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Epidemiology of relapsing fever borreliosis in Europe

Stanislas Rebaudet, Philippe Parola
DOI: http://dx.doi.org/10.1111/j.1574-695X.2006.00104.x 11-15 First published online: 1 October 2006


Tick-borne relapsing fever is a bacterial infection caused by spirochetes of the genus Borrelia. This zoonotic disease is transmitted to humans through the bite of soft ticks of the genus Ornithodoros. It is responsible for recurring fever access associated with spirochetemia. We present here an overview of tick-borne relapsing fever occurring in Europe, as well as of the potential threat to travellers.

  • relapsing fever
  • recurrent fever
  • Borrelia
  • ticks
  • Ornithodoros
  • Europe

Relapsing fever (RF) is a disease caused by several spirochetes of the genus Borrelia (Cutler, 2006). Relapsing fever borrelioses are characterized by recurrent febrile episodes and spirochetemia. Currently, two categories of RF are known to affect human beings. The louse-borne relapsing fever (also known as urban or epidemic RF) is caused by Borrelia recurrentis, and is transmitted by the body louse Pediculus humanus humanus. Historically, massive outbreaks have occurred in Eurasia and Africa, especially during wartime, when people were highly parasitized with body lice (Barbour & Hayes, 1986). Currently, the disease is found only in Ethiopia and neighbouring countries (Raoult & Roux, 1999). Although its occurrence among homeless people of industrialized European cities has been suspected (Brouqui et al. 2005), louse-borne relapsing fever will not be discussed further in this paper.

Endemic tick-borne relapsing fever (TBRF), on the other hand, is a zoonotic disease transmitted worldwide by soft-body ticks of the genus Ornithodoros. It is caused by at least 15 distinct Borrelia species throughout the world. The disease was mentioned in 1857 by Livingston, who described a recurrent febrile illness among African natives who were exposed to ticks (Carlisle, 1906). The causative link with ticks was reported in 1905 by Dutton and Todd, who demonstrated spirochetes in Ornithodoros moubata in East Africa (Dutton & Todd, 1905). TBRF is reported in North and South America, Africa, Asia and Europe. Within each region, specific relationships usually exist between the Ornithodoros vector species, Borrelia species, and the distribution area (Fig. 1). Reservoir hosts are usually wild rodents.

Figure 1

Distribution of tick-borne relapsing fever borreliosis agents and their specific vectors of the genus Ornithodoros.

Borrelia are wavy, helical, flagellated bacteria, with length and diameter ranging from 8 to 30µm and from 0.2 to 0.5µm, respectively (Barbour & Hayes, 1986). An interesting feature of TBRF borreliae is their ability to undergo spontaneous antigenic variation on their outer membrane proteins, which are termed variable major proteins (vmp). These vmp antigenic variants determine serotype identity (Schwan & Hinnebusch, 1998; Nordstrand et al. 2000). Genomic data (from sequencing of rrs and flageline genes) has provided new insights on RF Borrelia phylogenetic classification and taxonomy (Fukunaga et al. 1996; Ras et al. 1996). Consequently, the genus Borrelia includes three main clusters: (1) Lyme Borrelia species (agents of Lyme disease, and transmitted by hard ticks of the genus Ixodes); (2) New World TBRF Borrelia; and (3) Old World TBRF Borrelia. This third cluster includes the louse-borne B. recurrentis.

Ornithodoros ticks are included in the soft-tick family Argasidae (Parola & Raoult, 2001; Horak et al. 2002). These arthropods are hematophagous at all growing stages. Apart from the larval stages, argasids may feed up to 10 times, during which they become replete in a few hours. They live close to their host, although the time spent on the host is relatively short. After each meal they are found in their habitats, typically cracks and crevices of rodent burrows, but also human shelters or just below the soil surface. Ticks are infected during a blood meal on a vertebrate with spirochetemia. Borrelia then spread in all tissues, including ovaries (responsible for transmission between the different tick stages and between generations), salivary glands and excretory organs. Vertebrates and humans become infected during a blood meal through contamination of the feeding site by salivary and/or coxal secretions (Parola & Raoult, 2001). Transmission of TBRF has also occurred through transfusion, during laboratory accident, and through placenta (Hira & Husein, 1979; Melkert & Stel, 1991).

