International Health (2009) 1, 17—25 available at www.sciencedirect.com journal homepage: http://www.elsevier.com/locate/inhe REVIEW Old and new tick-borne rickettsioses ∗ Aurélie Renvoisé, Oleg Mediannikov, Didier Raoult Downloaded from https://academic.oup.com/inthealth/article/1/1/17/677376 by guest on 28 September 2021 Unité des Rickettsies, CNRS-IRD UMR6236-198, Université de la Méditerranée, Faculté de Médecine, 27 bd Jean Moulin, 13385 Marseille cedex 5, France Received 30 January 2009; received in revised form 10 March 2009; accepted 18 March 2009 KEYWORDS Summary The field of rickettsiology is rapidly evolving. Rickettsiae are small Gram-negative Arthropods; bacteria that can be transmitted to humans by arthropods. In most cases they are transmitted Ticks; transovarially in the arthropod; human beings are incidental hosts. In recent years the use of Emerging infectious cell culture and molecular biology has profoundly changed our knowledge of rickettsiae and has disease; led to the description of several new species. New rickettsial diseases have been found in three Inoculation; main situations: firstly, in places where no new species have been identified, typical rickettsial Eschar; symptoms have been observed (Japan, China); secondly, typical rickettsioses have been found to Rickettsioses be caused by different organisms — in such cases a new Rickettsia species has been misdiagnosed as a previously identified bacterium (for example, R. parkeri was confused with R. rickettsii); thirdly, atypical clinical symptoms have been found to be caused by rickettsial organisms such as R. slovaca. These findings challenge the old dogma that only one tick-borne rickettsiosis is prevalent in one geographical area. Many Rickettsia spp. have been identified in ticks, but have not yet been implicated in human pathology. These rickettsiae should be considered as potential pathogens. All known or suspected rickettsial diseases should be treated (including in children) with doxycycline. © 2009 Published by Elsevier Ltd on behalf of Royal Society of Tropical Medicine and Hygiene. 1. Introduction in the Rickettsia genus are regularly described,3 and some of them have been shown to play a role in human pathology.2 Among the well-known group of diseases named rickettsioses Rickettsiae are small obligate intracellular bacteria that are found both well-characterized diseases1 and emerging are strongly associated with eukaryotic cells. They are often pathologies that have only recently been described.2 The found in arthropods (ticks, mites and other insects, includ- 4 5 latter group represents diseases that have been discovered ing lice, fleas, beetles and homopterans), amoebae and 6 during the last 15—20 years, concurrently with advances in leeches. Only blood-sucking arthropods may transmit the molecular biology and cell culture techniques. New species disease to humans, via transdermal inoculation with the arthropod’s saliva.4 Rickettsia akari and Orientia tsutsug- amushi are transmitted by mites, Candidatus R. felis and R. ∗ typhi are transmitted by fleas, and R. prowazekii is trans- Corresponding author. Tel.: +33 491 385 517; fax: +33 491 387 772. mitted by body lice; the other human rickettsioses, which E-mail addresses: [email protected] (A. Renvoisé), are reviewed here, are transmitted by ticks. [email protected] (O. Mediannikov), [email protected] Tick-borne rickettsioses are diseases of marked endemi- (D. Raoult). city. Their prevalence is strongly linked with vector and 1876-3413/$ — see front matter © 2009 Published by Elsevier Ltd on behalf of Royal Society of Tropical Medicine and Hygiene. doi:10.1016/j.inhe.2009.03.003 18 A. Renvoisé et al. natural host distribution. In those regions where both are Here, we summarize the clinical findings associated with common, morbidity and seropositivity may be high. More- tick-transmitted rickettsiae. The implications of these find- over, recent findings provide evidence that warmer weather ings for human pathology are described (Table 2 and Fig. 1). is linked to an increase in the aggressiveness of the brown dog tick, Rhipicephalus sanguineus.7 Increased aggressive- ness would likely lead to an increased incidence of rickettsial 3. Spotted fever group with inoculation diseases. It must be emphasized that if the proper treatment eschar does not begin shortly after infection, the consequences of rickettsiosis can be very serious. Mortality is as high as 5% Diseases grouped here have some common clinical fea- in cases of Rocky Mountain spotted fever in children, for tures, such as fever, rash, regional lymphadenopathy and example. Another important issue is the significant risk to cutaneous eschar following the tick bite (Fig. 2). The clin- travellers in regions where such diseases are endemic. Anal- ical course is usually mild to moderate. Four subspecies of ysis of data in the GeoSentinel database showed that 3.1% the R. conorii complex were proposed in 2005, based on of febrile travellers have rickettsiosis.8 differences in epidemiology and clinical findings. These sub- The economic aspects of tick-borne rickettsioses have species are R. conorii subsp. conorii, israelensis, caspia and yet to be elucidated, but their significance is evident since indica.12 Downloaded from https://academic.oup.com/inthealth/article/1/1/17/677376 by guest on 28 September 2021 human contact with the natural environment, as well as the The aetiological agent of Mediterranean spotted fever number of emerging rickettsial infections and the morbidity (MSF) is R. conorii subsp. conorii. The main vector is the they cause, is increasing continuously. brown dog tick, Rh. sanguineus, which is found through- out the world.1,4 The agent is found in Europe and Africa. 