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Epidemiology of European Lyme Borreliosis
Zent.bl. Bakteriol. 287, 229-240 © Gustav Fischer Verlag 1998
Zentralblatt fUr
Balderioloaie
Review
Epidemiology of European Lyme Borreliosis S. O'Connell, M. Granstrom, J.
s. Gray, and G. Stanek
Summary Lyme borreliosis occurs throughout Europe and is particularly prevalent in the east. In a small proportion of untreated cases serious sequelae may occur, but Lyme borreliosis alone does not cause death. Clinical and serological diagnosis can still be problematic and the various genomospecies may cause different disease manifestations as well as differing immunological responses. However, considerable progress has been made in standardising case definitions and serological testing and interpretation. Few countries have official reporting systems for Lyme borreliosis and most figures on incidence are extrapolated from serodiagnosis data and seroprevalence studies. Geographical varia tions in incidence seem to correlate with the prevalence of infected ticks, which are main ly associated with varied deciduous forest. The complex ecology of Lyme borreliosis makes it difficult to implement preventive measures, so improving public knowledge of risk factors and methods for personal protection remain the best option at present.
Introduction The presence of Borrelia burgdorferi in an ecosystem is only part of the equa tion leading to Lyme borreliosis in the human being. Human infection occurs only if borrelial transmission results from the bite of an infected tick, but the factors that determine the presence of infected ticks in a particular habitat to gether with those that put humans at risk are complex and may vary in differ ent European countries. Lyme borreliosis has been reported throughout Europe where it is the most common tick-borne infection, as it is in the USA. National surveillance methods in Europe, when in place, vary between countries and do not allow direct comparisons of disease incidence and prevalence rates (1). The United States, with a federal epidemiological surveillance organisation, report a major increase in notified disease incidence over the past 10 years, which is partly due to increased medical and public awareness of Lyme borreliosis, but also to a geographical expansion of the disease to previously less affected or unaffected areas (2) . This is presumed to be due to the rapid increase in the num-
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ber of white-tailed deer, with an increased presence of these animals in densely populated areas. There is no firm evidence for a similar increase in Lyme bor reliosis prevalence in Europe, though an increase in the roe deer population has been noted in some countries (3), which may have increased local abundance of the vector tick, Ixodes ricinus. Despite the fact that Lyme borreliosis has probably been more static than in the USA, the American experience has had a considerable influence on awareness of this disease in Europe. European public perceptions of Lyme borreliosis, and to a lesser but signif icant extent those of health care workers, have been coloured by media reports suggesting that the infection is difficult to diagnose and treat and has a high morbidity (4). This has led to public anxiety, incidents of unnecessary and po tentially dangerous treatment (5) and restriction of recreational activities, which may adversely affect the economies of Lyme borreliosis affected areas (6). Misdiagnosis (mainly overdiagnosis) occurs because clinical presentations of Lyme borreliosis are not unique to that condition, but may form part of the differential diagnosis in many other conditions, some with a poor prognosis. The diagnosis of Lyme borreliosis is primarily clinical, in a patient who has been exposed to the risk of tick bite. Supporting evidence is provided by labor atory investigation, usually antibody tests. Antibody test specificity is often poor and this results in low positive predictive value of serological testing, es pecially when applied to patients with non-specific symptoms and little or no risk of tick exposure. Furthermore, test sensitivity is low in early infection, be cause the antibody response takes several weeks to reach detectable levels. However, seronegativity is extremely rare in later disease. The two-step anti body test approach recently recommended by American authorities and some European workers has generally improved specificity (7). Direct detection by polymerase chain reaction is also widely available now and may provide addi tional information in cases where there is diagnostic uncertainty. The applica tion of more stringent clinical and laboratory diagnostic criteria, as demon strated in recent European studies (8, 9) reduces diagnostic error and should facilitate more accurate public perceptions of Lyme borreliosis in the future. The clinical presentations of Lyme borreliosis are variable and well docu mented (10). They range from asymptomatic infection to significant illness, usually affecting the skin, nervous and musculoskeletal systems and rarely the heart. Very few deaths associated with Lyme borreliosis have been reported in the world medical literature, and they have occurred mainly in immunocom promised patients and in patients with other concurrent tick-borne infections (11, 12). Erythema migrans (EM), the characteristic rash which may appear some days to weeks following infection, is the most common manifestation. The rash resolves completely even without treatment, but it is estimated that about 10-15 % of untreated or inadequately treated patients may develop later com plications which might require more aggressive therapy. The satisfactory out come of appropriate early treatment has been well documented in several large prospective studies (13, 14). Prompt recognition and treatment of early
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Lyme borreliosis is thus highly desirable and is achievable provided that phy sicians and people at risk of infection are aware of the condition. In contrast, chronic neuroborreliosis, probably the most feared complica tion of Lyme borreliosis, is very uncommon. It is thought to occur in fewer than 111000 cases of Lyme borreliosis, or about 3-5 cases per million population at risk (15). It is important to distinguish chronic neuroborreliosis from other conditions such as chronic fatigue syndrome and fibromyalgia, which may be triggered by many other infectious and non-infectious events, because the clin ical management strategies for these latter conditions are very different. The different manifestations of Lyme borreliosis do not show an even geo graphical distribution, partly due to the fact that several different genomospe cies of the causal agent (collectively referred to as B. burgdorferi sensu lato) are known to exist, some of which seem to be associated with particular symp toms. Only one of them, B. burgdorferi sensu stricto, has been implicated as the cause of disease in North America, mainly causing arthritis, but in Europe three genomospecies, B. afzelii, B. garinii and B. burgdorferi s. s., are known to be pathogenic and still others such as B. valaisiana (formerly VS116) and B.lusitaniae (formerly PotiB2) have been identified, but are of unknown pa thogenicity at present. B. afzelii seems to be associated with a degenerative skin condition, acrodermatitis chronica atrophicans, and B. garinii with neu rological symptoms. However, these associations are not clear cut and there is considerable overlap (16).
