkova D, Danielova V, Dusbabek F, Holubova J, HonzakovaE: Tick-Borne Encephalitis in Recreation Areas of Prague. In:Kunz C, editor. Tick-Borne Encephalitis. Wien: Facultas,1981: 251–256.

49) Takeda, T, Ito T, Osada M, Takahashi K, Takashima I: Isolationof tick-borne encephalitis virus from wild rodents and aseroepizootiologic survey in Hokkaido, Japan. Am- J TropMed Hyg. 1999, 60: 287–291.

50) Barrett PN, Dorner F, Ehrlich HJ, Plotkin SA: Tick-borne ence-phalitis virus vaccine. In: Plotkin SA , Orenstein WA (Ed.): Vac-cines, 4th edition, 2004, Elsevier Inc (USA)

51) Bormane A, Lucenko I, Duks A, Mavtchoutko V, Ranka R, Sal-mina K, Baumanis V: Vectors of tick-borne diseases andepidemiological situation in Latvia in 1993–2002. Int J MedMicrobiol. 2004 Apr; 293 Suppl 37: 36–47.

52) Süss J, Klaus C, Diller R, Schrader C, Wohanka N, Abel U: TBEincidence versus virus prevalence and increased prevalenceof the TBE virus in Ixodes ricinus removed from humans. Int JMed Microbiol 2006; 296 S1, 63-68

53) Süss J, Schrader C, Abel U, Bormane A, Duks A, Kalnina V:Characterization oftick- borne encephalitis (TBE) foci in Ger-many and Latvia (1997–2000). Int J Med Microbiol. 2002 Jun;291 Suppl 33: 34–42.

54) Süss J, Schrader C, Falk U, Wohanka N: Tick-borne encepha-litis (TBE) in Germany-epidemiological data, development ofrisk areas and virus prevalence in field-collected ticks and inticks removed from humans. Int J Med Microbiol. 2004 Apr;293 Suppl 37: 69–79.

55) Labuda M, Stünzner D, Kozuch O, Sixl W, Kocianova E,Schäffler R, et al.: Tick-borne encephalitis virus activity in Sty-ria, Austria. Acta Virol. 1992; 37: 187–190.

56) Saikku P: Tick-Borne viruses. Med. Biol. 1975; 53: 317–320.57) Verani P, Ciufolini MG,Nicoletti L, Lopes MC, Amaducci, L,

Fratiglioni L, et al: Circulation of TBE Virus in Italy: Seroepide-miological and Ecovirological Studies. In: Kund C, editor. Tick-Borne Encephalitis. Wien: Facultas 1981: 265–272.

58) Gustafson R: Epidemiological Studies of Lyme Borreliosis andTick-Borne encephalitis. Scand. J. Infect. Dis. 1994; suppl. 92.

59) Freundt EA: Endemisk forehomst pa Bornholm af centraleu-ropaeish virus meningo-encephalitis, overfort af shovflater.Ugeshr laeger 1963; 125: 1098–1104.

60) Matile H, Aeschlimann A, Wyler R: Seroepidemiologic Investi-gation on the Incidence of TBE in Man and Dog in Switzer-land. In: Kunz C, editor. Tick-Borne Encephalitis. Wien: Facul-tas, 1981: 227–234.

61) Brummer-Korvenkontio M, Saikku P, Korhonen P, Oker-BlomN: Arboviruses in Finnland. I. Isolation of Tick-Borne Ence-phalitis (TBE) Virus from Arthrophods, Vertebrates, andPatients. Amer. J. Trop. Med. Hyg. 1973; 22: 382–289.

62) Ernek E, Kozuch O: Zeckenencephalitis-Virus neutralisierendeAntikörper bei Rindern als Indikator der Virusanwesenheit inmitteleuropäischen Naturherden. Zbl. Bakt. Parasit. 1970;213: 151–160.

63) Danielova V, Rudenko N, Daniel M, Holubova J, Materna J,Golovchenko M, Schwarzova L: Extension of Ixodes ricinusticks and agent of tick-borne diseases to mountain in theCzech Republic. Int J Med Microbiol 2006; 296 S1, 48-53

64) Oehme R, Hartelt K, Backe H, Brockmann S, Kimmig P: Fociof tick-borne diseases in southwest Germany. Int J MedMicrobiol. 2002 Jun; 291 Suppl 33: 22–9.

