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African tick bite fever
Review
African tick bite fever
African tick bite fever
Mogens Jensenius, Pierre-Edouard Fournier, Patrick Kelly, Bjørn Myrvang, and Didier Raoult
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African tick bite fever is an acute febrile illness that is frequently accompanied by headache, prominent neck muscle myalgia, inoculation eschars, and regional lymphadenitis. The disease is caused by Rickettsia africae, a recently identified spotted fever group rickettsia, which is transmitted by ungulate ticks of the Amblyomma genus in rural sub-Saharan Africa and the French West Indies. Whereas reports on African tick bite fever in indigenous populations are scarce, the number of reported cases in travellers from Europe and elsewhere has recently increased significantly. Treatment with doxycycline is associated with rapid recovery in most patients. An immunofluorescence assay is recommended for the diagnosis but seroconversion is commonly delayed and this limits the usefulness of the test. Travellers to endemic areas should be informed of the risk of contracting African tick bite fever and be encouraged to take personal protective measures against tick bites.
Figure 1. Adult A variegatum tick.
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Historical background International travel, one of the largest and most rapidly evolving industries worldwide,1 has a significant impact on health care in many developed countries. An estimated 15–37% of short-term travellers experience a health problem related to overseas travel,2 and about 4–8% of travellers to developing areas seek medical attention on return to their home countries.3 Increasing numbers of international travellers visit tropical and subtropical regions of the world, where they may be exposed to a range of exotic microbes. As a consequence, physicians assessing ill returnees may today not only encounter well-known conditions such as malaria, hepatitis A, and traveller’s diarrhoea, but also less familiar diseases including dengue, melioidosis, Japanese encephalitis, trypanosomiasis, schistosomiasis, and relapsing fever.4–8 One example of such recently recognised travelassociated diseases is African tick bite fever, a spotted fever group rickettsioses, which, in the wake of the rapidly expanding international safari tourism to southern Africa, has emerged as a common cause of imported fever in Europe and elsewhere.9–12 In this review we describe the current status of the biology, epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, and possible prevention of African tick bite fever. THE LANCET Infectious Diseases Vol 3 September 2003
The early description of African tick bite fever, probably a very old disease in sub-Saharan Africa, is tightly intertwined with that of Mediterranean spotted fever. Mediterranean spotted fever was described by Conor and Bruch in Tunisia in 191013 and soon also reported from other regions around the Mediterranean basin, from the Black Sea littoral, India, the Middle East, and southern Africa. In the early 1930s, the brown dog tick Rhipicephalus sanguineus was recognised as a vector in Europe, and a spotted fever group rickettsia was shown to be the causative agent; in honour of the work of Conor, this organism was named Rickettsia conorii. The clinical picture of Mediterranean spotted fever is characterised by acute flu-like symptoms, a generalised maculopapular cutaneous rash, and a single inoculation eschar but usually no regional lymphadenitis. Complications are frequent and, if left untreated, mortality rates may exceed 2%.14 MJ is at the Department of Internal Medicine, Aker University Hospital, Oslo, Norway; BM is at the Department of Infectious Diseases, Ullevål University Hospital, Oslo; P-EF and DR are at the Unité des Rickettsies, CNRS, UMR 6020, Université de la Mediterranee, Marseille, France; and PK is at the Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Palmerston North, New Zealand. Correspondence: Dr Mogens Jensenius, Division of Infectious Diseases, Department of Internal Medicine, Aker University Hospital, N-0514 Oslo, Norway. Tel +47 22 89 40 00; fax +47 22 89 40 08; email [email protected]
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In 1911—ie, just 1 year after the first description of Mediterranean spotted fever—a similar flu-like disease was described in Mozambique and South Africa.15,16 This illness was also transmitted by ticks and was named tick bite fever. The epidemiology and clinical presentations of the two conditions were investigated by Pijper in South Africa in the 1930s.17,18 Whereas patients with Mediterranean spotted fever typically acquired the disease in urban areas with dogs, Pijper noted that most patients with tick bite fever became ill after contact with cattle ticks in the bush. Also, the clinical manifestations of tick bite fever were milder with few complications and frequently no cutaneous rash.17,18 Pijper was able to isolate the causative rickettsia of tick bite fever in guineapigs and showed using cross-protection studies that the organism differed from R conorii. Unfortunately, his isolate was lost and subsequent workers were unable to confirm his findings, and—erroneously—tick bite fever became a synonym for Mediterranean spotted fever in Africa for several decades.19 In August 1992, a spotted fever group rickettsia was isolated from the blood of a 36-year-old woman presenting with tick bite fever at a hospital in Zimbabwe. By PCR and restriction endonuclease fragment length polymorphism, this isolate was seen to be distinct from all other spotted fever group rickettsiae, including R conorii. It was, however, indistinguishable from a strain isolated from Amblyomma variegatum ticks (figure 1) collected from cattle in Ethiopia 20 years earlier,20 and from six isolates recovered from Amblyomma hebraeum ticks collected in Zimbabwe in the 1980s.21 The case report was published 2 months later, in which the authors proposed the name African tick bite fever for the disease and the name Rickettsia africae for the causative agent,22 nomenclatures that were made official in 1996.9
could be differentiated from all other spotted fever group rickettsiae except Rickettsia parkeri, a species of unknown pathogenicity transmitted by Amblyomma maculatum ticks in the USA.9 Sequencing studies of the 16S rRNA gene sequences have shown that R parkeri and Rickettsia sibirica, the agent of Siberian tick typhus, are the two closest relatives (homology ⭓99·6%) and that Rickettsia akari and Rickettsia australis, the agents of rickettsial pox and Queensland tick typhus, respectively, are the most distant relatives (homology 97·9%) to R africae (figure 2). Recently, three variant strains of R africae were detected in adult A variegatum ticks collected from cattle in Mali and Niger (rOmpA homology with the type strain 99·3%–99·5%).24 In-vitro susceptibility data for R africae are available for 13 antibiotics,25,26 and show that the organism is resistant to -lactam antibiotics, aminoglycosides, and co-trimoxazole, semi-susceptible to erythromycin, and susceptible to tetracyclines, chloramphenicol, rifampin, fluoroquinolones, the newer macrolides, and ketolides.
Vectors R africae is transmitted by the members of the Amblyomma genus, of which two, A variegatum (the tropical bont tick) and A hebraeum (the southern African bont tick), are recognised as principal vectors.9 Noteworthy, A hebraeum, and supposedly also A variegatum, not only act as vectors of R africae but are also important reservoirs in which infection is maintained through transovarial transmission (from adult female to offspring) and trans-stadial transmission (from larva to nymph to adult).27 The rates of R africae infection in A variegatum and A hebraeum ticks are frequently high and may exceed 30% and 70%, respectively.22,27–30
Causative agent R africae is an obligate intracellular Gram-negative, rod-shaped bacterium that measures 0·3–0·5⫻0·9–1·6 m. Electron microscopy shows that the bacteria occurs free in the cytoplasm, and has an outer slime layer and a trilaminar cell wall. The cell wall of R africae contains lipopolysaccharide antigens, which are highly immunogenic and responsible for extensive crossreactivity with the other spotted fever group rickettsiae.23 Species-specific protein antigens are located in the high-molecular-weight rickettsial outer membrane protein A (rOmpA) and B (rOmpB). R africae cannot be cultivated in cell-free media but will grow in yolk sacs of developing chicken embryos, and in cell cultures.9 The genome of R africae consists of a single circular chromosome with an estimated size of 1248 kb. Based on initial genotypic studies, R africae
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R conorii R rickettsii R honei
Spotted fever group
R africae R parkeri R sibirica R slovaca R japonica R aeschlimanni R massiliae R rhipicephali R montanensis R helvetica R felis R australis R akari R prowazekii Typhus group R typhi R canadensis Ancestral group R bellii 0·02 Figure 2. Dendogram of Rickettsia africae.
