Bull. Org. mond. Sant Bull. Wid Hlth Org. f11967, 36, Suppl. 1, pp. 5-13

The Public Health Importance of -borne Encephalitis in Europe D. BLAWKOVI?1

After an historical survey establishing the distinction between Russian spring-summer encephalitis, a serious disease with a high mortality rate caused by a spread by the tick persulcatus, and the milder Central European encephalitis, which is spread by I. ricinus, the public health aspects ofthe latter disease are discussed. Thefactors affecting the incidence of the disease-tick population, role of rodents and insectivores, etc.-are considered. Only a smallproportion ofthose infected develop clinical symptoms. Measures for the control of the disease include (a) vaccination of humans, (b) reduction of the tick population by cultivation of the land, by spreading the enemies of and by dusting with insecticides, and (c) reduction ofthe infectivity ofticks by vaccination ofdomestic aninals. It is concluded that, under the conditions prevailing in Central Europe, mass vaccination is not to be recommended, although those working regularly within a naturalfocus ofinfection should be vaccinated.

HISTORY others), it was realized that many other areas of the USSR were experiencing an exactly similar disease. In 1937-39, three successive research expeditions A milder form of the disease was also observed in the were organized by the Ministry of Health of the European part of the USSR, where the tick Ixodes USSR to try to elucidate the origin of an infection ricinus was found to be the vector of the virus. of the central nervous system occurring in different Tick-borne encephalitis was recognized in the areas of the Far East of the USSR. The infectious Leningrad region in 1945, in the Byelorussian SSR character of the disease had been established in in 1944, in Krasnoyarsk in 1945, in Kaliningrad in 1933-35. Investigations carried out by, e.g., clini- 1952, and elsewhere (Karpov & Fedorov, 1963). cians, microbiologists, virologists and zoologists, After the Second World War, the disease and its quickly established the viral origin of the disease agent-tick-borne encephalitis virus-were shown and the tick Ixodes persulcatus was shown to be the to be present in other countries. In Czechoslovakia, vector of the virus. The disease was called Russian Gallia et al. (1949) and Rampas & Gallia (1949) spring-summer encephalitis (or Far East or taiga identified tick-borne encephalitis in West Bohemia, encephalitis) and the virus later became known as the and later other workers observed the disease in tick-borne encephalitis virus. The clinical course of different regions of the country. the disease, its pathology and epidemiology, as well In Hungary, the first positive proof of as the properties of the new virus, its ecology and tick-borne the ecology of vectors, have been carefully and encephalitis was reported by Fornosi & Molnar thoroughly studied. The most recent studies have (1952). Shortly afterwards studies were carried out been concerned with the possibility of effective in Poland (Przesmycki et al., 1954; Szajna, 1954), short- and long-term prophylaxis and with the Bulgaria (Vaptsarov & Tarpomanov, 1954), Yugo- effective control of ticks in order to eradicate the slavia (Bedjanic et al., 1955; Kmet et al., 1955; virus in the natural focus of infection (e.g., Grascen- Vesenjak-Zmijanac et al., 1955) and Austria (Pattyn kov, 1964). & Wyler, 1955; Richling, 1955; Moritsch & Krausler, When the results of the early studies became more 1957). A review (von Zeipel et al., 1958) summarized widely known 1959; Zil'ber, 1939; and the evidence for tick-borne encephalitis in Sweden, (6umakov, and the disease was reported in Finland (Oker Blom, 1 Director, Institute of Virology, Czechoslovak Academy 1956), Romania (Draganescu, 1959) and eastern of Sciences, Bratislava, Czechoslovakia. Germany (Sinnecker, 1960). Recent reports from

