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


In 1994, the causative agent of what was initially known as human granulocytic ehrlichiosis (HGE) agent[37] and was later named human granulocytic anaplasmosis (HGA), Anaplasma phagocytophilum, was found to cause disease in humans. It was also found to be genetically different from the agent responsible for human monocytic ehrlichiosis, Ehrlichia chaffeensis.[38] There exists, however, a close relationship with Ehrlichia equi and Ehrlichia phagocytophila, known to infect neutrophils in animals. The HGE agent was originally placed in the genus Ehrlichia, but with the reorganization of the genera in the Rickettsiaceae and Anaplasmataceae families (order Rickettsiales), E. phagocytophila, E. equi and the HGE agent were united as a single species – A. phagocytophilum – in the genus Anaplasma.[39] Several A. phagocytophilum strains were identified; for example, A. phagocytophilum-HZ, -Webster, -USG3 and genotypes Ap1–6.[40]

In Europe, I. ricinus (the sheep tick) is, according to current knowledge, the only vector for A. phagocytophilum. All instars of I. ricinus bite humans, but nymphs are probably more involved in pathogen transfer than larvae or adults.[41] Numerous mammalian species have been suggested or identified as reservoirs for A. phagocytophilum (Apodemus agrarius, Apodemus sylvaticus, Apodemus flavicollis, Apodemus peninsulae and Rattus norvegicus).[42–46] White-tailed and roe deer (Odocoileus virginiansusand Capreolus capreolus) are reservoirs, but most likely not for the strains that cause disease in humans.[47] Domestic dogs may also be acting as a reservoir in urban environments.[48] Massung et al. also demonstrated that goats are reservoir-competent for the Ap-variant 1 strain.[49] Birds (Turdus merula and Fringella coelebs) could also be competent reservoirs.[40,50–52]

Human granulocytic anaplasmosis can thus be described as a tick-borne rickettsial infection of neutrophils caused by infection with A. phagocytophilum. The numbers of HGA cases in the USA – the region where the disease was first described – have increased markedly.[38] HGA infections in Europe are also now commonly recognized.[53] In the USA, a mortality rate of 7–10% has been reported, whereas in Europe no fatal cases have been noted to date.[38] Pathogen prevalence in ticks ranges from moderate to high in European studies and suggests that this infection is widespread in most of Europe but is also still largely unrecognized.[38,54] The first European HGA case was reported from Slovenia in 1995.[55] Although serological evidence of the disease has been reported frequently in most European countries, few acute cases have been described – the presence of morulae in granulocytes (a hallmark for infection in the USA) was only noted in approximately 30% of the European cases. Cases have been reported from Slovenia (first confirmed case in Europe[55–57]), The Netherlands,[58] Germany,[59,60] France,[61,62] Italy,[63,64] Spain,[65,66] Sweden,[67,68] Norway,[69,70] Austria,[71,72] Switzerland (first serological evidence in Europe[73,74]), Greece,[75] Poland[76,77] and Belgium.[78,79] Limited evidence is currently available for A. phagocytophilum persistence in humans.[80] The median infection prevalence in European I. ricinus ticks is approximately 3%.[38]

As a rule, and supported by the recommendations of the guidelines published by the Infectious diseases Society of America, all symptomatic patients suspected of HGA should receive antimicrobial therapy given the risk of complications, and antibiotic therapy should not be delayed in a patient with a suggestive clinical presentation pending laboratory results;[81] although mild, self-limited illness in most cases and serious manifestations of infection, in some cases with fatal outcome, have been reported in immunosuppressed patients.[82] Chronic infection due to A. phagocytophilum has not been described thus far in humans. Serologic testing is often the only way of diagnosis if the patient, as is often the case in Europe, is already on antibiotic treatment.

Human granulocytic ehrlichiosis is suspected when a patient presents with acute onset of unexplained fever, headache, chills and a history of tick bite – in Europe by I. ricinus, in the USA by I. scapularis or I. pacificus ticks – 10 days to 3 weeks before the onset of symptoms. In the majority of the cases of thrombocytopenia, leukopenia and/or increased liver enzyme levels (GOT and GPT) are the hallmarks of diseases (see CDC HGA case definition 2008[302]).

Doxycycline is the treatment of choice for patients with suspected HGA. This treatment should be succesful in patients with HGA alone or with B. burgdorferi coinfection. Persistence of fever for more than 48 h after doxycycline treatment was initiated is suggestive of an incorrect diagnosis of HGA. Asymptomatic individuals with antibodies to A. phagocytophilum should not receive antibiotics.