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African tick bite fever
A hebraeum and A variegatum, as other hard tick species, have three active stages: larvae, nymphs, and adults. Larvae are minute and may be difficult to detect on skin and clothing, whereas a fully engorged adult female may approach the size of a grape. Adults are easily recognised by their bright, reddish colours (figure 1). A blood meal is needed at each stage for development into the next. In places with a single rainy season, one generation occurs per year,31 but where there are two rainy seasons, shorter generations are possible.32
KwaZulu-Natal province, as well as in the northeastern regions where many popular wildlife attractions are situated. A hebraeum is also present in eastern Botswana, southern Mozambique, and in the southern half of Zimbabwe.37,39 Although A variegatum and A hebraeum have similar requirements they are rarely seen in the same areas. This is probably due to interspecific competition and the production of sterile hybrids.40
Epidemiology Hosts and host-seeking behaviour
By contrast with most other hard ticks of medical importance, which exhibit a passive ambush host-seeking strategy, members of the Amblyomma genus actively converge on nearby hosts.33 The ticks are notoriously aggressive, and a single host may be attacked by many ticks, and several hosts may be attacked simultaneously. Cattle are the most important domestic hosts for adult A hebraeum and A variegatum although sheep, horses, donkeys, and pigs are also frequently attacked. Adult ticks also feed readily on a range of wild ungulates including giraffes, buffalo, antelope, and warthogs, which are Figure 3. important in maintaining the species Distribution map of principal tick in areas where domestic hosts are the vectors of Rickettsia 34 absent or dipped intensively. Larvae africae. Dotted line and nymphs use similar hosts to denotes approximate adults, but can also be seen on lizards, border between mountain tortoises, smaller mammals, A hebraeum (in southern Africa) and and ground-feeding birds.35,36 People, A variegatum. who are only accidental hosts, are Adapted from usually attacked on the legs, but once reference 47. on the skin amblyommas may crawl around for hours before attaching, typically behind the knee, in the groin or axilla where the skin is thin, moist, and warm. Ecology and distribution
A hebraeum and A variegatum occur only in tropical and subtropical environments, and need an annual rainfall of 300–800 mm.36 Both species prefer habitats with tall grass or bush offering shade, and are not present on steppes with only short grass, in arid or urban areas.31 Although present throughout the year in most infested areas, these species are most abundant during the rainy season, in Zimbabwe from February to May, in Tanzania, Zambia, and Malawi from November to January, and in Somalia from April to May.32 The two tick species have different geographical distributions (figure 3). A variegatum is distributed throughout rural areas of west, central, and east Africa south of the Sahara desert, as well as the horn of Africa.37 In addition, the species is present in Yemen, on several islands in the Indian Ocean, on the Cape Verde Islands in the Atlantic Ocean, and in the eastern Caribbean.37,38 A hebraeum, by contrast, is only present in southern Africa. In South Africa, the species is distributed along the coast of the Indian Ocean, including the THE LANCET Infectious Diseases Vol 3 September 2003
R africae has been detected or isolated from Amblyomma spp ticks or human beings from 14 African countries: South Africa, Botswana, Zimbabwe, Tanzania, Kenya, Burundi, Sudan, Ethiopia, Central African Republic, Gabon, Mali, Niger, Côte d’Ivoire, and Gambia,12,20,21,24,28–30 and on Guadeloupe in the French West Indies.41 In addition, several studies have shown very high seroprevalence rates (up to 70%) for spotted fever group rickettsial infections in areas of sub-Saharan Africa where A variegatum or A hebraeum ticks are prevalent and/or where cattle-breeding is intense.41–47 Thus, direct and indirect epidemiological data suggest that R africae occurs widely throughout sub-Saharan Africa and the eastern Caribbean, and that it actually may be the most widespread of all spotted fever group rickettsiae known to be pathogenic in human beings.48 Indigenous populations
Despite the wide geographical distribution of R africae, reports on African tick bite fever in indigenous African populations are unexpectedly scarce with only one confirmed case reported.22 Studies have shown that indigenous people are generally infected at a young age when the disease might be very mild or subclinical, and that many patients do not seek medical attention.43,44,49 It is also difficult to see inoculation eschars in pigmented skin and this important clue might not be seen unless without thorough and extensive physical examinations. Moreover, definitive diagnosis of African tick bite fever requires sophisticated diagnostic tests that are not available in many African countries. Anecdotal reports indicate that African tick bite fever may pose a significant problem to local populations. During the Zimbabwean war of independence in the late 1970s, army medical authorities reported that several thousand cases of tick typhus had been treated. Both European and African soldiers were affected, although the infection rate seemed to be greater among the former. Zimbabwean cases occurred mainly among presumably non-immune soldiers of urban origin who were deployed to rural areas. No
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microbiological data are available; however, this period coincided with a major disruption of local cattle-dipping programmes and an ensuing extensive spread of A hebraeum.34 More recently, medical practitioners surveyed in Zimbabwe reported case incidence rates of African tick bite fever of 60–80 per 100 000 patients each year in areas where A hebraeum is endemic.49 International travellers
Traditionally, rickettsioses have been regarded as curiosities in international travel medicine. During the past few years, however, the number of travel-associated cases of African tick bite fever has increased significantly worldwide. Since 1983, 388 cases of spotted fever group rickettsioses acquired by international travellers to sub-Saharan Africa or the French West Indies have been reported in published material. Of these, 171 cases were microbiologically confirmed as African tick bite fever.11,12,50–57 Another 78 cases could, based on positive (but not species-specific) microbiological tests in combination with typical features (such as multiple inoculation eschars, a vesicular cutaneous rash, and/or clustering of cases), retrospectively be classified as probable African tick bite fever.52,54,58–75 The mean age of these 249 cases of African tick bite fever was 40 years; most patients (72%) were male, and most (64%) originated from Europe. Typically, more than 80% of the patients acquired the disease in South Africa, where many popular wildlife attractions are highly endemic for R africae infection76 and where the abolition of apartheid in the early 1990s was followed by a sixfold rise in international tourism.1 Any person who enters the tick vectors’ habitats in endemic areas is at risk of contracting African tick bite fever, and reported cases represent a wide range of travellers, including leisure safari tourists, backpackers, hunters, sports competitors, students, foreign aid workers, film crew staff, and deployed soldiers. Characteristically, up to 74% of travelassociated cases of African tick bite fever occur in clusters,12,56 which may seem spectacular and affect up to 100% of those exposed.11,50 Game hunting (an activity typically characterised by heavy exposure to ground vegetation, ungulates, and their hides), travel to southern Africa (where A hebraeum is the principal vector), and travel between November and April
(when tick activity peaks in many endemic areas) have recently been identified as independent risk factors of African tick bite fever.56 How common is African tick bite fever in international travellers to endemic areas? Three studies have addressed this question. In a seroepidemiological study of first-time Norwegian travellers to rural subequatorial Africa, specific antibodies to R africae were seen in 9% of the patients.77 Similarly, serological evidence of recent spotted fever group rickettsial infection was detected in 11% of returnees from southern Africa who presented at a German outpatient clinic with various medical complaints including fever.78 Finally, in a prospective cohort study of 940 Norwegian mostly short-term travellers to rural subequatorial Africa, the incidence-rates of African tick bite fever ranged from 4·0–5·3%,56—ie, estimates that widely exceed those reported for other tropical fevers in temporary visitors to sub-Saharan Africa, including malaria and typhoid fever.3,5,73,79,80 Thus, if the data from these three studies are extrapolated to the 6·4 million travellers to South Africa in 2002,1 as well as to the large annual numbers of tourists visiting other destinations in sub-Saharan Africa, it seems likely that thousands of cases of African tick bite fever should occur in international travellers each year.
