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

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


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

In This Article

Lyme Borreliosis

Lyme borreliosis (LB) is caused by Gram-negative spirochetes of the B. burgdorferi sensu latu group. It is an extracellular organism belonging to the order Spriochaetales. Publications reflecting clinical signs of LB date back to 1910 in Europe.[83] However, LB was not identified as a distinct clinical entity until 1975, following the detection of a geographic cluster of children with arthritis in the town Old Lyme (CT, USA).[84] In the early 1980s, B. burgdorferi sensu lato was first cultured from ticks and from patients with LB.[85,86] After identification of the causative agent, the disease has emerged as the most prevalent tick-borne infection in northern temperate climate zones around the world. In Europe, the principal vector of Borrelia is the tick I. ricinus.

Borrelia causes a multisystem, multistage inflammatory infection in humans. The most common clinical manifestation of LB is an expanding red skin lesion called erythema migrans, due to cutaneous infection with Borrelia at the site of the tick bite. This skin lesion appears approximately 7–14 days (range: 2–30 days) after the tick bite, and is recognized in approximately 75–90% of patients with objective evidence of LB. Serological diagnosis is not helpful during this stage, so early LB is diagnosed on the basis of physician-observed clinical manifestations and a history of probable exposure to infected ticks. When treated early in its course, LB responds very well to oral antibiotics. In Europe, various antibiotics are used for the therapy of LB, with a usual duration of treatment of 14 days. Patients who have solitary erythema migrans or borrelial lymphocytoma are treated orally with doxycycline, phenoxymethylpenicillin (penicillin V), amoxicillin, cefuroxime–axetil or azithromycin, and in exceptional cases with erythromycin.[87,88] However, when the infection remains untreated, the spirochete can disseminate and cause severe disease months or years after infection, affecting the skin, CNS, heart and joints.[81,87] With the exception of erythema migrans, all manifestations of LB require laboratory confirmation. This can be established by detection of antibodies against Borrelia in serum or in intrathecal fluids in case of nervous system involvement. Sometimes, direct detection of borrelial infection can be performed, such as culturing to detect the spirochetes from tissue or fluids, and PCR to detect borrelial DNA.[87–90] Nervous system involvement and Lyme carditis are treated with intravenous ceftraxione or penicillin G for 2–3 weeks and only in exceptional cases with oral doxycycline or amoxicillin. Ceftriaxone, penicillin G, doxycycline or amoxicillin are used for the therapy of acrodermatitis chronica atrophicans (duration of treatment usually 3–4 weeks) and arthritis (duration of treatment usually 4 weeks).[81,87,88,90]

Despite the proven efficacy of these regimens, there still is much controversy about the treatment of two poorly defined entities: chronic Lyme disease and post-treatment Lyme disease syndrome. These disabling syndromes occur in a small percentage (<5%) of individuals previously treated for correctly diagnosed early LB, and may last for years.[89–91]

The main clinical features of LB seem to be similar worldwide. However, due to local differences in genospecies of Borrelia, there are some obvious differences. For instance, skin disorders such as acrodermatitis chronica atrophicans and borrelial lymphocytoma occur in Europe, but are rarely observed in the USA where B. burgdorferi sensu stricto is the only cause of LB. In Europe, however, there are several other genospecies next to B. burgdorferi sensu stricto associated with LB, such as Borrelia afzelii, Borrelia garinii and, to a lesser extent, Borrelia valaisiana, Borrelia spielmanii, Borrelia bissettiiand Borrelia lusitaniae.[87,88,92] Recently, additional molecular data were reported supporting the involvement of B. bissettii in LB.[93]