Reporting/Notification of Lyme borreliosis in European countries Lyme borreliosis is compulsorily notifiable to public health authorities in only two countries, Slovenia and Scotland. There appears to be a high awareness of the condition in Slovenia and over 2000 cases per year (approximately 120/100000 population), mainly EM, have been notified (8). In contrast, fewer than 10 cases per year are reported in Scotland, but it has been estab lished through reconciliation with laboratory data that notification is very in complete. Lyme neuroborreliosis is notifiable in Denmark, but this manifesta tion has limited value for the estimation of overall incidence. Lyme borreliosis temporarily became notifiable in the seven southern counties of Sweden in 1992-3 for a detailed prospective study (9). The area investigated consisted of 11 % of the area of Sweden and 24 % (2.13 million) of the population. The study reported an annual incidence of 69 cases per 100000 population (range 26-160), 77% of which were erythema migrans. Neurological presentations accounted for 16% and arthritis for 7%. Carditis was rare. Incidence rates varied in different locations within the study area, and foci of high infection risk were identified. In most other European countries notification is voluntary and is conduct ed mainly through diagnostic laboratories reporting available details of pa-
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tients with positive tests. There are several drawbacks in estimating prevalence and incidence from such data: • Seropositivity may be linked to past exposure rather than current infection, especially for residents in endemic areas. • Erythema migrans is likely to be under-reported as many patients do not have detectable antibody at this early stage of infection. This biases report ed data towards a higher proportion of more complicated later stage infec tion. • Serodiagnostic criteria vary between laboratories and may be suboptimal. • Patterns of test referral vary between countries, depending on awareness of the condition, infection prevalence, availability of resources etc. • Reporting of positive tests and relevant clinical/exposure history is likely to be more complete from publicly funded laboratories than from those in the private sector. Nevertheless voluntary reporting systems can provide some indication of en demic areas and populations at risk and may help to monitor changing epi demiology.
Incidence and prevalence studies in European countries Prospective clinically based studies yield the most accurate information about incidence, clinical presentations and outcome. Several European groups have published results of well-designed prospective studies of epidem iological and clinical features of Lyme borreliosis in defined populations (9, 13,17,18). In these studies the diagnosis of Lyme borreliosis was validated through use of clinical case definitions and, where appropriate, defined la boratory criteria. This approach, exemplified by the Swedish study (9) de scribed earlier, has the advantage of identifying early seronegative, clinically apparent infection, in addition to later stage seropositive Lyme borreliosis, thus more accurately describing the range of Lyme borreliosis presentations. In Slovenia B. burgdorferi strains from a large series of well-documented pa tients were cultured, which permitted organisms of known pathogenicity to be speciated and characterised further by a range of recently developed mo lecular methods. This approach could result in improvements in serodiagno sis and strains isolated from humans can also be compared with local tick derived strains to assess features associated with tick-human transmission, which may be relevant to vaccine development. A major advantage of pros pective studies is that long-term follow-up of well-documented groups of pa tients is possible and enables efficacy of modern treatment regimens to be assessed accurately (13, 17). While prospective studies yield the most useful data they are more costly in terms of time and resources than indirect methods, which may represent the only means to carry out surveys in some areas.
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Indirect methods may include the measurement of the abundance of Ixodes ricinus ticks, the prevalence of B. burgdorferi-infected ticks and seropreva
lence studies. All of these indirect measures have, however, weaknesses as in dicators of Lyme borreliosis. Tick abundance data give a rough estimate of disease prevalence, for example low tick abundance correlates with low inci dence of disease in northern Scandinavia (19). However, high tick abundance may occur in areas with low disease rates, for example in Ireland (20), due to a number of confounding factors. These ecological approaches may have a future for risk assessment in particular locations (21), but at present human seroprevalence studies probably represent the best indirect method to obtain epidemiological data. There are, however, many drawbacks and comparisons between studies should be made with caution, because study populations may differ widely and laboratory methods vary, using a wide range of antibody tests with differing antigens and cut-off points and varying sensitivity and specificity. Results of seroprevalence studies cannot be directly related to dis ease prevalence as a proportion of seropositive individuals may have had sub clinical infections rather than significant disease. Nevertheless, seroprevalence studies are useful, in providing snapshots of infection prevalence and baselines for future comparison, especially in high risk groups, provided that compar able laboratory methods are used and the risk groups can be properly identi fied. In this way it is possible to detect trends and several studies have shown that workers in occupations of presumed infection risk such as forestry and agriculture seemed to have higher seroprevalence rates in certain areas than city dwellers (22, 23). Information from seroprevalence studies may also be useful in identifying populations who might benefit from more in-depth stud ies or from the provision of resources for educational and prevention meas ures. Taking the limitations of seroprevalence methods into account, it is clear that the disease shows a gradient of increasing incidence from west to east, al though pockets of high-endemicity are also present in low-prevalence coun tries (19,24,25). A gradient of decreasing incidence from south to north in Scandinavia and north to south in Italy, Spain and Greece has been noted (3, 26,27,28,29). The highest incidence rates are reported from central-eastern Europe (8, 30, 31, 32), for example in local areas in Austria an average rate of Lyme borreliosis of 300/100000 inhabitants, peaking at 350/100000 in habitants for the eastern and southern states Wien, Niederosterreich, Steier mark and Karnten (30). Estimates of annual incidence in Europe are present ed in Table 1, which is based on a WHO workshop on Lyme Borreliosis Di agnosis (1). Some of the figures have been obtained by extrapolation and ex cept for the few based on detailed studies all these estimates should be regard ed with caution. Although many need to be reassessed in the light of improved case definitions (33) and laboratory diagnostic methods (7), the overall in creasing incidence from west to east is clear. The prevalence of infected ticks in Europe also seems to show this trend (21) and is probably a contributory factor to the trend in case incidence.