1916 5 - 6 D. BLA§KOVI

FIG. I DISTRIBUTION OF THE TICKS I. RICINUS AND I. PERSULCATUS a

a Dotted line: I. ricinus; full line: I. persulcatus. After Smorodincev (1958). south-west Germany (Scheid et al., 1964), based on summer encephalitis, tick-borne encephalitis, taiga serological investigations, suggested the existence encephalitis, spring epidemic encephalitis, spring- of natural foci of tick-borne encephalitis in the summer meningo-encephalitis, and Far East tick- Federal Republic of Germany. borne encephalitis. These designations all relate to The louping-ill virus, which causes a serious the disease whose vector, the tick I. persulcatus, had meningo-encephalitis in sheep, is antigenically very been established. The disease has often been very closely related to the tick-borne encephalitis virus. serious, with a mortality rate of 30 %-38 % (Panov, In Scotland, north-west England and Ireland, natural 1956). foci of louping-ill were detected and the tick Ixodes A milder form of the disease was observed in some ricinus was also proved to be the vector of the virus. European areas of the USSR, where the tick The geographical distribution of louping-ill and I. ricinus (tumakov & Naidenova, 1944) was proved tick-borne encephalitis in Europe, based on to be the vector and where later it was established the geographical distribution of I. ricinus, is shpwn that infection resulted from drinking raw goat's milk. in Fig. 1, which also indicates the distribution of Zil'ber & gubladze (1946) suggested that these milder I. persulcatus. cases of tick-borne meningo-encephalitis might be TERMINOLOGY caused by louping-ill virus. Smorodincev et al. (1953) and Davidenkov et al. (1953) classified the more be- Discussion is at present taking place on the nign form of tick-borne encephalitis as a new clinical nomenclature of the diseases and the respective entity and named it biphasic virus meningo-ence- viruses of the tick-borne encephalitis group. The phalitis. The disease acquired by people who drank louping-ill virus is excluded from this discussion, infected milk was called biphasic milk by because louping-ill was a disease well known to Cumakov et al. (1954). In 1951, an outbreak of farmers before the discovery of the tick-borne milk-borne meningo-encephalitis was described in encephalitis virus. Rolinava, a town in south-east Slovakia (Blagkovic, The clinical picture and epidemiology of Russian 1954). Because more than 600 persons who were meningo-encephalitis in the Far East of the USSR found to be infected had drunk raw cow's milk to were well described in 1933-35 (Panov, Finkel & which goat's milk had been added, this previously Shapoval, cited in Karpov & Fedorov, 1963). This unknown way of infection with tick-borne ence- disease sui generis was variously called spring- phalitis virus was suspected. A clinically distinct PUBLIC HEALTH IMPORTANCE OF TICK-BORNE ENCEPHALTIS IN EUROPE 7 disease is Omsk haemorrhagic fever (cumakov et People become infected (a) by being bitten by a al., 1951), caused by a virus with an identical anti- tick, (b) by drinking infected raw milk or (c) by genic structure to the tick-borne encephalitis virus. inhaling infected material. The last is most likely to This situation was complicated by the fact that occur under laboratory conditions, but the possibility viruses with identical antigenic structures were of infection taking place in this way in a natural reported from Czechoslovakia (1948) and other environment cannot be excluded; for example, a European countries, and the viruses isolated were man might be infected as a result of inhaling dust named according to the country in which they were containing the infected faeces of a tick while working discovered (see under "History "). in a stable. Some clarification of the terminology used by In Europe the disease shows a seasonal incidence, virologists resulted after Clarke (1962) reported that, corresponding to the two peaks in the tick popula- by the agar gel precipitin method, the following tion; the first peak occurs in May-June and the viruses-members of the tick-borne encephalitis second in September-October. Comparison of the group-could be distinguished: louping-ill, Russian tick population curves and the morbidity rate in spring-summer encephalitis, Omsk haemorrhagic humans shows that there is approximately 14 days' fever, and Langat, and the difference in the two peaks; this gap is roughly the virus isolated in Czechoslovakia and designated same as the incubation period of the disease, which Central European tick-borne encephalitis virus. varies between four and 14 days (Libikowa, 1961). More recent work (Clarke, 1964) has shown that Age-distribution curves show that the disease louping-ill virus, Central European tick-borne primarily affects those over 20 years old. This is encephalitis virus, Russian spring-summer ence- brought out in the results of serological surveys on phalitis virus, and Powassan and Negishi viruses people living near a natural focus of infection. form a group whose members are antigenically Forestry workers and persons collecting fruit in closely related and which can therefore be con- woods, campers and shepherds are usually infected sidered as subtypes of one virus. by a tick bite. Small family outbreaks caused by It is certainly useful to distinguish these viruses drinldng raw goat's milk mostly affect women and and the diseases caused by them. The designation of children. one of these viruses as Central European is unfor- Most of those infected do not develop clinical tunate, because viruses with the same characteristics symptoms, latent infections being common, parti- occur in the north, centre, south, west and east of cularly among people living within the natural focus Europe. A geographical approach to the designa- of infection, presumably because of immunization tion of this virus is not adequate. Virologists from with small doses of virus. People requiring hospita- different countries are considering the desirability of lization suffer from severe headaches and various distinguishing Russian spring-summer (Far-East, symptoms of meningitis and encephalomyelitis, taiga) encephalitis virus from the European sub- which are often alarming. These symptoms are type; perhaps the first could be called the Eastern characteristic of the second (localized) phase of the subtype and the second the Western subtype of disease, the first (viraemic) having the usual tick-borne encephalitis virus. symptoms of an acute viral infection. The upper respiratory tract is most commonly affected. Hospi- PUBLIC HEALTH ASPECTS talization lasts on the average 3-6 weeks and there is a prolonged convalescence during which general In considering the public health aspects of tick- pains and weakness may predominate. borne encephalitis in Europe, we shall omit louping- The mortality rate generally does not reach 1%, ill and discuss the infection caused by the virus whose although in some regions of Austria during 1954 it vector was proved to be the tick I. ricinus. was reported to be 2%-4.5 % (Grinschgl, 1955). Epidemiology A characteristic of the epidemiology of tick-borne There is no need to describe in detail the epi- encephalitis is its increased incidence in some years demiology of the disease (see BlagkoviQ, 1961); the (Fig. 2; Kolman, 1965).1 The incidence depends on general features and certain peculiarities will, how- the many factors that affect the number of viruses ever, be mentioned. In the other papers in this circulating in a given focus of infection; this in turn Supplement, new findings or the confirmation of 1 See also the paper by Blafkovid et al., this Supplement, some previous ones are described more fully. page 89. 8 D. BLA§KOVKC