Pathogenesis Recent studies have given insights into the pathophysiology of African tick bite fever. The first step of infection, rickettsial invasion of endothelial cells, occurs with an increased secretion of endothelium-associated mediators such as von Willebrand factor and soluble E-selectin.81 Subsequent damage to the endothelium is followed by perivascular infiltration of T cells and macrophages resulting in a lymphohistiocytic vasculitis, the histopathological hallmark of rickettsial disease.57 Finally, the clearance of R africae, which is believed to involve complex interactions between T cells, macrophages, natural killer cells, B lymphocytes, and antibodies, is characterised by increased circulating concentrations of cytokines (eg, tumour necrosis factor alpha, interleukin 6, and interleukin 10), as well as CC-chemokines (eg, RANTES and macrophage inflammatory protein 1 alpha), and CXC-chemokines (eg, interleukin 8).81 There are no convincing data that secreted toxins are involved in the pathogenesis of African tick bite fever.
Clinical features
Figure 4. Inoculation eschar in groin with large red halo.
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The modern clinical description of African tick bite fever is mainly based on four studies (table): one consecutive series of an outbreak affecting 39 US soldiers deployed to Botswana in 1992,54 one consecutive series describing an outbreak affecting 13 French sports competitors infected in South Africa in 1997,11 one consecutive series of 38 Norwegian cases diagnosed in 1999–2001,56 and one retrospective series of 119 cases diagnosed in ten European and North American countries from 1996–2000.12 The time lag from tick bite to symptom onset is usually 5–7 days but may be as long as 10 days. Most patients present with abrupt flu-like symptoms such as fever, nausea, fatigue, headache, and myalgia. Of note is a prominent neck muscle myalgia with subjective neck THE LANCET Infectious Diseases Vol 3 September 2003
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African tick bite fever
stiffness that is reported by four of five cases. This symptom, which has also been described in Rocky Mountain spotted fever caused by Rickettsia rickettsii,82 probably indicates central nervous system affection. An inoculation eschar, a black crust surrounded by a red halo at the site of the tick bite (figure 4), is present in most cases but may easily be overlooked, particularly on dark skin, in the hair, or in the anogenital region. Sometimes, nontypical eschars mimicking acne are seen. Up to 54% of patients with African tick bite fever have multiple eschars, a pathognomonic clinical sign which indicates the aggressive behavior of the implicated tick vectors (figure 5). The number of skin lesions may be impressive, as was seen during the investigation of an outbreak among Italian safari tourists to South Africa, where five patients presented with a total of 34 eschars.50 Regional lymphadenitis is common and may be seen also in the absence of a frank eschar. A generalised cutaneous rash, sometimes vesicular and usually best seen close to the eschar, is present in 15–46% of the patients. Less common signs of African tick bite fever include aphthous stomatitis, which was reported in six patients infected in South Africa,10,56,72 and lymphangitis, which was recorded in one case from Zimbabwe and one case from South Africa.10,50 Complications seem to be rare in African tick bite fever. A fever of more than 3 weeks’ duration was reported in one case from Zimbabwe and one case from the French West Indies71,83 These reports suggest that African tick bite fever should be considered when assessing travellers from endemic areas with prolonged fevers. Reactive arthritis has occasionally been seen in cases infected in South Africa.56 Most important, and by contrast with other spotted fever group rickettsioses, life-threatening complications have never been reported in African tick bite fever, and there are no known fatal cases. The sequential kinetics of haematological and biochemical parameters during the acute phase of African tick bite fever mimic those reported in other spotted fever group rickettsioses.82,84 During the first 10 days of illness, when most patients are likely to present, increased concentrations of serum C-reactive protein and moderate lymphopenia are seen in most cases. Elevated serum liver enzymes and thrombocytopenia are also common, and are detected in 40% and 20% of patients, respectively.85 Signs and symptoms in African tick bite fever Characteristic Fever
Frequency (%) 59–100
Headache
62–83
Myalgia Neck muscle myalgia
63–87 81
Inoculation eschar Multiple eschars
53–100 21–54
Regional lymphadenitis
43–100
Cutaneous rash Maculopapular Vesicular Aphthous stomatitis
15–46 15–26 0–21 11
Data compiled from four studies (references 11,12,54,56)
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Figure 5. Patient with multiple inoculation eschars on ankles.