TBRF begins between 4 and 14 days after the tick bite with an acute onset of high fever, chills, constitutional symptoms and iritis (Johnson & Golightly, 2000). Severity depends on Borrelia species, inoculum density, and underlying medical condition. Children and women appear to have a more intense course of disease (Barbour, 1999). Neurological findings are frequent and may sometimes be severe (Cadavid & Barbour, 1998). Abortion is frequent (up to 50%) in patients who are infected during pregnancy (Jongen et al. 1997). Recent data suggest that visceral manifestations and particularly neurological presentation may be caused by vascular microemboli secondary to erythrocytes rosetting around borreliae (Shamaei-Tousi et al. 2001). Case fatality rate is 2–5% without treatment. The primary episode usually last 3 days and is followed, after a fever-free interval of 7 days, by multiple other alternating episodes, often shorter and milder. During the febrile periods, numerous borreliae are circulating in the blood (Johnson & Golightly, 2000). This relapsing pattern has been attributed to vmp antigenic variation, and provides a way for borreliae to persist in the host's blood for as long as possible, thereby increasing the chances of transmission by an arthropod from one host to another. Each resolution is the consequence of a specific antibody production against the vmp serotype, and each relapse is the consequence of antigenic variation and apparition of a new serotype. Between bacteriemic periods, spirochetes can still be found in certain organs, especially in the central nervous system (Cadavid & Barbour, 1998; Nordstrand et al. 2000).

Diagnosis is usually made during the primary attack by observation of spirochetemia on thin- or thick-blood smears with dark-field microscopy or with conventional microscopy after Giemsa, Wright or Diff-Quick® staining (Barbour, 1999; Johnson & Golightly, 2000). Thick-blood smears provide 20 times the sensitivity of thin-blood smears. Quantitative buffy coat (QBC) fluorescence analysis has also been described as a very sensitive and specific technique for detecting borreliae in blood (van Dam et al. 1999). Mouse inoculation has been used for a long time for the isolation of RF Borrelia, but RF borreliae can be cultured on axenic medium. Kelly's medium serves as the basis for Barbour Stoenner Kelly medium, which has been used for the cultivation of Lyme disease spirochetes as well as for the recent successes with RF Borrelia (Cutler et al. 1999; van Dam et al. 1999). Molecular methods are used with increasing frequency and offer the possibility of species identification (Brahim et al. 2005). Specific serological assays are to date not available for most of the known tick-borne relapsing fevers, because of the lack of available antigens. If they were available, they could be useful if the blood smear is negative and PCR unavailable. The recommended treatment is tetracycline, 500mg three to four times a day for five to ten days. Doxycycline, 100mg twice daily, can also be used. Penicillin, erythromycin or ceftriaxone may also be effective. In some patients, treatment may provoke a Jarisch–Herxheimer reaction (Cadavid & Barbour, 1998; Johnson & Golightly, 2000).

Six TBRF borrelioses are known to occur in Europe or close to its boundaries. At present, the greatest endemic risk in Europe lies in the Iberian peninsula, particularly in the Mediterranean portion, and in Asia Minor.

Borrelia hispanica is found in Spain, Portugal, Cyprus, Greece and North Africa. It has been isolated in O. erraticus, an endophilic tick commonly found under Mesomediterranean vegetation in south-western Europe. This tick species usually lives in the burrows of wild rodents, its natural host. In Spain and Portugal, however, it has adapted to bite domestic pigs that are kept in continuous grazing and sometimes overnight in large burrows or inside old buildings, and the tick has adapted to live in these habitats (Estrada-Pena & Jongejan, 1999). Humans may be bitten, and hence relapsing fever was sporadically reported in countries such as Spain during the twentieth century, probably with an underestimated incidence (Sanchez-Yebra et al. 1997). The disease caused by B. hispanica is one of the less severe TBRFs, which presents with neurological signs in less than 5% of cases (Cadavid & Barbour, 1998).