FIG. 2 ECOLOGY OF THE TICK-BORNE ENCEPHALIS VIRUS MORBIDITY RATE OF IN CZECHOSLOVAKIA, 1945-60 The vector of the virus is the tick in all stages of development. The tick is also a 20 reservoir of the virus, because the latter is trans- mitted from one instar to the next. Transovarial transmission also occurs; it was found to account for 6% of experimental transmissions under con- ditions holding in Czechoslovakia (Benda, 1958c). 15 Cc Despite the fact that the percentage of transovarial c transmissions under European conditions is much lower than in Siberian taiga encephalitis, it is suffi- 10 cient under certain conditions to ensure the con- C tinuity of virus. Insectivores and rodents are able to harbour the virus during the winter; either long- lasting viraemia is produced, which supplies the 8~~~~~~ parasitizing larvae with the virus, or viraemia is evoked shortly after the winter sleep (posthiberna- tion viraemia).1 10 The circulation of tick-borne encephalitis virus under European conditions and its relation to the 194 190 a 9a155 ticks and their hosts is illustrated in Fig. 4 (see who61122 Year also Blaskovic & Nosek, 1965). The circulation of the virus in nature is ensured without man's activity. Man acquires the infection when any starving virus-carrying instar of the tick feeds on him. While engorging the blood-the process of full engorgement lasts several days-the .,,"_Slovakia. tick transmits the virus to man. Man, however, does not represent a further source of infection, because depends on the population of vertebrate hosts and during his viraemic stage he falls ill and, instead of vectors (BlagkoviO, 1960). The factors involved in pursuing his occupation in the wood, where he the transmission of infection from might be bitten by a starving non-infected tick, he to man have been well described by Smith (1964) rests in bed. Man is therefore a blind link in the and can be sumaizd as follows: (1) duration of circulation of tick-borne encephalitis in nature. infectivity, (2) duration of incubation period, (3) The epidemiological features of the infections stability of virus, (4) population factors, (5) climate depend on the conditions under which the virus and microclimate, (6) and human behaviour circulates in nature. These in turn depend on whether and (7) susceptibility of the host. the land is in its natural state or has been modified There are many unanswered questions concerning for raising game or domestic animals. Game-type the epidemiology, diagnosis and prophylaxis of tick- natural foci are characterized by vegetation suitable borne encephalitis. These problems are very closely for the raising of game; in these foci man becomes related to the principal one, namely, the ecology of infected only by tick bite. Pasture-type natural foci the virus. In order to supplement existing know- have developed by the conversion of wooded ledge, the team of the WHO Regional Reference habitats into pastures; man becomes infected either Laboratory for at the Institute of by tick bite or by drinking raw goat's milk. Mixed Virology, Czechoslovak Academy of Sciences, game-and-pasture natural foci are characterized by ]Bratislava, has investigated the natuiral focus of alternating wooded, bushy and grassy vegetation; tick-borne encephalitis in the Tribe region in both ways of infection are possible. Primary natural Central Slovakia. The region under investigation foci unaffected by the activity of man no longer is shown in Fig. 3; the other papers 'in this Supple- ment are devoted to the work carried out in this 1 See the paper by Nosek & Grulich, this Supplement, area. I page 31. PUBLIC HEALTH IMPORTANCE OF TICK-BORNE ENCEPHALITIS IN EUROPE 9