Microbiological diagnosis Culture and antigen detection
Isolation of R africae from clinical specimens, the ultimate confirmation of African tick bite fever, poses several inherent limitations and should be reserved to specialised laboratories equipped with biohazard facilities. Cell culture is currently the most widely used system for primary isolation, with human embryonic lung fibroblast (HEL) cell being one of the most useful cell lines. Shipment of specimens should be done in dry ice and be swift, since inoculation of cell cultures should ideally take place within 24 h after sampling. The sensitivity of isolation of R africae in African tick bite fever is generally poor, less than 15% in heparinised blood and 44% in skin-biopsy specimens.12 Detection of R africae antigen may be done either by immunohistochemistry using monoclonal antibodies86 or by PCR. The former method is reserved to reference centres but the latter technique may be used by any laboratory equipped for molecular diagnosis. PCR may be applied to an array of samples including blood, skin biopsy samples, and arthropod tissues. Detection strategies based on recognition of sequences within the genes encoding the 16S rRNA, outer membrane proteins rOmpA, rOmpB, and PS120 have effectively been used for R africae.87–90 The best human specimen is undoubtedly the inoculation eschar biopsy. With use of standard PCR, R africae DNA can be detected in 48% of skin-biopsy specimens, whereas the sensitivity approaches 100% when suicide PCR, a nested PCR using single-use primers targeting a gene never amplified previously in the laboratory, is used.12,91 However, eschar specimens may not be easy to obtain, and during the
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investigation of an outbreak of African tick-bite fever among French sports competitors, 12 of 13 patients refused to undergo skin biopsy.11 Serology
In addition to the archaic and poorly specific Weil-Felix test, which continues to be used as a first-line test in many countries, immunofluorescence assay is the most widely used microbiological test in rickettsial diseases worldwide.92 No immunofluorescence assay for African tick bite fever is commercially available but due to extensive cross-reactions, commercial kits based on R conorii or R rickettsii antigens can be used. When testing, however, it is important to note that diagnostic antibody titres are seen late in African tick bite fever, frequently more than 3 weeks after the onset of symptoms, or not at all in mild cases or in patients treated early with doxycycline.93 More specific serological tests for African tick bite fever are laborious and expensive, and at present are only available at reference centres. Such tests include multiple-antigen immunofluorescence assay (where reactions to several spotted fever group rickettsial antigens, including R africae, can be compared directly), western blotting (where speciesspecific antibodies directed to high-molecular-weight proteins [rOmpA, rOmpB and PS120] are detected), and cross-adsorption assays (where the infecting species may be determined by removing non-specific antibodies).11,12
focally very abundant on vegetation, they are highly aggressive feeders and are usually active 24 h a day. During bush walks, travellers should be recommended to wear protective clothing, preferably impregnated or sprayed with acaricides. They should also use topical insect repellents on any exposed skin97 and regularly examine themselves for ticks. Unfortunately, most commercially available insect repellents based on diethyl-3methylbenzamide (DEET), piperidine compounds, or citronella oil have only short-lasting efficacy against Amblyomma spp ticks, typically for less than 2 h.98–100 US authorities advocate the use of DEET products containing 33% DEET against biting arthropods,101 but lotions containing more than 19·5% are not widely available in Europe and Africa. A hebraeum and A variegatum ticks should be removed carefully as they have long mouth parts and are often very firmly attached. The minimum attachment time needed for transmission of R africae to people is unknown. In the only feeding study done with this pathogen, A hebraeum ticks were allowed to feed until fully engorged and all feeding stages transmitted infections to rabbits.27 There are also few data for the other spotted fever group rickettsiae. Dermacentor andersonii ticks may transmit R rickettsii, the agent of Rocky Mountain spotted fever, after only 6 h of attachment although it usually requires 10 to 24 h, and R sanguineus requires more than 20 h to transmit R conorii, the agent of Mediterranean spotted fever.102
Treatment There are only limited data on the optimal antibiotic treatment of African tick bite fever, including indication, drug of first choice, and proper dosing. No reliable randomised clinical trials have been done. Certainly, one study describes the inefficacy of erythromycin in six of 17 hospitalised patients with tick bite fever in South Africa,94 but in this series many cases did probably represent Mediterranean spotted fever and not African tick bite fever. Of the 249 aforementioned published cases of African tick bite fever and for whom data on antibiotic treatment were provided, 149 of 179 (83%) were treated with antibiotics. In virtually all of these cases, the prescribed treatment was doxycycline, usually as 100 mg twice daily for 7 to 10 days, or, rarely for 1 to 5 days.64,95 Possible treatment failures occurred in only three cases, two treated with doxycycline56,83 and one treated with azithromycin.50 In most cases, symptoms were reported to resolve within 24–48 h after start of treatment. Currently, then, doxycycline 100 mg twice daily for 7 days or until 48 h after defervescence can be recommended in cases of African tick bite fever with high fever, intense headache, or other more pronounced symptoms. Fluoroquinolones may also be of benefit. The use of chloramphenicol or josamycin, the recommended regimen for pregnant women with spotted fever group rickettsioses,96 has never been reported in African tick bite fever.
Prevention Travellers to sub-Saharan Africa should be informed that they are very likely to encounter the tick vectors of African tick bite fever if they visit rural areas. The ticks may be
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Unsolved issues Although a substantial body of information has been collected since the description of R africae as a human pathogen in 1992, several central aspects of African tick bite fever still need to be elucidated. Most importantly, the precise geographical distribution of R africae, as well as those of other spotted fever group rickettsiae endemic to sub-Saharan Africa (eg, R conorii,12,103 Rickettsia aeschlimanii,104 and “Rickettsia mongolotimonae”24) is largely unknown and warrant further epidemiological studies in human beings, mammals, and ticks. Moreover, the apparent paucity of African tick bite fever in indigenous populations, even in regions highly endemic to R africae, is puzzling.49 Co-infection with HIV and R africae is probably common throughout sub-Saharan Africa, as is indicated by a study at five gold-panning communities in rural Gabon,105 but so far no studies on possible interactions between these two pathogens have been reported. The issue is interesting, since scrub typhus, a rickettsial disease with widespread distribution in southeast Asia, may suppress HIV-1 viral load in co-infected patients,106 and since some rickettsioses may cause clinical relapse several years after the primary infection in immunocompromised subjects.107 The incidence of travel-associated African tick bite fever is clearly increasing, and further studies on risk factors in travellers would be welcomed, as would assessments of personal protective measures against Amblyomma tick bites. The diagnostic armamentarium of R africae infection is limited in many areas92 and better availability of the current
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Search strategy and selection criteria We did a computer-aided search of Pubmed from 1983 through to March 2003 using the key words “Rickettsia africae”, “Rickettsia conorii” and “rickettsial infection”. We also surveyed relevant doctoral theses, textbook chapters, and conference proceedings in English.
microbiological tests, as well as development of new, sensitive and easy-to-perform tests, are of crucial importance. Finally, and as mentioned above, current recommendations of antibiotic treatment of African tick bite fever are largely based on extrapolations from case reports, and no randomised clinical trials have been published.
travellers to sub-Saharan Africa, and should now be considered along with malaria, typhoid fever, and other tropical fevers when assessing febrile returnees from this region. The clinical diagnosis is not always straightforward, but several signs and symptoms, including inoculation eschars and neck muscle myalgia, are important clues. Anti-rickettsial chemotherapy seems to shorten the clinical course, and is recommended in cases with more pronounced symptoms. Travellers to endemic areas should be informed about the risk of contracting African tick bite fever, and should be encouraged to protect themselves against tick bites. Conflicts of interest
Conclusion African tick bite fever has recently emerged as one of the most common causes of flu-like illness in international References 1 2 3 4 5 6 7
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None declared. Funding was received from the Research Council of Norway (grant No. 136239/320), Research Forum at Aker University Hospital, and Centre for Imported and Tropical Diseases, Ullevål University Hospital, Oslo, Norway.