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Table 1. Estimated Lyme borreliosis annual incidence in selected European countries Country
Incidence per 100,000 population
Estimated annual number of cases
*UK
0.3 0.6 16.0 25 .0 30.4 39.0 55.0 69.0 120.0 130.0
200 30 7,200 20,000 2,000 3,500 3,500 7,120 2,000 14,000
Ireland France '·Germany *Switzerland *Czech Republic Bulgaria Sweden (south) Slovenia Austria
,. No published figures available. All these data should be regarded with caution in view of recent improvements in case definitions and serodiagnosis.
Seroprevalences are also increased in individuals involved in certain occu pations (forestry workers [22, 23, 34, 35, 36]) in some recreational activities (Swiss orienteers [34]) and when visiting high-endemic areas both in Europe and the east coast of the US as tourists (20). However, identification of high risk groups is not always straight forward and confounding factors are evi dently present. For example, Swedish orienteers have been shown to have sim ilar seroprevalences to the general population (19), and in Ireland, park rang ers who are frequently exposed to ticks in areas where cases have occurred, were found to be seronegative (Robertson et aI., in preparation). Gender appears to influence seroprevalence and disease incidence rates and most studies report higher rates for males. This is presumed to be due to high er occupational risk and outdoor recreational activity (31). The nature of dis ease manifestations, are also influenced by age. Radiculopathy, a relatively common complication in adults, is rarely seen in children, while facial palsy is the most common paediatric neurological manifestation of Lyme borrelio sis (37, 38, 39). Acrodermatitis chronica atrophicans, the chronic skin mani festation, mainly occurs in elderly women (40) and while a specific age-related reactivity is not evident in Lyme borreliosis arthritis, most cases occur in adults (41). Some reports suggest that Lyme borreliosis incidence is generally higher in children, because of their greater tendency to make close contact with tick habitat (42) . Local areas of extremely high seroprevalence and disease incidence have been identified in several countries (8, 19). For instance, a study in the Stock holm area included four areas in the archipelago of islands outside Stockholm and one island in Lake Malaren. The seroprevalence of B. burgdorferi s. 1. in fection among the inhabitants, representing mainly people from the greater
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Stockholm area spending summer vacations in their cottages on the islands, varied between 7-29% and increased with age. In an area with 29% seroposi tivity by sonicate antigen ELISA, 3.9% of the inhabitants developed clinical Lyme borreliosis during a two-year survey (19). Seroprevalence studies in large samples of the general population are not available from any European country, but would represent the best indirect measure of infection prevalence if the sample groups were well characterised. Seroepidemiological studies in blood donors are a way of obtaining represen tative samples of the general population in a country (43,44), though results may be limited to certain areas and may be difficult to compare between coun tries, or even laboratories, due to methodological differences. However, com parisons may be made within Europe if the studies are large and extensive enough, since European blood donors are healthy, unpaid volunteers and blood samples are available at well-organised blood banks. Although a cer tain bias in age and gender in relation to the general population can be ex pected, for example donors are more likely to be young and male, the same bias may be expected all over Europe. In a recent study involving blood donors in Sweden (M. Granstrom, unpub lished) it was shown that seroprevalence could be related to case incidence. Using a B. burgdorferi flagellar antigen ELISA, the highest seroprevalence rates were found in southern (eastern) Sweden, largely corresponding to the study area of a southern Sweden incidence study (9). The exact incidence data (kindly provided by J. Berglund for this review) were found to be highly cor related with the seroprevalence data (correlation coefficient r =0.9, p = 0.0031).
Prevention I risk reduction measures Exposure to ticks is the prime risk factor for Lyme borreliosis acquisition, but widespread environmental manipulation to reduce tick numbers is unlikely to be feasible or environmentally acceptable. The tick maintenance hosts and spirochaete reservoir hosts in Lyme borreliosis foci are usually wild animals and targeting ticks on these animals is very difficult. Success depends largely on the development of systems for the self-application of acaricides (45, 46, 47), and while the technology for effective systems will undoubtedly be devel oped in time, their use will probably be limited to highly focal situations, such as suburban areas or small recreational parks. Attempts to control deer, the main reproduction host for ticks, have included exclusion by fencing (48) and depopulation by culling and removal (49) (and perhaps contraception in the future), but there is a widespread view that such measures would not be suf ficiently practical for large scale use. On a smaller scale, local environmental measures such as keeping grass verges short, application of acaricides to veg etation and/or hosts and use of deer fencing, may be appropriate in certain limited circumstances, particularly in gardens and recreational parks (50).
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Considerable interest has been shown in the development of safe and effec tive vaccines against Lyme borreliosis and recombinant versions of two outer surface proteins (OspA and OspC) are the subject of human trials (51). How ever, the heterogeneity of these outer surface proteins is considerable and it is unlikely that adequate protection against all B. burgdorferi s.l. strains in any one geographical area will be achieved. This is likely to be a particular prob lem in Europe, where several different genomospecies exist (52), each of which especially B. garinii, shows heterogeneity. Multivalent subunit vaccines are only at an early stage of development. At present personal measures to avoid tick bites, prompt removal of feed ing ticks and early recognition of infection remain the major protection against Lyme borreliosis. For some years the conventional wisdom has been that little risk of disease transmission exists if feeding ticks are removed dur ing the first 24 hours (53). However, studies by EUCALB participants have shown that transmission by I. ricinus can occur much earlier than this. In a case control study (G. Stanek. pers. comm.) mean I. ricinus tick attachment periods for a group of patients that developed erythema migrans (EM) (30 hours) did not differ significantly from those for another group in which no symptoms manifested (27 hours). However, several patients in the first group showed EM symptoms after tick attachment periods of less than 2 hours. The suggestion that early transmission can take place is supported by laboratory experiments carried out by other EUCALB participants which showed that transmission of B. burgdorferi s.l. by I. ricinus nymphs to gerbils can take place after only 17 hours of feeding (54). In the light of these data it is evident that very frequent personal inspection for ticks may be necessary in some Lyme borreliosis foci. The most effective preventive measures against Lyme borreliosis currently depend on awareness of Lyme borreliosis. Workers in high-risk occupations and long-term residents of endemic areas are likely to recognise ticks and may have some Lyme borreliosis awareness, whereas many other people, especial ly city dwellers and visitors from non- and low endemic regions, may have lit tle or no knowledge of ticks and inaccurate perceptions of the disease. These people may acquire infection during brief exposure in high endemic areas and the condition may not be recognised by them or their doctors, so that a pro portion of them could go on to develop disseminated or chronic disease, which may remain undiagnosed. To combat this, awareness of Lyme borreliosis in the general population should be increased throughout Europe, even in areas of low endemicity. In conclusion it is evident that the prevalence of Lyme borreliosis varies considerably in different European countries with an overall increasing prev alence from west to east. Although much data were obtained when awareness was sometimes low and the available clinical case definitions and serological methods were not optimal, recent studies suggest that the overall trends re ported here are genuine. Information on the distribution of genomospecies of B. burgdorferi (52), on the prevalence of infected ticks and on the nature of
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habitats in Lyme borreliosis foci (21) show differences within Europe which seem to be relevant to human infection prevalence and possibly to the differ ent manifestations encountered. It is also apparent that a high level of aware ness of the complex nature of this disease is desirable for its recognition, treat ment and prevention.