FIG .3 THE TRIBEC REGION OF CZECHOSLOVAKIA

Scale, 1: 320 000. exist in Europe, except perhaps in some national habitats-uncultivated and slightly, moderately or parks or in very small relict areas. highly cultivated regions-where the incidence of The cultivation of land greatly influences the ticks is inversely proportional to the degree of culti- viability of a natural focus of tick-borne encephalitis. vation of the land (Rosicky & Hejny, 1959). In a Complete cultivation, with control of small rodents, given geographical area, however, different degrees leads to almost complete eradication of ticks and to of cultivation and different natural foci may exist. control of infection. This is the case in very fertile There are micro-areas where the virus is absent and regions, converted to the efficient production of very closely related habitats where ticks are abundant cereals or vegetables. There are, however, other and may be harbouring the virus. 10 I0 ~~~~~~~~~D.BLAgKOVI'5

FIG. 4 TROPHIC CONNECTIONS OF 1. RICINUS AND POSSIBILITY OF TRANSMISSION OF TICK-BORNE ENCEPHALITIS VIRUS FROM RESERVOIRS IN TRIBEC REGION a

Free-living Artiodactyla and Carnivora Corvus, CapaeoloS, Qx'!'

Voices -K -E

The life cycle 6

Smallvertebrates ~~~~~~~Smallvertebrates

Homoiatherms: 4podemus flavicall'is, A. sylvaticos, Clethrionomys gla'realus, Micratqa arvalis, Pitymys subterreneus Micremys minotos, Scioros volgas Lepos eourpaeus, Talpa eouopaea, Sores araneus, Ayes Imperfect hemajothermns: Erinaceus reumanicos usgs, Citellos citellus Heteretherms: L.acefle viridis owWH6121 a Hosts established as reservoirs of TBE virus are underlined with a solid line, and those not established with a broken line.

Control measures The original method of protection was bythe well- proved immunological procedure, a specific vaccina- It is evident the effective control of tick-borne that tion programme with a formol-inactivated mouse-. encephalitis in man must be based on an exact braln vaccine being established (Smorodincev et al., knowledge of the conditions that govern the circula- 1940). Simultaneously, the use of serum from con- of the virus in nature. This how- dion knowledge is, valescent patients in the treatment of the acute ever, not yet fully available and further studies are phase of the disease was recommended (Shapoval needed to elucidate (a) how a natural focus of given et at., 1939). In addition to the use of human con- tick-borne encephalitis how it becomes persists, (b) valescent serum, the administration of hyperimmune extinct, and how a focus in an area (c) develops horse and goat sera was suggested (tumakov, 1940). where no human infection has occurred. previously The individual protection of man agalnst infection These problems are closely related to the possibility in a natural focus of infection is achieved by wearing of forecasting the spread of the virus in nature and suitable clothes, using repellents and, chiefly, care- making an epidemiological prognosis (the pro- fully removing unfed ticks from the body. Such of gramme epidemiological surveillance). individual protection is suitable for scientists and