GA, Raoult D. A new pathogenic spotted fever group rickettsia from Africa. J Trop Med Hyg 1994; 97: 129–37. Kelly P, Matthewman L, Beati L, et al. African tickbite fever: a new spotted fever group rickettsiosis under an old name. Lancet 1992; 340: 982–83. Hechemy KE, Raoult D, Fox J, Han Y, Elliott LB, Rawlings J. Cross-reaction of immune sera from patients with rickettsial diseases. J Med Microbiol 1989; 29: 199–202. Parola P, Inokuma H, Camicas JL, Brouqui P, Raoult D. Detection and identification of spotted fever group rickettsiae and ehrlichiae in African ticks. Emerg Infect Dis 2001; 7: 1014–17. Rolain JM, Maurin M, Vestris G, Raoult D. In vitro susceptibilities of 27 rickettsiae to 13 antimicrobials. Antimicrob Agents Chemother 1998; 42: 1537–41. Rolain JM, Maurin M, Bryskier A, Raoult D. In vitro activities of telithromycin (HMR 3647) against Rickettsia rickettsii, Rickettsia conorii, Rickettsia africae, Rickettsia typhi, Rickettsia prowazekii, Coxiella burnetii, Bartonella henselae, Bartonella quintana, Bartonella bacilliformis, and Ehrlichia chaffeensis. Antimicrob Agents Chemother 2000; 44: 1391–93. Kelly PJ, Mason PR. Transmission of a spotted fever group rickettsia by Amblyomma hebraeum (Acari: Ixodidae). J Med Entomol 1991; 28: 598–600. Beati L, Kelly PJ, Matthewman LA, Mason PR, Raoult D. Prevalence of rickettsia-like organisms and spotted fever group rickettsiae in ticks (Acari: Ixodidae) from Zimbabwe. J Med Entomol 1995; 32: 787–92. Dupont HT, Cornet JP, Raoult D. Identification of rickettsiae from ticks collected in the Central African Republic using the polymerase chain reaction. Am J Trop Med Hyg 1994; 50: 373–80. Macaluso KR, Davis J, Alma U, et al. Spotted fever group rickettsiae in ticks from the Masai Mara region of Kenya. Am J Trop Med Hyg 2003; 68: 551–53. Rechav Y. Dynamics of tick populations (Acari: Ixodidae) in the eastern Cape Province of South Africa. J Med Entomol 1982; 19: 679–700. Petney TN, Horak IG, Rechav Y. The ecology of the African vectors of heartwater, with particular reference to Amblyomma hebraeum and Amblyomma variegatum. Onderstepoort J Vet Res 1987; 54: 381–95. Norval RAI, Butler JF, Yunker CE. Use of carbon dioxide and natural or synthetic aggregationattachment pheromone of the bont tick, Amblyomma hebraeum, to attract and trap unfed adults in the field. Exp Appl Acarol 1989; 7: 171–80. Norval RAI. Ticks of Zimbabwe VII. The genus Amblyomma. Zimb Vet J 1983; 14: 3–18. Barre N, Garris G, Camus E. Propagation of the tick Amblyomma variegatum in the Caribbean. Rev Sci Tech. 1995; 14: 841–55. Paine GD. Ticks (Acarina: Ixodidae) in Botswana. Bull Entomol Res 1982; 72: 1–16. Walker JB, Olwage A. The tick vectors of Cowdria ruminantium (Ixodoidea, Ixodidae, genus Amblyomma) and their distribution. Onderstepoort J Vet Res 1987; 54: 353–79.
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38 Uilenberg G, Barre N, Camus E, Burridge MJ, Garris G. Heartwater in the Caribbean. Prev Vet Med 1984; 2: 255–67. 39 Peter TF, Perry BD, O’Callaghan CJ, et al. Distributions of the vectors of heartwater, Amblyomma hebraeum and Amblyomma variegatum (Acari: Ixodidae), in Zimbabwe. Exp Appl Acarol 1998; 22: 725–40. 40 Rechav Y, Norval RAI, Oliver JH. Interspecific mating of Amblyomma hebraeum and Amblyomma variegatum (Acari: Ixodidae). J Med Entomol 1982; 19: 139–42. 41 Parola P, Vestris G, Martinez D, Brochier B, Roux V, Raoult D. Tick-borne rickettiosis in Guadeloupe, the French West Indies: isolation of Rickettsia africae from Amblyomma variegatum ticks and serosurvey in humans, cattle, and goats. Am J Trop Med Hyg 1999; 60: 888–93. 42 Dupont HT, Brouqui P, Faugere B, Raoult D. Prevalence of antibodies to Coxiella burnetti, Rickettsia conorii, and Rickettsia typhi in seven African countries. Clin Infect Dis 1995; 21: 1126–33. 43 Julvez J, Michault A, Kerdelhue C. Serological study of rickettsia infections in Niamey, Niger. Med Trop (Mars) 1997; 57: 153–56. 44 Kelly PJ, Mason PR. Tick-bite fever in Zimbabwe. Survey of antibodies to Rickettsia conorii in man and dogs, and of rickettsia-like organisms in dog ticks. S Afr Med J 1991; 80: 233–36. 45 Ndip LM, Bouyer DH, Walker DH. Prevalence of antibodies to Rickettsia africae in Cameroon. In: Program and abstract of American society for rickettsiology—Bartonella as an emerging pathogen group joint conference; Big Sky, Montana; August 2001 (abstract #36). 46 Niang M, Parola P, Tissot-Dupont H, Baidi L, Brouqui P, Raoult D. Prevalence of antibodies to Rickettsia conorii, Ricketsia africae, Rickettsia typhi and Coxiella burnetii in Mauritania. Eur J Epidemiol 1998; 14: 817–18. 47 Okabayashi T, Hasebe F, Samui KL, et al. Short report: prevalence of antibodies against spotted fever, murine typhus, and Q fever rickettsiae in humans living in Zambia. Am J Trop Med Hyg 1999; 61: 70–72. 48 Raoult D, Roux V. Rickettsioses as paradigms of new or emerging infectious diseases. Clin Microbiol Rev 1997; 10: 694–719. 49 Kelly PJ, Mason PR, Matthewman LA, Raoult D. Seroepidemiology of spotted fever group rickettsial infections in humans in Zimbabwe. J Trop Med Hyg 1991; 94: 304–9. 50 Caruso G, Zasio C, Guzzo F, et al. Outbreak of African tick-bite fever in six Italian tourists returning from South Africa. Eur J Clin Microbiol Infect Dis 2002; 21: 133–36. 51 Fournier PE, Beytout J, Raoult D. Tick-transmitted infections in Transvaal: consider Rickettsia africae. Emerg Infect Dis 1999; 5: 178–81. 52 Kager PA, Dondorp AM. Fever and vesiculopapular exanthema due to infection with Rickettsia africae after a sojourn in South Africa. Ned Tijdschr Geneeskd 2001; 145: 138–41.