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31. Hulinska, D., D.]anovska, and]. Basta: Lyme borreliosis - Epidemiological sur vey in the Czech Republic in 1994. In: Report of WHO workshop on Lyme Bor reliosis diagnosis and surveillance, Warsaw, Poland, 20-22 june, 1995, WHO/ CDSNPHl95.141-1 (1996) 53-60 32. Lakos, A.: Lyme borreliosis in Hungary - epidemiological analysis of 1175 cases. In: Report of WHO workshop on Lyme Borreliosis diagnosis and surveillance, Warsaw, Poland, 20-22 june, 1995, WHO!CDSNPHl95.141-1 (1996) 84-102 33. Stanek, G., S. O'Connell, M. Cimmino, E. Aberer, W. Kristoferitsch, M. Gran strom, E. Guy, and j. Gray: European Union Concerted Action on risk assessment in Lyme borreliosis: clinical case definitions for Lyme borreliosis. Wien. Klin. Wo chenschr. 106 (1996) 741-747 34. Gern, L.: Lyme borreliosis in Switzerland. In: Report of WHO workshop on Lyme Borreliosis diagnosis and surveillance, Warsaw, Poland, 20-22 june, 1995, WHO! CDSNPHl95.141-1 (1996) 152-156 35. Schwartz, B. S. and M. D. Goldstein: Lyme disease in outdoor workers: risk fac tors, preventative measures, and tick removal methods. Amer. J. Epidemiol. 131 (1990) 877-885 36. Cinco, M., D. Balanzin, P. Benussi, and G. Trevisan: Seroprevalence and incidence of Lyme borreliosis in forestry workers in Friuli Venezia Giulia (Northern Italy) Alpe Adria Microbiol. j. 2 (1993) 91-98 37. Christen, H.].: Lyme neuroborreliosis in children. Ann. Med. (1996) 28 235-240 38. Dressler, F.: Lyme borreliosis in European children and adolescents. Clin. Exp. Rheumatol. suppl. 10 (1994) 49-54 39. Hammers-Berggren, S., U. Andersson, and G. Stiernstedt: Borrelia arthritis in Swedish children. Clinical manifestation in 10 children. Acta. Paediat. 81 (1992) 921-924 40. Asbrink, E., A. Hovmark, and B. Hederstedt: The spirochetal etiology of acroder matitis chronica atrophicans Herxheimer Acta. Derm. Venereol. (Stockholm). 64 (1984) 506-512 41. Stanek, G., M. Pletschette, H. Flamm, A. M. Hirschi, E. Aberer, W. Kristoferitsch, and E. Schmutzhard: European Lyme borreliosis. Ann. NY. Acad. Sci. 539 (1988) 274-282 42. Christen, H.-j., F. Hanefeld, H. Eiffert, and R. Thomssen: Lyme borreliosis in chil dren in "Lyme Borreliosis" Edited by J. S. Axford and D. H . E. Rees, Plenum Press, New York, (1994) 13-20 43. Weiland, T., P. Kuhnl, R. Laufs, and]. Heesemann: Prevalence of Borrelia burgdor feri antibodies in Hamburg blood donors. Beitrage zur Infusionther. 30 (1992) 9295 44. Bohme, M., j. Schembra, H. Bocklage, S. Schwenecke, E. Fuchs, H. Karch, and D. Wiebecke: Infections with Borrelia burgdorferi in Wurzburg blood donors: anti body prevalence, clinical aspects and pathogen detection in antibody positive do nors. Beitrage zur Infusionsther. 30 (1992) 96-99 45. Mather, T. N., j. Ribeiro, and A. Spielman: Lyme disease and babesiosis: acaricide focused on potentially infected ticks. Am. j. Trop. Med. Hyg. 36 (1987) 609-614 46. Sonenshine, D. E., S. A. Allan, R. A. Norval, and M.]. Burridge: A selfmedicating applicator for control of ticks on deer. Med. Vet. Entomol. 10 (1996) 149-154 47. Pound,]. M.,]. A. Miller, j. E. George, D. D. Oehler, and D. E. Harmel: Systemic treatment of white-tailed deer with ivermectin-medicated bait to control free-living populations of lone star ticks (Acari: Ixodidae). J. Med. Entomol. 33 (1996) 385394
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48. Stafford, K. c.: Reduced abundance of Ixodes scapularis (Acari: Ixodidae) with ex clusion of deer by electric fencing. J. Med. Entomol. 30 (1993) 986-96 49. Wilson, M. L., S. R. Telford, III, j. Piesman, and A. Spielman: Reduced abundance of immature Ixodes dammini (Acari: Ixodidae) following elimination of deer. J. Med. Entomol. 4 (1988) 224-228 50. Fish, D.: Environmental risk and prevention of Lyme disease. Am. J. Med. 98 (1995) p2S-8S; discussion 8S-9S 51. Wormser, G. P.: Lyme disease vaccine. Infection 24 (1996) 203-207 52. Saint Girons, I., L. Gem, j. S. Gray, E. C. Guy, E. Korenberg, P. A. Nuttall, D. Post ic, S. Rijpkema, A. Schonberg, and G. Stanek: Identification of Borrelia burgdorfe ri sensu lato species in Europe. Zbl. Bakt. (this publication) 53. Piesman, j., T. N. Mather, R.J. Sinsky, and A. Spielman: Duration of tick attach ment and Borrelia burgdorferi transmission. Clin. Microbiol. 25 (1987) 557-556 54. Kahl, 0., c.Janetzki-Mittman, j. S. Gray, R.Jonas, J. Stein, and R. de Boer: Risk of infection with Borrelia burgdorferi sensu lato for a host in relation to the dura tion of nymphal Ixodes ricinus feeding and the method of tick removal. Zent.bl. Bakteriol. in press
Zentralblatt fUr
Balderioloaie
Review
Epidemiology of European Lyme Borreliosis S. O'Connell, M. Granstrom, J.