In 1996, a new Borrelia species was isolated in southern Spain from three patients with RF and from Ornithodoros erraticus ticks found in nearby areas (Anda et al. 1996). The reservoir of this bacteria is still unknown, but may be rodents. Although this new Borrelia has not yet been cultivated, molecular analyses have shown that it is closely related to B. hispanica, Borrelia duttoni and Borrelia crocidurae.

Borrelia crocidurae is present in Turkey. It also occurs in Morocco, Libya, Egypt, Iran, and above all in Senegal and Kenya. It is transmitted by Ornithodoros sonrai. This tick is found in rodent (mostly rat) burrows in desert and steppe regions (Estrada-Pena & Jongejan, 1999). TBRF caused by B. crocidurae has become rare in Near East and Northeastern Africa, but its frequency is increasing in Senegal and Sahel, probably because of the persistence of sub-Saharan drought (Trape et al. 1996). The disease is generally benign, but neurological and ocular complications may occur. Its diagnosis is difficult owing to the low numbers of spirochetes in the bloodstreams of patients. The culture of this species was only achieved in 1999 (van Dam et al. 1999).

On the borders of Europe, several other TBRF borrelioses are present. Borrelia persica, the agent of Persian relapsing fever, is found in Israel, Syria, Egypt, Iran, and Central Asia. It is transmitted by Ornithodoros tholozani (from Tholozan, who first described the disease and its link with ticks in Iran in 1879) (Rodhain, 1998). This tick commonly lives in localities where livestock is housed, for example man-made shelters, caves, and rocky overhangs (Estrada-Pena & Jongejan, 1999). This TBRF is sometimes severe, although neurological complications occur in less than 5% of cases (Cadavid & Barbour, 1998). Borrelia caucasica, present in Caucasus and Iraq, is transmitted by Ornithodoros asperus (former Ornithodoros verrucosus), another soft-tick parasite of rodents. Borrelia latyschevii is transmitted by Ornithodoros tartakovskyi in Central Asia, the former USSR and Iran (Estrada-Pena & Jongejan, 1999).

Although not present in Europe or close to its boundaries, other TBRF Borrelia species are of interest to European physicians because of increasing travel. Indeed, imported RF has already been described in European tourists. Tourists might, for instance, acquire infection with B. crocidurae in Senegal from sleeping outdoors on a terrace (Colebunders et al. 1993; Trape et al. 1996), or with B. hermsii in a Rocky Mountain cabin of Colorado, USA (Trevejo et al. 1998), or with B. duttonii, transmitted by O. moubata, in indigenous huts of South, Central and East Africa (Dupont et al. 1997). Furthermore, a new RF Borrelia was recently described in East Africa (Tanzania), being transmitted by Ornithodoros porcinus (Kisinza et al. 2003; Mitani et al. 2004) (Fig. 1). Therefore, TBRF borrelioses are considered as emerging diseases. As a consequence, TBRF should be considered in all patients returning from the tropics with recurring fever, especially if no malaria parasites are detected.

Finally, future data may challenge current concepts. New Borrelia species related to the RF spirochetes group have recently been isolated from hard ticks, such as the emerging human pathogen Borrelia lonestari that has been identified in Amblyomma americanum in the USA (Barbour et al. 1996). Other relapsing fever-like spirochetes have been isolated from hard ticks of the genus Ixodes in Japan (Borrelia miyamotoi sp. nov.) (Fukunaga et al. 1995), northern America (Scoles et al. 2001), Sweden (Fraenkel et al. 2002), Germany, and France (Richter et al. 2003). More recently, a further Borrelia species has been isolated from hard ticks infesting Turkish tortoises. A phylogenetic tree, generated from 16S rRNA gene sequences, demonstrated that this spirochete isolates from Hyalomma aegyptium was related to Lyme-disease-related and RF-associated Borrelia but formed a different cluster (Guner et al. 2003, 2004). For all these species, further microbiological, clinical and epidemiological studies are needed to determine implications for human health.

In conclusion, the incidence of TBRF borrelioses appears to be rare in Europe with the exception of specific settings. However, European physicians can face imported and/or emerging TBRF. Risk factors should be investigated in patients in order to identify exposure to Ornithodoros tick vectors in their specific biotopes.


  • Editor: Willem van Leeuwen


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