2. Bacteriology and taxonomy MSF is an urban and peri-urban disease and is endemic in the Mediterranean area, but has also been reported in Rickettsiae are strictly intracellular bacteria whose size central Europe, central Africa and southern Africa.1,4 This ranges from 0.3 × 0.8 ␮mto0.5× 2.0 ␮m. The morphology disease affects all age groups1,4 and occurs mainly in sum- is that of Gram-negative bacteria and the bacterium is sur- mer. Recent findings7 provide evidence that warmer weather rounded by a glycocalyx or slime. Gram staining does not is linked to an increase in the aggressiveness of Rh. san- visualize rickettsiae, but Gimenez9 and Giemsa stains do. guineus. Typically,1,4 the incubation period is asymptomatic For intracellular bacteria, which express few phenotypic and lasts approximately 6 days. At the end of the incubation characteristics, molecular techniques have been particu- period the infected person rapidly develops a high fever, a larly important for classification. Molecular analysis has maculopapular rash, flu-like symptoms and an inoculation significantly altered rickettsial taxonomy, which is a con- eschar (‘tâche noire’). The eschar is painless and is most troversial domain that has undergone many changes over often found on the trunk and the limbs. The rash generally time. The Rickettsiaceae family includes only the genera develops 2—3 days after the fever and is initially macular, Rickettsia and Orientia (Table 1). For the taxonomy of rick- then maculopapular and disseminated; the face is usually ettsiae, the isolated study of 16S rRNA is not useful as this spared. Symptoms usually last for 12—20 days and clinical gene is often highly homologous between species (more than improvement generally occurs following 48 h of antibiotic 97%). Currently, five rickettsial genes have been proposed to treatment. Severe disease occurs in 5—6% of cases and is define the genus, the group and the species.10 They are 16S associated with disseminated vasculitis, with renal, neuro- rRNA (rrs), gltA, ompA, ompB and sca4 (gene D). Members of logical and cardiovascular complications as well as phlebitis. the genus Rickettsia may be classified into the spotted fever Mortality may reach up to 2.5% in this group.1,4 group, the typhus group, R. bellii and R. canadensis; the The aetiological agent of Israeli spotted fever is R. conorii latter two groups lie outside the spotted fever and typhus subsp. israelensis.14 Although, like R. conorii subsp. conorii, groups (Table 2).10,11 it is transmitted by Rh. sanguineus, molecular studies show At this time, there are 25 formally recognized species in differences above the strain level. The bacterium is found in the genus Rickettsia. Many other isolates exist, but they are Israel, but new isolations, for example in Italy and Portugal, either not recognized or not characterized. Official criteria support the suggestion that the geographical distribution is have been proposed for the creation of subspecies within R. wider than previously thought.4,14 An eschar generally does conorii12 and R. sibirica13 based on epidemiological, clini- not develop following infection with R. conorii israelensis, cal, serotypical and genotypical differences that were found which makes the diagnosis more difficult; serious and lethal after multi-spacer typing. forms are more common with this agent.15 The aetiological agent of Astrakhan spotted fever is R. conorii subsp. caspia,12 which is transmitted by Rh. Table 1 Taxonomic position of the genus Rickettsia. pumilio. Acute febrile disease with the characteristic rash was noted in the Astrakhan region of Russia and was pro- Genus Rickettsia visionally named ‘viral exanthema of unknown aetiology’. Family Rickettsiaceae (genera included: Rickettsia It was proved to be a spotted fever group rickettsiosis in and Orientia) 1991.16 Younger men are mostly affected, and most infec- Order Rickettsiales tions take place during the summer.17 Cases are usually Class Alpha-proteobacteria described around the Caspian Sea,17 but the geographic zone Phylum Proteobacteria could be wider than previously thought (Chad, Kosovo).12 Domain Bacteria Clinically, the disease resembles MSF except for the absence of fatal forms and a lower incidence of a cutaneous eschar.12 Old and new tick-borne rickettsioses 19 Table 2 The family Rickettsiaceae, main members of clinical interest. Group Species Disease Typhus group R.