Nymphal ticks probably cause the most LB cases, because they are more numerous than adult ticks, and are responsible for approximately 80% of tick bites in many areas. Furthermore, nymphs are more likely to have a longer duration of attachment, because they are relatively small compared with adult ticks, and therefore less likely to be detected.[94,95] Important competent host reservoirs in Europe are rodents, insectivores, hares and several bird species. Rodents are the main reservoir hosts for B. afzelii, whereas birds are more likely to carry B. garinii, and B. burgdorferi sensu stricto is found to a lesser extent in both birds and rodents.[96] In Europe, the mean prevalence of Borrelia infection in I. ricinus is approximately 10% for nymphs and 19% for adults. But there is a substantial variation in infection rate from 0 to 50% between and within countries. Even though comparison between studies is difficult owing to considerable differences in study methods throughout Europe, it appears that the infection rate in adult ticks shows a rising slope from western Europe (14%) to eastern Europe (24%), and from northern Europe (12%) to southern Europe (23%). Over time, however, no significant increase in tick infection rate was observed when the studies throughout Europe from 1986 to 1993 were compared with studies from 1994 to 2002.[97]

Reports of human cases with erythema migrans show a distinct seasonality. As the skin lesion usually occurs within a month after a tick bite, the seasonal pattern of early LB lags slightly behind the seasonal pattern of tick activity. From a public health perspective, the highest risk periods occur when there is an overlap of activities between reservoir hosts, ticks and humans. These activities may be influenced by climate change, since the activity of ticks is dependent on a minimal day temperature and humidity. During the past decades, ticks have increased in density and spread into higher latitudes and altitudes in Europe. Future climate change in Europe will possibly facilitate a further spread of LB and contribute to increased disease occurrence in endemic areas.[98,99] In some locations, where climate conditions will become too hot and dry for tick survival, LB may disappear.[98,99]

The surveillance of LB patients in Europe does not allow a direct comparison between countries, due to dissimilar case definitions and laboratory methods used. Despite these limitations, a geographical trend is observed for erythema migrans case patients, which is similar to the distribution of tick infection rate. It appears that both disease incidence and antibody prevalence are higher in the central and eastern parts of Europe than in the western parts, with a decreasing incidence from south to north in Scandinavia, and from north to south in Italy, Spain and Greece.[100,101] The lowest annual incidence rates for LB are found in the UK (1.5 per 100,000 in 2006) and in Portugal (0.4 per 100,000 from 1999 to 2004). In northern Europe, the highest incidences are found in the Baltic States (between 21 and 34 per 100,000) and southern Sweden (464 per 100,000 from 1997 to 2003). In central Europe, the highest incidences are found in Austria (135 per 100,000 in 2005) and Slovenia (206 per 100,000 in 2005).[100–102] Assuming a degree of stability in the European surveillance systems within countries, increases in LB have been observed in several European countries during the past decade, and the geographic distribution of cases has also expanded. This is partly due to an increased level of awareness in the general population and among medical personnel, and to better reporting.[101,100] However, several countries with increasing incidence of LB have observed changes in tick abundance, as well as changes in latitudinal or altitudinal distribution of ticks during the same time period.[99]

Apart from the preventive measures against tick bites in general, the risk of LB can be reduced by prompt tick removal. Borrelia spirochetes remain dormant in an infected tick until the tick feeds. They then multiply within the tick midgut, and migrate to their salivary glands. This process takes approximately 24–48 h, which provides a window of opportunity for prevention of Borrelia transmission.[81,103–105] Following tick removal, a person should be alert and seek treatment for signs and symptoms of LB. Testing of ticks removed from patients for Borrelia is not recommended as a diagnostic aid, because the methods are not standardized and the results do not necessarily correlate with the risk of infection. Medical guidelines from the USA suggest that antibiotic treatment should be given after the removal of ticks that have fed for more than 24 h. However, this approach is only justified in areas of very high risk where a high proportion of ticks (>20%) carry pathogenic strains of Borrelia.[81]

Vaccination against Lyme disease might be helpful to reduce the disease burden, but no Borrelia-specific vaccines have been approved in Europe. In 1998, a human vaccine was on the market in the USA, based on a highly immunogenic outer surface protein (OspA), but it was withdrawn in 2002. Although new vaccines based on B. burgdorferi antigens are currently undergoing testing, the use of an OspA vaccine in Europe will be complicated due to the greater sequence diversity in OspA among the genospecies of Borrelia circulating in Europe, necessitating the use of a multivalent OspA vaccine. With very limited targets in development for anti-Borrelia vaccines and no advanced vaccine candidates for babesiosis or anaplasmosis, the development of an anti-tick vaccine would be favorable in the future.