Ecological studies on the vector and its host their helpers who are investigating a natural focus of animals have opened up another way of control: the infection 'or for other specialists (e.g., engineers., control of ticks and rodents and the ind'iv'idual geologists and foresters) during their exploratory protection of man. work in woods. Tt is not practical for woodcutters, PUBLIC HEALTH MPORTANCE OF TICK-BORNE ENCEPHALITIS IN EUROPE 11 other people who workregularly in woods or campers. European countries. There is the danger of extermi- Other measures, which lower or even eradicate nating useful insects (e.g., bees) or, if pastures are the tick population in woods, are more important. treated, of impairing the health of grazing domestic Two ways are recommended: agricultural improve- animals or the quality of their milk. ment of fields and meadows, with a ban on pasturing The individual protection of domestic animals cattle in the woods, and dusting the ground with against ticks by applying 10% DDT powder locally insecticides (Blaskovic, 1961). on their skin is also being recommended. Ticks infest neglected pastures, fields and the edges of woods. Small rodents and grazing cattle Specific measures in the protection ofpeople provide them with food. The removal of shrubs from Very soon after the discovery of the virus, immu- pastures and the improvement of meadows, fields nization with 1 %, and later with 5 %, mouse- and footpaths reduce the number of ticks and brain formol (1: 2000)-inactivated vaccine was intro- therefore weaken the source of infection. These duced, mainly for forestry workers in the taiga methods have probably contributed largely to the region of the USSR (Smorodincev et al., 1940). eradication of tick-borne encephalitis in countries Two or three applications of the vaccine were such as Denmark and the Netherlands, where recommended. Three different strains of tick-borne agriculture has reached a high level of efficiency. encephalitis virus were used at first, but later a Two biological means of reducing the infectivity monovalent vaccine was introduced. Local reactions of ticks in nature can also be recommended. The were often observed and, exceptionally, lethal ones first consists in spreading the natural enemies of (one death among 168 000 vaccinated persons: ticks, e.g., Hunterellus hookeri and Ixodiphagus Karpov & Fedorov, 1963, p. 184). Not all of those texanus (Karpov & Fedorov, 1963). The second is vaccinated remained uninfected, but the course of more specific and uses the well-known fact that the the disease in vaccinated persons was mild. stage of immunity of an organism is a limiting factor Use of a 5 % formolized suspension from chick- in the circulation of any infectious agent in nature. embryotissuesinfectedwithtick-borneencephalitisdid Blaskovic (1962) suggested vaccinating with tick- not give a vaccine of higher immunogenic potency borne encephalitis vaccine all domestic animals than the mouse-brain vaccine, but it represented (goats, sheep, cattle) grazing on meadows and the an attempt to avoid the undesirable allergenic effect edges of woods in a natural focus ofinfection. After of brain substances (gubladze & Anjaparidze, 1954). vaccination, the animals develop specific antibodies The use of formolized, inactivated and lyophilized that protect them from further infection and conse- tissue-culture vaccine from infected culture medium quently prevent the excretion of virus in their milk. (chick-embryo fibroblasts) has been proposed Immune domestic animals may reduce the amount (Benda & Danes, 1960; Danes & Benda, 1960; of circulating virus in nature in two ways. First, Levkovich & Zasukcina, 1960). Such a vaccine is they do not develop significant, if any, viraemia being produced at present in the USSR. Three and cannot become the source of the virus for non- doses of the vaccine (1 ml each), followed by a infected ticks and, second, they regulate the amount booster dose a year after the first inoculation, are of virus in ticks that have engorged the immune being recommended (tumakov et al., 1965). The blood (Benda, 1958a, 1958b). immunogenic capacity of the vaccine is enhanced by Dusting of woods and shrubs locally or from the the addition of aluminium hydroxide. This vaccine air can be an important measure in the control of is administered to new inhabitants of a taiga region ticks. Dichlorodiphenyltrichloroethane (DDT) as a and to people working in woods known to be natural 10% dust has proved more satisfactory than hexa- foci of tick-borne encephalitis. All laboratory chlorocyclohexane (HCH) because of its higher personnel workingwiththevirusshouldbevaccinated. stability. Gorscakovskaja et al. (1953) and Gorsca- Under the conditions prevailing in Central kovskaja (1957) carried out many experiments and Europe, mass vaccination against tick-borne ence- found that 10% DDT powder used at a concentra- phalitis is not recommended. The likelihood of tion of 30-50 kg/ha kills all instars of I. persulcatus becoming infected is high only for people who come ticks. DDT should be applied in early spring while directly in contact with the circulating virus, i.e., snow is still on the ground. This massive application those who work daily in a natural focus of infection is suitable for taiga environments or large woods but (e.g., foresters, woodcutters). These people form a less so for the cultivated land and pastures of group for whom vaccination is highly desirable. 12 D. BLAtKOV16