65) Cisak E, Chmielewska-Badora J, Zwolinski J, Dutkiewicz J,Patorska-Mach E: Incidence of tick-borne encephalitis virusand Borrelia burgdorferi infections in farmers of the Lublinprovince. Med Pr. 2003; 54 (2): 139–44.

66) Juceviciene A, Vapalahti O, Laiskonis A, Ceplikiene J, LeinikkiP: Prevalence of tick-borne-encephalitis virus antibodies inLithuania. J Clin Virol. 2002 Jul; 25 (1): 23-7.

67) Randolph SE: The shifting landscape of tick-borne zoonoses:tick-borne encephalitis and Lyme borreliosis in Europe. PhilosTrans R Soc Lond B Biol Sci. 2001 Jul 29; 356 (1411): 1045-56.

68) Vorobyeva M, Voroncova T, Arumova E: Federal Centre ofSanitarian-Epidemiological Control of the Ministry of healthof Russion Federation.

69) Kunze U, Asokliene L, Bektimirov T, Busse A, Chmelik V,Heinz FX, Hingst V, Kadar F, Kaiser R, Kimmig P, Kraigher A,Krech T, Linquist L, Lucenko I, Rosenfeldt V, Ruscio M, SandellB, Salzer H, Strle F, Süss J, Zilmer K, Mutz I: Tick-borne ence-phalitis in childhood-consensus 2004. Wien MedWochenschr. 2004 May; 154 (9–10): 242-5.

70) Lesnicar G, Poljak M, Seme K, Lesnicar J: Pediatric tick-borneencephalitis in 371 cases from an endemic region in Slovenia,1959 to 2000. Pediatr. Infec Dis J 2003; 22: 612-17.

71) Kunz C: Epidemiology of tick-borne encephalitis and theimpact of vaccination on the incidence of disease. In: EiblMM, Huber C, Peter HH, Wahn U, editors. Symposium inImmunology V. Berlin: Springer Verlag Berlin Heidelberg,1996: 143.

72) Holmgren B, Forsgren M: Epidemiology of tick-borne ence-phalitis in Sweden 1956–1989: a study of 1116 cases. ScandJ Infect 1990; 22: 287-95.

73) Iff T, Meier R, Olah E, Schneider JF, Tibussek D, Berger C. Tick-borne meningoencephalitis in a 6-week-old infant. Eur JPediatr 2005 Dec; 164 (12) 787-8).

74) Libikova H: Epidemiological and Clinical Aspects of Tick-Bor-ne Encephalitis in Relation to Multiple Viral Infections. In:Kunz C, editor. Tick-Borne Encephalitis. Wien: Facultas,1981: 235–246.

75) Grygorczuk S, Mierzynska D, Zdrodowska A, Zajkowska J,Pancewicz S, Kondrusik M, Swierzbinska R, Pryszmont J, Her-manowska-Szpakowicz T: Tick-borne encephalitis in north-eastern Poland in 1997–2001: a retrospective study. Scand JInfect Dis. 2002; 34 (12): 904-9.

76) Anonymous editor: Tick-borne encephalitis in Sweden. 1971;144–147.

77) Krausler J: 23 years of TBE in the District of Neunkirchen(Austria). In: Kunz C., Editor. Tick-Borne Encephalitis. Wien:Facultas. 1981a: 6–12.

78) Loew J, Radda A, Pretzmann G, Studynka G: Untersuchun-gen in einem Naturherd der Frühsommer-Meningo-Encepha-litis (FSME) in Niederösterreich. Zbl. Bakt. Parasit. 1964;194:133–146.

79) Roggendorf M, Neumann-Haefelin D, Ackermann R: Prophy-laxe der Frühsommer-Meningoenzephalitis (FSME-IMMUN –Immuno). Deut. Aerztebl. 1989; 86: 1992–1998.

80) Heinz, FX: Presented at 7th annual meeting of ISW-TBE inVienna 2005.