s. Gray, and G. Stanek
Summary Lyme borreliosis occurs throughout Europe and is particularly prevalent in the east. In a small proportion of untreated cases serious sequelae may occur, but Lyme borreliosis alone does not cause death. Clinical and serological diagnosis can still be problematic and the various genomospecies may cause different disease manifestations as well as differing immunological responses. However, considerable progress has been made in standardising case definitions and serological testing and interpretation. Few countries have official reporting systems for Lyme borreliosis and most figures on incidence are extrapolated from serodiagnosis data and seroprevalence studies. Geographical varia tions in incidence seem to correlate with the prevalence of infected ticks, which are main ly associated with varied deciduous forest. The complex ecology of Lyme borreliosis makes it difficult to implement preventive measures, so improving public knowledge of risk factors and methods for personal protection remain the best option at present.
Introduction The presence of Borrelia burgdorferi in an ecosystem is only part of the equa tion leading to Lyme borreliosis in the human being. Human infection occurs only if borrelial transmission results from the bite of an infected tick, but the factors that determine the presence of infected ticks in a particular habitat to gether with those that put humans at risk are complex and may vary in differ ent European countries. Lyme borreliosis has been reported throughout Europe where it is the most common tick-borne infection, as it is in the USA. National surveillance methods in Europe, when in place, vary between countries and do not allow direct comparisons of disease incidence and prevalence rates (1). The United States, with a federal epidemiological surveillance organisation, report a major increase in notified disease incidence over the past 10 years, which is partly due to increased medical and public awareness of Lyme borreliosis, but also to a geographical expansion of the disease to previously less affected or unaffected areas (2) . This is presumed to be due to the rapid increase in the num-
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ber of white-tailed deer, with an increased presence of these animals in densely populated areas. There is no firm evidence for a similar increase in Lyme bor reliosis prevalence in Europe, though an increase in the roe deer population has been noted in some countries (3), which may have increased local abundance of the vector tick, Ixodes ricinus. Despite the fact that Lyme borreliosis has probably been more static than in the USA, the American experience has had a considerable influence on awareness of this disease in Europe. European public perceptions of Lyme borreliosis, and to a lesser but signif icant extent those of health care workers, have been coloured by media reports suggesting that the infection is difficult to diagnose and treat and has a high morbidity (4). This has led to public anxiety, incidents of unnecessary and po tentially dangerous treatment (5) and restriction of recreational activities, which may adversely affect the economies of Lyme borreliosis affected areas (6). Misdiagnosis (mainly overdiagnosis) occurs because clinical presentations of Lyme borreliosis are not unique to that condition, but may form part of the differential diagnosis in many other conditions, some with a poor prognosis. The diagnosis of Lyme borreliosis is primarily clinical, in a patient who has been exposed to the risk of tick bite. Supporting evidence is provided by labor atory investigation, usually antibody tests. Antibody test specificity is often poor and this results in low positive predictive value of serological testing, es pecially when applied to patients with non-specific symptoms and little or no risk of tick exposure. Furthermore, test sensitivity is low in early infection, be cause the antibody response takes several weeks to reach detectable levels. However, seronegativity is extremely rare in later disease. The two-step anti body test approach recently recommended by American authorities and some European workers has generally improved specificity (7). Direct detection by polymerase chain reaction is also widely available now and may provide addi tional information in cases where there is diagnostic uncertainty. The applica tion of more stringent clinical and laboratory diagnostic criteria, as demon strated in recent European studies (8, 9) reduces diagnostic error and should facilitate more accurate public perceptions of Lyme borreliosis in the future. The clinical presentations of Lyme borreliosis are variable and well docu mented (10). They range from asymptomatic infection to significant illness, usually affecting the skin, nervous and musculoskeletal systems and rarely the heart. Very few deaths associated with Lyme borreliosis have been reported in the world medical literature, and they have occurred mainly in immunocom promised patients and in patients with other concurrent tick-borne infections (11, 12). Erythema migrans (EM), the characteristic rash which may appear some days to weeks following infection, is the most common manifestation. The rash resolves completely even without treatment, but it is estimated that about 10-15 % of untreated or inadequately treated patients may develop later com plications which might require more aggressive therapy. The satisfactory out come of appropriate early treatment has been well documented in several large prospective studies (13, 14). Prompt recognition and treatment of early
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Lyme borreliosis is thus highly desirable and is achievable provided that phy sicians and people at risk of infection are aware of the condition. In contrast, chronic neuroborreliosis, probably the most feared complica tion of Lyme borreliosis, is very uncommon. It is thought to occur in fewer than 111000 cases of Lyme borreliosis, or about 3-5 cases per million population at risk (15). It is important to distinguish chronic neuroborreliosis from other conditions such as chronic fatigue syndrome and fibromyalgia, which may be triggered by many other infectious and non-infectious events, because the clin ical management strategies for these latter conditions are very different. The different manifestations of Lyme borreliosis do not show an even geo graphical distribution, partly due to the fact that several different genomospe cies of the causal agent (collectively referred to as B. burgdorferi sensu lato) are known to exist, some of which seem to be associated with particular symp toms. Only one of them, B. burgdorferi sensu stricto, has been implicated as the cause of disease in North America, mainly causing arthritis, but in Europe three genomospecies, B. afzelii, B. garinii and B. burgdorferi s. s., are known to be pathogenic and still others such as B. valaisiana (formerly VS116) and B.lusitaniae (formerly PotiB2) have been identified, but are of unknown pa thogenicity at present. B. afzelii seems to be associated with a degenerative skin condition, acrodermatitis chronica atrophicans, and B. garinii with neu rological symptoms. However, these associations are not clear cut and there is considerable overlap (16).
