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

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

Disclosures

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

In This Article

Tick-borne Rickettsiosis

Rickettsiae are Gram-negative, obligate, intracellular alpha-proteobacteria in the family Rickettsaceae and order Rickettsiales. Rickettsiae are usually transmitted via arthropod vectors such as ticks, mites, lice and fleas. These vectors transmit Rickettsiae between humans, between animals, and also from animals to humans. For example, Rickettsia prowazekii, the causative agent of epidemic typhus, is transmitted between humans by fleas and lice whereas Rickettsia typhi, which causes endemic typhus, is transmitted from rats to humans by the rat flea.[106] Historically, the genus Rickettsia is divided into three groups based on clinical signs: the typhus group, the scrub typhus group and the spotted fever group. Hard ticks (Ixodidae) have been identified as the main vectors of the spotted fever syndrome in humans, which is caused by approximately 20 different Rickettsia species, of which approximately half circulate in Europe (Table 1). Many more Rickettsia species have been associated with ticks, but their potential for pathogenicity is still unknown.[107]

The clinical symptoms of spotted fever rickettsiosis usually begin 4–10 days after a tick bite, and vary depending on the rickettsial species involved. Typical signs include febrile illness, headache, malaise, muscle pain, rash, local lymphadenopathy and, for most of the spotted fevers, a characteristic inoculation eschar at the site of bite. Nonspecific laboratory anomalies comprise mild leukopenia, anemia and thrombocytopenia. The mortality rate of tick-borne rickettsiosis varies, but can be as high as 32%, which occurred in Portugal.[108] Laboratory diagnosis is predominantly based on serology or PCR, and is usually performed 1–2 weeks after the onset of illness. Thus, initial diagnosis is based on clinical signs and symptoms, and is confirmed once treatment has started. Finally, European clinicians should keep in mind other tick-borne rickettsiosis in travellers, for example Rocky Mountain spotted fever (R. rickettsii), African tick-bite fever (Rickettsia africae) and Oriental spotted fever (Rickettsia japonica).

Currently, micro-immunofluorescence is considered as a reference serological assay, but most commercially available tests offer a very limited set of antigens, mostly R. rickettsii and/or R. conorii, and serological cross-reactions with other Rickettsial pathogens are common. As a consequence, serological species identification is only possible in a few laboratories. DNA amplification and related techniques are also used for rapid and specific detection, and species identification in blood and skin samples, but reliable diagnostic tests are still lacking.[109,110]

Rickettsial diseases respond well to antibiotic therapy, particularly tetracyclines and, of these, doxycycline is the drug of choice.[111] A delay in treatment can lead to severe disease and fatal outcome for tick-borne rickettsiosis, and treatment should therefore be initiated immediately after a clinician suspects that the diagnosis could be tick-borne rickettsiosis. Fever typically subsides within 2 days after treatment when the patient receives doxycycline or another tetracycline during the first 4–5 days of illness. If a patient fails to respond to early treatment with a tetracycline antibiotic, then this indicates that their condition is not a tick-borne rickettsiosis. Severely ill patients might require longer treatment periods before clinical improvement is noted, especially if they have multiple organ dysfunctions.

In Europe, spotted fever rickettsiosis was thought to be caused by R. conorii only and was limited to the Mediterranean. In the last decade, many studies have reported increasing numbers of spotted fever rickettsiosis from central and even northern Europe. Routine serological techniques cannot distinguish among different rickettsiae species of the spotted group, and it is not always clear which Rickettsia species caused disease. In Europe, emerging tick-borne rickettsiosis caused by Rickettsia helvetica, Rickettsia massiliae, Rickettsia sibirica mongolitimonae and Rickettsia slovaca have been identified by cross-absorption serological techniques.[107] National epidemiological surveillance on spotted fever rickettsiosis is only performed in Italy and Portugal, and there the surveillances are passive and not mandatory. As a consequence, epidemiological data are scarce and dependent on the interest of physicians and scientists. In Italy and Portugal, a steep increase in spotted fever rickettsiosis in the 1970s and 1980s may be related to the advent of improved laboratory diagnostics and a shift in effectiveness of prescribed antibiotics in combination with increased awareness.[112] Since then, the incidence of spotted fever rickettsiosis fluctuated with unknown causes, which is also observed for Rocky Mountain spotted fever in the USA.[111] The annual incidence rates for Mediterranean spotted fever in Italy and Portugal are approximately 1.7 and 9.8 per 100,000 in 2006, respectively.[108] Still, tick-borne rickettsiosis is emerging and re-emerging in several European countries,[112–114] just like other tick-borne diseases. Common causes, such as an increased number of (infected) ticks, increased human contact with tick habitats, and ecological and climatological changes might underlie the increases and fluctuations in tick-borne rickettsiosis.[115,116] Sporadic cases in nondisease-endemic countries due to tourism have also been reported.[117]

The epidemiology of tick-borne rickettsiosis is intangibly linked to the biology of the vector.[118] For example, the eschar of R. slovaca is usually found on the scalp during early spring and autumn. In these seasons, Dermacentor ticks, which preferentially bite in the scalp, are mostly active.[119] Furthermore, the geographic distribution of R. slovaca coincides with the distribution of Dermacentor ticks. The underlying mechanisms of the vector specificity are unresolved. Some Rickettsiae, such as R. conorii, may be associated with only one tick vector, whereas others, for example, R. helvetica, are found in several different ticks from several different genera. Experimental infections with more than one Rickettsial species suggest that infection with one Rickettsia may block or compete with a second infection with a second Rickettsia.[120] Contrary to other tick-borne pathogens, ticks not only serve as vectors for rickettsiae, but are also considered to be the predominant and life-long reservoir host. Rickettsia is transmitted horizontally (tick–animal–tick), but can also be transmitted transstadial (from one life stage to the next) and, most importantly, transovarial, thus to their offspring. However, transovarial transmission has only been demonstrated under experimental conditions and for a few tick-borne rickettsiae. Tick-borne rickettsia's have been isolated from many natural sources, including mice, squirrels, rabbits, deer and pet animals. As humans are only occasional hosts for ticks and rarely play a role in the subsequent transmission of these Rickettsia species, they can be considered as 'accidental' or 'dead-end' hosts. Thus, Rickettsia's are thought to circulate in enzootic and epizootic cycles between wild vertebrates and ticks.

Naive ticks become infected with spotted fever rickettsiae after a blood meal from an infected host. Rickettsiae withstand digestion in the gut, and are able to pass the gut barrier via unknown mechanisms. Although experimental data are scarce, it is believed that once the tick has completed engorgement and has molted to the next developmental stage, all the tick organs are infected, including the salivary glands and ovaries. Rickettsial infection of oocysts and oogonia may result in transovarial transmission.[121] How rickettsiae survive within the tick during molting and regain infectivity during the subsequent feeding is poorly understood. It is generally believed that rickettsiae are transmitted to a vertebrate host through saliva while a tick is feeding, and that it usually takes only several hours of attachment and feeding before the rickettsiae are transmitted to the host.[303] In experimental animals, R. rickettsii infection was seldom transmitted before 10 h of feeding and often not until 24 h.[122]

As no vaccine is available, prevention is based on education and tick control. Pets should also be inspected for ticks before allowing them to enter the home.

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