81) Moritsch H: Arboviren in Österreich. Wiener med. Wschr.1965; 115: 680–681.

82) Süss J: Presented at 7th annual meeting of ISW-TBE in Vienna2005.

83) Danielova V: Recent situation in TBE in Czech Republic. Pots-dam Symposium 1997.

84) Krech T: TBE foci in Switzerland. Int J Med Microbiol. 2002Jun; 291 Suppl 33: 30-3.

85) Korenberg E, Kovalevskii Y: Main Reatures of Tick-borneEncephalitis – Eco-epidemiology in Russia. Zent.bl. Bakteriol.1999, 289: 525–539.

86) Kunz C: TBE vaccination and the Austrian experience. Vacci-ne 2003, 21: S2/50–55.

87) Cizman M, Avsic-Zupanc T, Petrovec M, Ruzic-Sabljic E,Pokorn M: Seroprevalence of Ehrilchiosis, Lyme borreliosisand Tick-borne encephalitis infections in children and youngadults in Slovenia. Wiener Klin. Wschr. 2000; 112: 842–5.

88) Kunz C: Tick-Borne encephalitis in Europe. Acta Leiden.1992; 2: 114.

89) Han X, Aho M, Vene S, Brummer-Korvenkontio M, Jucevicie-ne A, Leinikki P, Vaheri A, Vapalahti O: Studies on TBE epide-

References


37

References

miology in Finland (and Lithuania). Int J Med Microbiol. 2002Jun; 291 Suppl 33: 48-9.

90) Skarpaas T, Sundøy A, Bruu A-L, Vene S, Pedersen J, Eng PG,Csângò PA. Skogflåttencefalitt i Norge. Tidsskr Nor Laege-foren 2002; 122: 30-2.

91) Kaiser R: Tick-borne encephalitis (TBE) in Germany and clini-cal course of the disease. Int J Med Microbiol. 2002 Jun; 291Suppl 33: 58–61.

92) Radda A: Die Frühsommer-Meningoenzephalitis in Öster-reich. Dr. Med. 1980; 4:4–8.

93) Mickiene A: Personal e-mail communication (2005)94) Mickiene A, et al.: TBE-clinical course and outcome. Review

of literature in Progress 95) Lotric-Furlan S, Avsic-Zupanc T, Strle F: An abortive form of

tick-borne encephalitis (TBE) – a rare clinical manifestation ofinfection with TBE virus. Wien Klin Wochenschr. 2002 Jul 31;114 (13–14): 627-9.

96) Jereb M, Muzlovic I, Avsic-Zupanc T, Karner P: Severe tick-borne encephalitis in Slovenia: epidemiological, clinical andlaboratory findings. Wien Klin Wochenschr. 2002 Jul 31; 114(13–14): 623-6.

97) Holzer E: Zum Vordringen der Zentraleuropäischen Enzepha-litis in Südbayern. Münch. med. Wschr. 1976; 118: 1613–1614.

98) Ackermann R, Krueger K, Roggendorf M, Behse-Kuepper B,Moertter M, Schneider M, et al.: Die Verbreitung der Früh-sommer-Meningozephalitis in der Bundesrepublik Deutsch-land. Dtsch. Med. Wochenschr. 1986; 111: 927–933.

99) Köck T, Stunzner D, Freidl W, Pierer K: [Clinical aspects of ear-ly summer meningoencephalitis in Styria] Zur Klinik der Früh-sommermeningoenzephalitis (FSME) in der Steiermark. Ner-venarzt 1992; 63: 205–208.

100) Kunz C: Frühsommer-Meningoenzephalitis (FSME) in Europa.In: Süss J, editor. Durch Zecken übertragbare Erkrankungen –FSME und Lyme-Borreliose. Schriesheim: Weller Verlag, 1994:23–30.

101) Radl B, Ladurner G, Lechner H, Stunzner D: Klinik und Verlaufder Frühsommermeningoenzephalitis (FSME, TBE). Neuro-psychiatr. Clin. 1983; 2: 131–135.