Reporting/Notification of Lyme borreliosis in European countries Lyme borreliosis is compulsorily notifiable to public health authorities in only two countries, Slovenia and Scotland. There appears to be a high awareness of the condition in Slovenia and over 2000 cases per year (approximately 120/100000 population), mainly EM, have been notified (8). In contrast, fewer than 10 cases per year are reported in Scotland, but it has been estab lished through reconciliation with laboratory data that notification is very in complete. Lyme neuroborreliosis is notifiable in Denmark, but this manifesta tion has limited value for the estimation of overall incidence. Lyme borreliosis temporarily became notifiable in the seven southern counties of Sweden in 1992-3 for a detailed prospective study (9). The area investigated consisted of 11 % of the area of Sweden and 24 % (2.13 million) of the population. The study reported an annual incidence of 69 cases per 100000 population (range 26-160), 77% of which were erythema migrans. Neurological presentations accounted for 16% and arthritis for 7%. Carditis was rare. Incidence rates varied in different locations within the study area, and foci of high infection risk were identified. In most other European countries notification is voluntary and is conduct ed mainly through diagnostic laboratories reporting available details of pa-
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tients with positive tests. There are several drawbacks in estimating prevalence and incidence from such data: • Seropositivity may be linked to past exposure rather than current infection, especially for residents in endemic areas. • Erythema migrans is likely to be under-reported as many patients do not have detectable antibody at this early stage of infection. This biases report ed data towards a higher proportion of more complicated later stage infec tion. • Serodiagnostic criteria vary between laboratories and may be suboptimal. • Patterns of test referral vary between countries, depending on awareness of the condition, infection prevalence, availability of resources etc. • Reporting of positive tests and relevant clinical/exposure history is likely to be more complete from publicly funded laboratories than from those in the private sector. Nevertheless voluntary reporting systems can provide some indication of en demic areas and populations at risk and may help to monitor changing epi demiology.
Incidence and prevalence studies in European countries Prospective clinically based studies yield the most accurate information about incidence, clinical presentations and outcome. Several European groups have published results of well-designed prospective studies of epidem iological and clinical features of Lyme borreliosis in defined populations (9, 13,17,18). In these studies the diagnosis of Lyme borreliosis was validated through use of clinical case definitions and, where appropriate, defined la boratory criteria. This approach, exemplified by the Swedish study (9) de scribed earlier, has the advantage of identifying early seronegative, clinically apparent infection, in addition to later stage seropositive Lyme borreliosis, thus more accurately describing the range of Lyme borreliosis presentations. In Slovenia B. burgdorferi strains from a large series of well-documented pa tients were cultured, which permitted organisms of known pathogenicity to be speciated and characterised further by a range of recently developed mo lecular methods. This approach could result in improvements in serodiagno sis and strains isolated from humans can also be compared with local tick derived strains to assess features associated with tick-human transmission, which may be relevant to vaccine development. A major advantage of pros pective studies is that long-term follow-up of well-documented groups of pa tients is possible and enables efficacy of modern treatment regimens to be assessed accurately (13, 17). While prospective studies yield the most useful data they are more costly in terms of time and resources than indirect methods, which may represent the only means to carry out surveys in some areas.
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Indirect methods may include the measurement of the abundance of Ixodes ricinus ticks, the prevalence of B. burgdorferi-infected ticks and seropreva
lence studies. All of these indirect measures have, however, weaknesses as in dicators of Lyme borreliosis. Tick abundance data give a rough estimate of disease prevalence, for example low tick abundance correlates with low inci dence of disease in northern Scandinavia (19). However, high tick abundance may occur in areas with low disease rates, for example in Ireland (20), due to a number of confounding factors. These ecological approaches may have a future for risk assessment in particular locations (21), but at present human seroprevalence studies probably represent the best indirect method to obtain epidemiological data. There are, however, many drawbacks and comparisons between studies should be made with caution, because study populations may differ widely and laboratory methods vary, using a wide range of antibody tests with differing antigens and cut-off points and varying sensitivity and specificity. Results of seroprevalence studies cannot be directly related to dis ease prevalence as a proportion of seropositive individuals may have had sub clinical infections rather than significant disease. Nevertheless, seroprevalence studies are useful, in providing snapshots of infection prevalence and baselines for future comparison, especially in high risk groups, provided that compar able laboratory methods are used and the risk groups can be properly identi fied. In this way it is possible to detect trends and several studies have shown that workers in occupations of presumed infection risk such as forestry and agriculture seemed to have higher seroprevalence rates in certain areas than city dwellers (22, 23). Information from seroprevalence studies may also be useful in identifying populations who might benefit from more in-depth stud ies or from the provision of resources for educational and prevention meas ures. Taking the limitations of seroprevalence methods into account, it is clear that the disease shows a gradient of increasing incidence from west to east, al though pockets of high-endemicity are also present in low-prevalence coun tries (19,24,25). A gradient of decreasing incidence from south to north in Scandinavia and north to south in Italy, Spain and Greece has been noted (3, 26,27,28,29). The highest incidence rates are reported from central-eastern Europe (8, 30, 31, 32), for example in local areas in Austria an average rate of Lyme borreliosis of 300/100000 inhabitants, peaking at 350/100000 in habitants for the eastern and southern states Wien, Niederosterreich, Steier mark and Karnten (30). Estimates of annual incidence in Europe are present ed in Table 1, which is based on a WHO workshop on Lyme Borreliosis Di agnosis (1). Some of the figures have been obtained by extrapolation and ex cept for the few based on detailed studies all these estimates should be regard ed with caution. Although many need to be reassessed in the light of improved case definitions (33) and laboratory diagnostic methods (7), the overall in creasing incidence from west to east is clear. The prevalence of infected ticks in Europe also seems to show this trend (21) and is probably a contributory factor to the trend in case incidence.