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Review 53 Sexton DJ, Corey GR, Greenfield JC Jr, Burton CS, Raoult D. Imported African tick bite fever: a case report. Am J Trop Med Hyg 1999; 60: 865–67. 54 Smoak BL, McClain JB, Brundage JF, et al. An outbreak of spotted fever rickettsiosis in US Army troops deployed to Botswana. Emerg Infect Dis 1996; 2: 217–21. 55 Roux O, Desruelles F, Delaunay P, Le Fichoux Y, Ortonne JP. Ticks and photo safari in South Africa. Br J Dermatol 2000; 143: 1109–10. 56 Jensenius M, Fournier PE, Vene S, et al. African tick bite fever in travellers to rural sub-Equatorial Africa. Clin Infect Dis 2003; 36: 1411–17. 57 Toutous-Trellu L, Peter O, Chavaz P, Saurat JH. African tick bite fever: not a spotless rickettsiosis! J Am Acad Dermatol 2003; 48: S18–S19. 58 Barret-Connor E, Ginsberg MM. Imported South African tick typhus. West J Med 1983; 138: 264–66. 59 Harris RL, Kaplan SL, Bradshaw MW, Williams TW. Boutonneuse fever in American travelers. J Infect Dis 1986; 153: 126–28. 60 Hutterer J, Konrad K, Tappeiner G. South African tick bite fever. Hautarzt 1987; 38: 172–74. 61 Grove DI. African tick typhus (Mediterranean spotted fever) in Australian travellers. Australas J Dermatol 1988; 29: 141–45. 62 McDonald JC, MacLean JD, McDade JE. Imported rickettsial disease: clinical and epidemiologic features. Am J Med 1988; 85: 799–805. 63 Kemper CA, Spivack AP, Deresinski SC. Atypical papulovesicular rash due to infection with Rickettsia conorii. Clin Infect Dis 1992; 15: 591–94. 64 Laubenberger CM, Mravak S, Huzly D, Hegenscheid B, Friedrich-Jänicke B, Bienzle U. Tick bite fever in travellers to South Africa. Z Allg Med 1994; 70: 843–46. 65 Puente S, Lago M, Subirats M, Verdejo J, Martinez ML, Gonzalez-Lahoz JM. Spotted fever attributable to Rickettsia conorii: ten cases imported from subSaharan Africa. J Travel Med 1995; 2: 204–5. 66 Ericsson CD, Long J, Septimus E. African tick-bite fever: a case report. J Travel Med 1997; 4: 197. 67 Kimura M, Fujii T, Iwamoto A. Two cases of spotted fever group rickettsiosis contracted in southern parts of Africa. Kansenshogaku Zasshi 1998; 72: 1311–16. 68 Neal S, Cieslak P, Hedberg K, Fleming D. African tick-bite fever among international travelers— Oregon, 1998. MMWR Morb Mortal Wkly Rep 1998; 47: 950–52. 69 Wesslen L, Torell E, Vene S. Three Swedish cases of African tick bite fever. Can our native Rickettsia species cause disease in humans? Lakartidningen 1999; 96: 3888–90. 70 Estrada-Pena A, Jongejan F. Ticks feeding on humans: a review of records on human-biting Ixodoidea with special reference to pathogen transmission. Exp Appl Acarol 1999; 23: 685–715. 71 Burgert SJ. Clinical manifestations of African tickbite fever in the returning traveler. Infect Dis Clin Pract 2000; 9: 137–38. 72 Martino O, Orduna T, Lourtau L, Scapellato P, Cernigo B, Seijo A. Spotted fever group rickettsial
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disease in Argentinean travellers. Rev Soc Bras Med Trop 2001; 34: 559–62. 73 O’Brien D, Tobin S, Brown GV, Torresi J. Fever in returned travelers: review of hospital admissions for a 3-year period. Clin Infect Dis 2001; 33: 603–09. 74 Hurtado, R. Rickettsiosis, tickborne—USA ex S Africa. Archive number 20020410.3928. http://www.promedmail.org. 75 Stockli R. African tick bite fever. Schweiz Rundsch Med Prax 2002; 91: 329–30. 76 Durrheim DN, Braack L, Grobler D, Bryden H, Speare R, Leggat PA. Safety of travel in South Africa: the Kruger national park. J Travel Med 2001; 8: 176–91. 77 Jensenius M, Hoel T, Raoult D, et al. Seroepidemiology of Rickettsia africae infection in Norwegian travellers to rural Africa. Scand J Infect Dis 2002; 34: 93–96. 78 Jelinek T, Löscher T. Clinical features and epidemiology of tick typhus in travelers. J Travel Med 2001; 8: 57–59. 79 MacLean JD, Lalonde RG, Ward B. Fever from the tropics. Travel Med Advisor 1994; 5: 27.1–27.14. 80 Phillips-Howard PA, Radalowicz A, Mitchell J, Bradley DJ. Risk of malaria in British residents returning from malarious areas. BMJ 1990; 300: 499–503. 81 Jensenius M, Ueland T, Fournier PE, et al. Systemic inflammatory responses in African tick bite fever. J Infect Dis 2003; 187: 1332–36. 82 Helmick CG, Bernard KW, D‘Angelo LJ. Rocky Mountain spotted fever: clinical, laboratory, and epidemiological features of 262 cases. J Infect Dis 1984; 150: 480–88. 83 Parola P, Jourdan J, Raoult D. Tick-borne infection caused by Rickettsia africae in the West Indies. N Engl J Med 1998; 338: 1391. 84 Drancourt M, Raoult D, Harle JR, et al. Biological variations in 412 patients with Mediterranean spotted fever. Ann N Y Acad Sci 1990; 590: 39–50. 85 Jensenius M, Fournier PE, Hellum KB, et al. Sequential changes of hematologic and biochemical parameters in African tick bite fever. Clin Microbiol Infect (in press). 86 Xu W, Beati L, Raoult D. Characterization of and application of monoclonal antibodies against Rickettsia africae, a newly recognized species of spotted fever group rickettsia. J Clin Microbiol 1997; 35: 64–70. 87 Fournier PE, Roux V, Raoult D. Phylogenetic analysis of spotted fever group rickettsiae by study of the outer surface protein rOmpA. Int J Syst Bacteriol 1998; 48: 839–49. 88 Roux V, Raoult D. Phylogenetic analysis of the genus Rickettsia by 16S rDNA sequencing. Res Microbiol 1995; 146: 385–96. 89 Roux V, Raoult D. Phylogenetic analysis of members of the genus Rickettsia using the gene encoding the outer-membrane protein rOmpB (ompB). Int J Syst Evol Microbiol 2000; 50: 1449–55. 90 Sekeyova Z, Roux V, Raoult D. Phylogeny of Rickettsia spp inferred by comparing sequences of “gene D”, which encodes an intracytoplasmic protein. Int J Syst Evol Microbiol 2001; 51: 1353–60.