A second group for whom vaccination is suitable virus is concerned. The serology of this group of includes people living within or near a. natural focus viruses has been well elaborated (WHO Study of infection and whose occupations or habits Group on -borne Viruses, 1961). (picking wood fruits, grazing cattle, and so on) Greater difficulties may arise when a new virus is facilitate infection. It is difficult to make vaccination isolated, and its classification and the determination obligatory for other persons who only occasionally of its health significance should be explored. For enter a natural focus, e.g., during holidays; it is, this reason, Regional Reference Laboratories for however, desirable that they should be warned Arboviruses and the World Centre for Arboviruses about the hazards of infection and its consequences have been set up by WHO. The World Centre and informed about means of personal protection maintains the prototypes of strains and immune against the ticks that carry the virus. sera, enabling isolates to be classified into known The main task, however, is to prevent circulation groups, identified with a prototype strain, or of the virus in nature, by breaking the chain of trans- accepted as new species. mission. At the same time, efforts should be con- The health importance of any new isolate should tinued to develop an attenuated live vaccine whose be carefully studied, both in the laboratory and in administration would ensure a high antigenicity and the clinic, and the epidemiology of the relevant immunogenicity, and which would be safe. disease should be invesiigated. This is very often a time-consuming procedure, further extending the LABORATORY DIAGNOSIS OF TICK-BORNE ENCEPHALMIIS effort being expended on the isolation of the virus The diagnosis of tick-borne encephalitis does not and on its biological and physicochemical charac- present any difficulties in so far as the isolation of the terization.

RtSUMt

L'auteur examine l'importance pour la sant6 publique infectes ne presentent aucun sympt8me clinique. Quant des encephalites transmises par les tiques en Europe au taux de 1etalite, il reste generalement inf6rieur a 1 %. centrale, apres un rappel historique qui montre la diffe- Le vecteur, I. ricinus, infectieux a tous les stades de son rence existant entre I'encephalite verno-estivale russe d6veloppement, assume egalement le r6le de reservoir de transmise par Ixodes persulcatus et 1'encephalite plus virus, de meme que certains rongeurs et insectivores. Wnigne d'Europe centrale transmise par I. ricinus. I1 Les facteurs epidemiologiques ne sont pas encore souligne la necessite et la difficulte de clarifier les donn6es entierement connus mais cependant les etudes detaillees actuelles concernant les nombreuses viroses du groupe de'ja effectuees justifient 1'emploi de certains moyens de des encephalites transmises par les tiques et d'adopter une lutte. Ceux-ci comprennent la vaccination des popula- terminologie plus precise. tions, des mesures d'hygiene generale, 1'extension des Certaines particularites de l'encephalite a tiques cultures, l'introduction d'ennemis naturels des tiques, ainsi d'Europe centrale sont signalees. La contamination peut que l'immunisation des animaux domestiques. Enfin r6sulter d'une morsure de tique, de l'ingestion de lait non 1'emploi des pesticides, notamment le DDT, quoique st6rilise ou de l'inhalation de poussieres infectees. En non depourvu d'inconvenients, complete la gamme des Europe, I'incidence de la maladie presente des variations mesures preventives. saisonnieres correspondant aux fluctuations des popu- L'auteur conclut que, si une vaccination de masse n'est lations de tiques. L'affection atteint principalement les pas a conseiller, tous les travailleurs sejournant reguliere- personnes agees de plus de vingt ans. Les infections ment dans un foyer naturel d'infection et le personnel de occultes sont trbs frequentes et la plupart des sujets laboratoire travaillant sur le virus devraient etre vaccin6s.

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