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Table 1. Estimated Lyme borreliosis annual incidence in selected European countries Country
Incidence per 100,000 population
Estimated annual number of cases
*UK
0.3 0.6 16.0 25 .0 30.4 39.0 55.0 69.0 120.0 130.0
200 30 7,200 20,000 2,000 3,500 3,500 7,120 2,000 14,000
Ireland France '·Germany *Switzerland *Czech Republic Bulgaria Sweden (south) Slovenia Austria
,. No published figures available. All these data should be regarded with caution in view of recent improvements in case definitions and serodiagnosis.
Seroprevalences are also increased in individuals involved in certain occu pations (forestry workers [22, 23, 34, 35, 36]) in some recreational activities (Swiss orienteers [34]) and when visiting high-endemic areas both in Europe and the east coast of the US as tourists (20). However, identification of high risk groups is not always straight forward and confounding factors are evi dently present. For example, Swedish orienteers have been shown to have sim ilar seroprevalences to the general population (19), and in Ireland, park rang ers who are frequently exposed to ticks in areas where cases have occurred, were found to be seronegative (Robertson et aI., in preparation). Gender appears to influence seroprevalence and disease incidence rates and most studies report higher rates for males. This is presumed to be due to high er occupational risk and outdoor recreational activity (31). The nature of dis ease manifestations, are also influenced by age. Radiculopathy, a relatively common complication in adults, is rarely seen in children, while facial palsy is the most common paediatric neurological manifestation of Lyme borrelio sis (37, 38, 39). Acrodermatitis chronica atrophicans, the chronic skin mani festation, mainly occurs in elderly women (40) and while a specific age-related reactivity is not evident in Lyme borreliosis arthritis, most cases occur in adults (41). Some reports suggest that Lyme borreliosis incidence is generally higher in children, because of their greater tendency to make close contact with tick habitat (42) . Local areas of extremely high seroprevalence and disease incidence have been identified in several countries (8, 19). For instance, a study in the Stock holm area included four areas in the archipelago of islands outside Stockholm and one island in Lake Malaren. The seroprevalence of B. burgdorferi s. 1. in fection among the inhabitants, representing mainly people from the greater
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Stockholm area spending summer vacations in their cottages on the islands, varied between 7-29% and increased with age. In an area with 29% seroposi tivity by sonicate antigen ELISA, 3.9% of the inhabitants developed clinical Lyme borreliosis during a two-year survey (19). Seroprevalence studies in large samples of the general population are not available from any European country, but would represent the best indirect measure of infection prevalence if the sample groups were well characterised. Seroepidemiological studies in blood donors are a way of obtaining represen tative samples of the general population in a country (43,44), though results may be limited to certain areas and may be difficult to compare between coun tries, or even laboratories, due to methodological differences. However, com parisons may be made within Europe if the studies are large and extensive enough, since European blood donors are healthy, unpaid volunteers and blood samples are available at well-organised blood banks. Although a cer tain bias in age and gender in relation to the general population can be ex pected, for example donors are more likely to be young and male, the same bias may be expected all over Europe. In a recent study involving blood donors in Sweden (M. Granstrom, unpub lished) it was shown that seroprevalence could be related to case incidence. Using a B. burgdorferi flagellar antigen ELISA, the highest seroprevalence rates were found in southern (eastern) Sweden, largely corresponding to the study area of a southern Sweden incidence study (9). The exact incidence data (kindly provided by J. Berglund for this review) were found to be highly cor related with the seroprevalence data (correlation coefficient r =0.9, p = 0.0031).
Prevention I risk reduction measures Exposure to ticks is the prime risk factor for Lyme borreliosis acquisition, but widespread environmental manipulation to reduce tick numbers is unlikely to be feasible or environmentally acceptable. The tick maintenance hosts and spirochaete reservoir hosts in Lyme borreliosis foci are usually wild animals and targeting ticks on these animals is very difficult. Success depends largely on the development of systems for the self-application of acaricides (45, 46, 47), and while the technology for effective systems will undoubtedly be devel oped in time, their use will probably be limited to highly focal situations, such as suburban areas or small recreational parks. Attempts to control deer, the main reproduction host for ticks, have included exclusion by fencing (48) and depopulation by culling and removal (49) (and perhaps contraception in the future), but there is a widespread view that such measures would not be suf ficiently practical for large scale use. On a smaller scale, local environmental measures such as keeping grass verges short, application of acaricides to veg etation and/or hosts and use of deer fencing, may be appropriate in certain limited circumstances, particularly in gardens and recreational parks (50).