91 Raoult D, Aboudharam G, Crubezy E, Larrouy G, Ludes B, Drancourt M. Molecular identification by “suicide PCR” of Yersinia pestis as the agent of Medieval Black Death. Proc Natl Acad Sci USA 2000; 97: 12800–3. 92 La Scola B, Raoult D. Laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases. J Clin Microbiol 1997; 35: 2715–27. 93 Fournier PE, Jensenius M, Laferl H, Vene S, Raoult D. Kinetics of antibody responses in Rickettsia africae and Rickettsia conorii infections. Clin Diagn Lab Immunol 2002; 9: 324–28. 94 Miller GB, Gear JHS. Treatment of tick-bite fever with erythromycin. S Afr Med J 1984; 66: 694–97. 95 Brouqui P, Dupont HT, Drancourt M, Bourgeade A, Raoult D. Spotless boutonneuse fever. Clin Infect Dis 1992; 14: 114–16. 96 Raoult D, Drancourt M. Antimicrobial therapy of rickettsial diseases. Antimicrob Agents Chemother 1991; 35: 2457–62. 97 Parola P, Raoult D. Ticks and tickborne bacterial diseases in humans: an emerging infectious threat. Clin Infect Dis 2001; 32: 897–928. 98 Pretorius AM, Jensenius M, Clarke F, Ringertz SH. Repellent efficacy of DEET and KBR 3023 against Amblyomma hebraeum (Acari: Ixodidae). J Med Entomol 2003; 40: 245–8. 99 Schreck CE, Fish D, McGovern TP. Activity of repellents applied to skin for protection against Amblyomma americanum and Ixodes scapularis ticks (Acari: Ixodidae). J Am Mosq Control Assoc 1995; 11: 136–40. 100 Solberg VB, Klein TA, McPherson KR, Bradford BA, Burge JR, Wirtz RA. Field evaluation of deet and a piperidine repellent (AI3-37220) against Amblyomma americanum (Acari: Ixodidae). J Med Entomol 1995; 32: 870–75. 101 Shulz HA. Department of defence doctrine and material for protecting personnel from biting arthropods. J Travel Med 2001; 8: 133–38. 102 Raoult D, Dupont HT, Chicheportiche C, Peter O, Gilot B, Drancourt M. Mediterranean spotted fever in Marseille, France: correlation between prevalence of hospitalized patients, seroepidemiology, and prevalence of infected ticks in three different areas. Am J Trop Med Hyg 1993; 48: 249–56. 103 Williams WJ, Radulovic S, Dasch GA, et al. Identification of Rickettsia conorii infection by polymerase chain reaction in a soldier returning from Somalia. Clin Infect Dis 1994; 19: 93–99. 104 Pretorius AM, Birtles RJ. Rickettsia aeschlimannii: a new pathogenic spotted fever group rickettsia, South Africa. Emerg Infect Dis 2002; 8: 874. 105 Bertherat E, Nabias R, Georges AJ, Renaut A. Seroprevalence of Rickettsia in a gold-panning population in north-eastern Gabon. Trans R Soc Trop Med Hyg 1998; 92: 393–4. 106 Watt G, Kantipong P, de Souza M, et al. HIV-1 suppression during acute scrub-typhus infection. Lancet 2000; 356: 475–79. 107 Lutwick LL. Brill-Zinsser disease. Lancet 2001; 357: 1198–200.
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African tick bite fever
African tick bite fever
Mogens Jensenius, Pierre-Edouard Fournier, Patrick Kelly, Bjørn Myrvang, and Didier Raoult
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African tick bite fever is an acute febrile illness that is frequently accompanied by headache, prominent neck muscle myalgia, inoculation eschars, and regional lymphadenitis. The disease is caused by Rickettsia africae, a recently identified spotted fever group rickettsia, which is transmitted by ungulate ticks of the Amblyomma genus in rural sub-Saharan Africa and the French West Indies. Whereas reports on African tick bite fever in indigenous populations are scarce, the number of reported cases in travellers from Europe and elsewhere has recently increased significantly. Treatment with doxycycline is associated with rapid recovery in most patients. An immunofluorescence assay is recommended for the diagnosis but seroconversion is commonly delayed and this limits the usefulness of the test. Travellers to endemic areas should be informed of the risk of contracting African tick bite fever and be encouraged to take personal protective measures against tick bites.
Figure 1. Adult A variegatum tick.
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Historical background International travel, one of the largest and most rapidly evolving industries worldwide,1 has a significant impact on health care in many developed countries. An estimated 15–37% of short-term travellers experience a health problem related to overseas travel,2 and about 4–8% of travellers to developing areas seek medical attention on return to their home countries.3 Increasing numbers of international travellers visit tropical and subtropical regions of the world, where they may be exposed to a range of exotic microbes. As a consequence, physicians assessing ill returnees may today not only encounter well-known conditions such as malaria, hepatitis A, and traveller’s diarrhoea, but also less familiar diseases including dengue, melioidosis, Japanese encephalitis, trypanosomiasis, schistosomiasis, and relapsing fever.4–8 One example of such recently recognised travelassociated diseases is African tick bite fever, a spotted fever group rickettsioses, which, in the wake of the rapidly expanding international safari tourism to southern Africa, has emerged as a common cause of imported fever in Europe and elsewhere.9–12 In this review we describe the current status of the biology, epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, and possible prevention of African tick bite fever. THE LANCET Infectious Diseases Vol 3 September 2003
The early description of African tick bite fever, probably a very old disease in sub-Saharan Africa, is tightly intertwined with that of Mediterranean spotted fever. Mediterranean spotted fever was described by Conor and Bruch in Tunisia in 191013 and soon also reported from other regions around the Mediterranean basin, from the Black Sea littoral, India, the Middle East, and southern Africa. In the early 1930s, the brown dog tick Rhipicephalus sanguineus was recognised as a vector in Europe, and a spotted fever group rickettsia was shown to be the causative agent; in honour of the work of Conor, this organism was named Rickettsia conorii. The clinical picture of Mediterranean spotted fever is characterised by acute flu-like symptoms, a generalised maculopapular cutaneous rash, and a single inoculation eschar but usually no regional lymphadenitis. Complications are frequent and, if left untreated, mortality rates may exceed 2%.14 MJ is at the Department of Internal Medicine, Aker University Hospital, Oslo, Norway; BM is at the Department of Infectious Diseases, Ullevål University Hospital, Oslo; P-EF and DR are at the Unité des Rickettsies, CNRS, UMR 6020, Université de la Mediterranee, Marseille, France; and PK is at the Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Palmerston North, New Zealand. Correspondence: Dr Mogens Jensenius, Division of Infectious Diseases, Department of Internal Medicine, Aker University Hospital, N-0514 Oslo, Norway. Tel +47 22 89 40 00; fax +47 22 89 40 08; email [email protected]
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In 1911—ie, just 1 year after the first description of Mediterranean spotted fever—a similar flu-like disease was described in Mozambique and South Africa.15,16 This illness was also transmitted by ticks and was named tick bite fever. The epidemiology and clinical presentations of the two conditions were investigated by Pijper in South Africa in the 1930s.17,18 Whereas patients with Mediterranean spotted fever typically acquired the disease in urban areas with dogs, Pijper noted that most patients with tick bite fever became ill after contact with cattle ticks in the bush. Also, the clinical manifestations of tick bite fever were milder with few complications and frequently no cutaneous rash.17,18 Pijper was able to isolate the causative rickettsia of tick bite fever in guineapigs and showed using cross-protection studies that the organism differed from R conorii. Unfortunately, his isolate was lost and subsequent workers were unable to confirm his findings, and—erroneously—tick bite fever became a synonym for Mediterranean spotted fever in Africa for several decades.19 In August 1992, a spotted fever group rickettsia was isolated from the blood of a 36-year-old woman presenting with tick bite fever at a hospital in Zimbabwe. By PCR and restriction endonuclease fragment length polymorphism, this isolate was seen to be distinct from all other spotted fever group rickettsiae, including R conorii. It was, however, indistinguishable from a strain isolated from Amblyomma variegatum ticks (figure 1) collected from cattle in Ethiopia 20 years earlier,20 and from six isolates recovered from Amblyomma hebraeum ticks collected in Zimbabwe in the 1980s.21 The case report was published 2 months later, in which the authors proposed the name African tick bite fever for the disease and the name Rickettsia africae for the causative agent,22 nomenclatures that were made official in 1996.9
could be differentiated from all other spotted fever group rickettsiae except Rickettsia parkeri, a species of unknown pathogenicity transmitted by Amblyomma maculatum ticks in the USA.9 Sequencing studies of the 16S rRNA gene sequences have shown that R parkeri and Rickettsia sibirica, the agent of Siberian tick typhus, are the two closest relatives (homology ⭓99·6%) and that Rickettsia akari and Rickettsia australis, the agents of rickettsial pox and Queensland tick typhus, respectively, are the most distant relatives (homology 97·9%) to R africae (figure 2). Recently, three variant strains of R africae were detected in adult A variegatum ticks collected from cattle in Mali and Niger (rOmpA homology with the type strain 99·3%–99·5%).24 In-vitro susceptibility data for R africae are available for 13 antibiotics,25,26 and show that the organism is resistant to -lactam antibiotics, aminoglycosides, and co-trimoxazole, semi-susceptible to erythromycin, and susceptible to tetracyclines, chloramphenicol, rifampin, fluoroquinolones, the newer macrolides, and ketolides.