102) Rehse-Kupper B, Danielova V, Klenk W, Abar B, AckermannR: Epidemiologie der Zentraleuropäischen Enzephalitis in derBundesrepublik Deutschland. Münch. med. Wschr. 1976;118: 1615–1616.

103) Reisner H: Clinic and Treatment of Tick-Borne Encephalitis(TBE) Introduction. In: Kunz C, editor. Tick-Borne Encephali-tis. Wien: Facultas, 1981: 1–5.

104) Zoulek G, Ruppert B, Roggendorf M: Die Frühsommer-Meningoenzephalitis: Klinisches Bild und Labordiagnose.Elipse 1985, 3: 17–21.

105) Dumpis U, Crook D, Oksi J: Tick-Borne Encephalitis. Clin InfDis 1999, 28: 882–890.

106) Kaiser R: Presented at 7th annual meeting of ISW-TBE in Vien-na 2005.

107) Günther G, Haglund M, Lindquist L, Forsgren M, SköldenberB: Tick-borne encephalitis in Sweden in relation to asepticmeningo-encephalitis of other etiology: a prospective studyof clinical course and outcome. J Neurol 1997, 244: 230–238.

108) Cizman M, Rakar R, Zakotnik B, Pokorn M, Arnez M: Severeforms of tick-borne encephalitis in children. Wiener klin.Wschr. 1999; 111: 484–487.

109) Haglund M, Günther G: Do tick-borne encephalitis patientsdevelop a post-encephalitic syndrome – a review of the lite-rature. Ellipse 1997; 13: 7–12.

110) Mamoli B, Pelzl G: Residualschaden nach FSME. Österr. Ärz-teztg 1990; 45: 45–51.

111) Mickiene A, et al.: TBE in an area of high endemicity in Lithu-ania: disease severity and long-term prognosis. Clin. Infect.Dis. 2002; 35: 650–658

112) Haglund M: Tick-Borne Encephalitis. Stockholm 2000.113) Kaiser R, Holzmann H: Laboratory findings in tick-borne

encephalitis-correlation with clinical outcome. Infection.2000 Mar–Apr; 28 (2): 78–84.

114) Arnez M, Luznik-Bufon T, Avsic-Zupanc T, Ruzic-Sabljic E,Petrovec M, Lotric-Furlan S, Strle F: Causes of ebrile illnessesafter a tick bite in Slovenian children. Pediatr Infect Dis J.2003 Dec; 22 (12): 1078-83.

115) Kunz C: Die Frühsommer-Meningoenzephalitis. Paediatr. Pra-xis 1974a; 14: 189–192.

116) Cimperman J, Maraspin V, Lotric-Furlan S, Ruzic-Sabljic E,Avsic-Zupanc T, Picken RN, Strle F: Concomitant infectionwith tick-borne encephalitis virus and Borrelia burgdorferisensu lato in patients with acute meningitis or meningoence-phalitis. Infection. 1998 May–Jun; 26 (3): 160-4.

117) Tomazic J, Pikelj F, Schwarz B, Kunze M, Kraigher A, MatjasicM, et al.: The clinical features of tick-borne encephalitis inSlovenia. A study of 492 cases in 1994. Antibiot Monitor1996, 12: 115–120.

118) Korenberg EI, Gorban’ LY, Kovalevskii YV, Frizen VI, Karava-nov AS: Risk for Human Tick-Borne Encephalitis, Borrelioses,and Double Infection in the Pre-Ural Region of Russia. EmergInfect Dis 7 (3), 2001.

119) Zeman P, Pazdiora P, Cinatl J: HGE antibodies in sera ofpatients with TBE in the Czech Republic. Int J Med Microbiol.2002 Jun; 291 Suppl 33: 190-3.

120) Krausler J, Kraus P, Moritsch H: Klinische und virologisch-serologische Untersuchungsergebnisse bei Frühsommer-Meningoenzephalitis und anderen Virusinfektionen des ZNSim Bezirk Neunkirchen. Wiener klin. Wschr. 1958; 70: 634–637.

121) Krech U: Epidemiological and Clinical Investigations on Tick-Borne Encephalitis in Switzerland. In: Kunz C, editor. Tick-Borne Encephalitis. Wien: Facultas, 1981: 217–226.