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Considerable interest has been shown in the development of safe and effec tive vaccines against Lyme borreliosis and recombinant versions of two outer surface proteins (OspA and OspC) are the subject of human trials (51). How ever, the heterogeneity of these outer surface proteins is considerable and it is unlikely that adequate protection against all B. burgdorferi s.l. strains in any one geographical area will be achieved. This is likely to be a particular prob lem in Europe, where several different genomospecies exist (52), each of which especially B. garinii, shows heterogeneity. Multivalent subunit vaccines are only at an early stage of development. At present personal measures to avoid tick bites, prompt removal of feed ing ticks and early recognition of infection remain the major protection against Lyme borreliosis. For some years the conventional wisdom has been that little risk of disease transmission exists if feeding ticks are removed dur ing the first 24 hours (53). However, studies by EUCALB participants have shown that transmission by I. ricinus can occur much earlier than this. In a case control study (G. Stanek. pers. comm.) mean I. ricinus tick attachment periods for a group of patients that developed erythema migrans (EM) (30 hours) did not differ significantly from those for another group in which no symptoms manifested (27 hours). However, several patients in the first group showed EM symptoms after tick attachment periods of less than 2 hours. The suggestion that early transmission can take place is supported by laboratory experiments carried out by other EUCALB participants which showed that transmission of B. burgdorferi s.l. by I. ricinus nymphs to gerbils can take place after only 17 hours of feeding (54). In the light of these data it is evident that very frequent personal inspection for ticks may be necessary in some Lyme borreliosis foci. The most effective preventive measures against Lyme borreliosis currently depend on awareness of Lyme borreliosis. Workers in high-risk occupations and long-term residents of endemic areas are likely to recognise ticks and may have some Lyme borreliosis awareness, whereas many other people, especial ly city dwellers and visitors from non- and low endemic regions, may have lit tle or no knowledge of ticks and inaccurate perceptions of the disease. These people may acquire infection during brief exposure in high endemic areas and the condition may not be recognised by them or their doctors, so that a pro portion of them could go on to develop disseminated or chronic disease, which may remain undiagnosed. To combat this, awareness of Lyme borreliosis in the general population should be increased throughout Europe, even in areas of low endemicity. In conclusion it is evident that the prevalence of Lyme borreliosis varies considerably in different European countries with an overall increasing prev alence from west to east. Although much data were obtained when awareness was sometimes low and the available clinical case definitions and serological methods were not optimal, recent studies suggest that the overall trends re ported here are genuine. Information on the distribution of genomospecies of B. burgdorferi (52), on the prevalence of infected ticks and on the nature of
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habitats in Lyme borreliosis foci (21) show differences within Europe which seem to be relevant to human infection prevalence and possibly to the differ ent manifestations encountered. It is also apparent that a high level of aware ness of the complex nature of this disease is desirable for its recognition, treat ment and prevention.
References 1. Report of WHO workshop on Lyme Borreliosis diagnosis and surveillance, War saw, Poland, 20-22 june, 1995, WHO/CDSNPHl95. (1996) 141-1220 2. Dennis, D. T.: Country report on Lyme disease. United States. In: Report of WHO workshop on Lyme Borreliosis diagnosis and surveillance, Warsaw, Poland, 20-22 june, 1995, WHO/CDSNPHl95.141-1 (1996) 160-181 3. Granstrom, M.: Country report: Sweden. In: Report of WHO workshop on Lyme Borreliosis diagnosis and surveillance, Warsaw, Poland, 20-22 june, 1995, WHO/ CDSNPHl95.141-1 (1996) 144-151 4. Sigal, L. H.: Lyme disease controversy; social and financial costs of misdiagnosis and mismanagement. Arch. Intern. Med. 156 (1996) 1493-1500 5. Ettestad, P. j., G. L. Campbell, S. F. Weibel, C. A. Genese, K. C. Spitalny, C. M. Marchetti, and D. T. Dennis: Biliary complications in the treatment of unsubstan tiated Lyme disease. J. Inf. Dis. 171 (1995) 356-361 6. Wormser, G. P.: Prospects for a vaccine to prevent Lyme disease in humans. Clin. Infect. Dis. 21 (1995) 1267-1274 7. Anonymous: Recommendations for test performance and interpretation from the second national conference on serologic diagnosis of Lyme disease. Morb. Morta!' Wkly. Rep. 44 (1995) 590-591 8. Strle, F. and M. Stantic-Pavlinic: Lyme disease in Europe. N. Eng!. j. Med. 334 (1996) 803 9. Berglund, ]., R. Eitrem, K.Ormstein, A. Lindberg, A. Ringner, H. Elmrud, M. Carlsson, A. Runehagen, C. Svanborg, and R. Norrby: An epidemiological study of Lyme disease in southern Sweden. N. Eng!. J. Med. 333 (1995) 1319-1324 10. Pfister, H. W, B. Wilske, and K. Weber: Lyme borreliosis: basic science and clinical aspects. Lancet 343 (1994) 1013-1016 11. Marcus, L. c., A. C. Steere, P. H. Duray, A. E. Anderson, and E. B. Mahoney: Fa tal pancarditis in a patient with coexistent Lyme disease and babesiosis. Ann. Intern. Med. 103 (1985) 374-376 12. Krause, P.]., S. R. Telford, A. Spielman, V. Sikand, D. Christianson, G. Burke, P. Brassard, R. Pollack, j. Peck, and D. H. Persing: Concurrent Lyme disease and babesiosis. Evidence for increased severity and duration of illness. j. Am. Med. As soc. 275 (1996) 1657-1660 13. Strle, F., ]. Nelson, E. Ruzic-Sabljic, j. Cimperman, V. Maraspin, S. Lotric-furlan, Y. Cheng, M. M. Picken, G. M. Trenholm, and R. M. Picken: European Lyme bor reliosis: 231 culture-confirmed cases involving patients with erythema migrans. Clin. Infect. Dis. 23 (1996) 61-65 14. Nadelman, R. B., ]. Nowakowski, G. Forseter, N. S. Goldberg, S. Bittker, D. Coo per, M. Aguero-Rosenfeld, and G. P. Wormser: The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans. Am. J. Med. 100 (1996) 502-508 16
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