122) Kaiser R: verbal communication 1998.123) Holzmann H: Diagnosis of tick-borne encephalitis. Vaccine.

2003 Apr 1; 21 Suppl 1: S36–40.124) Allwinn R, Doerr HW, Emmerich P, Schmitz H, Preiser W:

Cross-reactivity in flavivirus serology: new implications of anold finding? Med Microbiol Immunol (Berl). 2002 Mar; 190(4): 199–202.

125) Sonnenberg K, Niedrig M, Steinhagen K, Rohwader E, Mey-er W, Schlumberger W, Muller-Kunert E, Stocker W: State-of-the-art serological techniques for detection of antibodiesagainst tick-borne encephalitis virus. Int J M ed Microbiol.2004 Apr; 293 Suppl 37: 148-51.

126) European Union concerted action on lyme borreliosis. 2004.http://vie.dis.strath.ac.uk/vie/LymeEU/ (accessed 2/2006).

127) Lotric-Furlan S, Petrovec M, Avsic-Zupanc T, Logar M, Strle F:Epidemiological, clinical and laboratory distinction betweenhuman granulocytic ehrlichiosis and the initial phase of tick-borne encephalitis. Wien Klin Wochenschr. 2002 Jul 31; 114(13–14): 636-40.

128) Heinz FX, Asmera J, Januska J: Present Activity in Natural Fociof Tick-Borne Encephalitis in the CSSR. In: Kunz C, editor.Tick-Borne Encephalitis. Wien: Facultas, 1981: 279–281.

129) Kunz C: Immunprophylaxe gegen die Frühsommer-Menin-goenzephalitis (FSME). In: Spiess H, editor. Immunglobuline inProphylaxe und Therapie. 1977b: 163–169.

130) Waldvogel K, Bossart W, Huisman T, Boltshauser E, Nadal D:Severe tick-borne encephalitis following passive immuniza-tion. Eur J Pediatr 1996; 155: 7759.

131) Kunz C: Vaccination against TBE in Austria: The success storycontinous. IJMM 291, Suppl 33: S56–57 (2002)

132) Grubbauer HM, Dornbusch HJ, Spork D, Zobel G, Trop M,Zenz D: Tick-borne encephalitis in a 3-month-old child. Eur JPediatr 1992; 151: 743–4.

133) Labuda M, Austyn JM, Zuffova E, Kozuch O, Fuchsberger N,Lysy J, Nuttall PA: Importance of localized skin infection intick-borne encephalitis virus transmission. Virology 1996;219: 357-366


38

therapy

LIST OF ABBREVIATIONS

CNS Central nervous system

DDT Dichlorodiphenyltrichloroethane (organochlorine insecticide)

ELISA Enzyme-linked immunosorbent assay

FSME Frühsommer-Meningoenzephalitis, German term for TBE

IgG Immunoglobulin G

PCR Polymerase chain reaction

RNA Ribonucleic acid

TBE Tick-borne encephalitis

TBEV Tick-borne encephalitis virus

VIE U/ml Vienna units/ml – TBE ELISA concentration unit

References

FSME-IMMUN has received marketing authorization under the trade name of TICOVAC in Italy, France, Denmark, Nor-way, UK, Ireland, Finland, Latvia, Lithuania and Estonia. For product information please see the national SmPC from yourcountry. Baxter is a trademark of Baxter International Inc., FSME-IMMUN and TicoVac are trademarks of Baxter Healthca-re SA.Sources: pictures of ticks, patients and production: Baxter archive; animals: Museum of Natural History Vienna, Landes-museum Niederösterreich (F. Gauermann); art, illustrations: MedNews archive.

For questions please contact: Dr. Alexandra C. Gruberemail: [email protected]: ++43/1/20 100-2899

Baxter AG Industriestraße 67, A-1221 Vienna, Austria


Baxter AG, Industriestraße 67, A-1221, Austria

March 2007Project Number: BS-VA-007


tick-borne encephalitis (tbe, fsme) · pdf filetick-borne encephalitis (tbe, fsme) monograph...

Documents