Vectors R africae is transmitted by the members of the Amblyomma genus, of which two, A variegatum (the tropical bont tick) and A hebraeum (the southern African bont tick), are recognised as principal vectors.9 Noteworthy, A hebraeum, and supposedly also A variegatum, not only act as vectors of R africae but are also important reservoirs in which infection is maintained through transovarial transmission (from adult female to offspring) and trans-stadial transmission (from larva to nymph to adult).27 The rates of R africae infection in A variegatum and A hebraeum ticks are frequently high and may exceed 30% and 70%, respectively.22,27–30
Causative agent R africae is an obligate intracellular Gram-negative, rod-shaped bacterium that measures 0·3–0·5⫻0·9–1·6 m. Electron microscopy shows that the bacteria occurs free in the cytoplasm, and has an outer slime layer and a trilaminar cell wall. The cell wall of R africae contains lipopolysaccharide antigens, which are highly immunogenic and responsible for extensive crossreactivity with the other spotted fever group rickettsiae.23 Species-specific protein antigens are located in the high-molecular-weight rickettsial outer membrane protein A (rOmpA) and B (rOmpB). R africae cannot be cultivated in cell-free media but will grow in yolk sacs of developing chicken embryos, and in cell cultures.9 The genome of R africae consists of a single circular chromosome with an estimated size of 1248 kb. Based on initial genotypic studies, R africae
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R conorii R rickettsii R honei
Spotted fever group
R africae R parkeri R sibirica R slovaca R japonica R aeschlimanni R massiliae R rhipicephali R montanensis R helvetica R felis R australis R akari R prowazekii Typhus group R typhi R canadensis Ancestral group R bellii 0·02 Figure 2. Dendogram of Rickettsia africae.
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African tick bite fever
A hebraeum and A variegatum, as other hard tick species, have three active stages: larvae, nymphs, and adults. Larvae are minute and may be difficult to detect on skin and clothing, whereas a fully engorged adult female may approach the size of a grape. Adults are easily recognised by their bright, reddish colours (figure 1). A blood meal is needed at each stage for development into the next. In places with a single rainy season, one generation occurs per year,31 but where there are two rainy seasons, shorter generations are possible.32
KwaZulu-Natal province, as well as in the northeastern regions where many popular wildlife attractions are situated. A hebraeum is also present in eastern Botswana, southern Mozambique, and in the southern half of Zimbabwe.37,39 Although A variegatum and A hebraeum have similar requirements they are rarely seen in the same areas. This is probably due to interspecific competition and the production of sterile hybrids.40
Epidemiology Hosts and host-seeking behaviour
By contrast with most other hard ticks of medical importance, which exhibit a passive ambush host-seeking strategy, members of the Amblyomma genus actively converge on nearby hosts.33 The ticks are notoriously aggressive, and a single host may be attacked by many ticks, and several hosts may be attacked simultaneously. Cattle are the most important domestic hosts for adult A hebraeum and A variegatum although sheep, horses, donkeys, and pigs are also frequently attacked. Adult ticks also feed readily on a range of wild ungulates including giraffes, buffalo, antelope, and warthogs, which are Figure 3. important in maintaining the species Distribution map of principal tick in areas where domestic hosts are the vectors of Rickettsia 34 absent or dipped intensively. Larvae africae. Dotted line and nymphs use similar hosts to denotes approximate adults, but can also be seen on lizards, border between mountain tortoises, smaller mammals, A hebraeum (in southern Africa) and and ground-feeding birds.35,36 People, A variegatum. who are only accidental hosts, are Adapted from usually attacked on the legs, but once reference 47. on the skin amblyommas may crawl around for hours before attaching, typically behind the knee, in the groin or axilla where the skin is thin, moist, and warm. Ecology and distribution
A hebraeum and A variegatum occur only in tropical and subtropical environments, and need an annual rainfall of 300–800 mm.36 Both species prefer habitats with tall grass or bush offering shade, and are not present on steppes with only short grass, in arid or urban areas.31 Although present throughout the year in most infested areas, these species are most abundant during the rainy season, in Zimbabwe from February to May, in Tanzania, Zambia, and Malawi from November to January, and in Somalia from April to May.32 The two tick species have different geographical distributions (figure 3). A variegatum is distributed throughout rural areas of west, central, and east Africa south of the Sahara desert, as well as the horn of Africa.37 In addition, the species is present in Yemen, on several islands in the Indian Ocean, on the Cape Verde Islands in the Atlantic Ocean, and in the eastern Caribbean.37,38 A hebraeum, by contrast, is only present in southern Africa. In South Africa, the species is distributed along the coast of the Indian Ocean, including the THE LANCET Infectious Diseases Vol 3 September 2003
R africae has been detected or isolated from Amblyomma spp ticks or human beings from 14 African countries: South Africa, Botswana, Zimbabwe, Tanzania, Kenya, Burundi, Sudan, Ethiopia, Central African Republic, Gabon, Mali, Niger, Côte d’Ivoire, and Gambia,12,20,21,24,28–30 and on Guadeloupe in the French West Indies.41 In addition, several studies have shown very high seroprevalence rates (up to 70%) for spotted fever group rickettsial infections in areas of sub-Saharan Africa where A variegatum or A hebraeum ticks are prevalent and/or where cattle-breeding is intense.41–47 Thus, direct and indirect epidemiological data suggest that R africae occurs widely throughout sub-Saharan Africa and the eastern Caribbean, and that it actually may be the most widespread of all spotted fever group rickettsiae known to be pathogenic in human beings.48 Indigenous populations
Despite the wide geographical distribution of R africae, reports on African tick bite fever in indigenous African populations are unexpectedly scarce with only one confirmed case reported.22 Studies have shown that indigenous people are generally infected at a young age when the disease might be very mild or subclinical, and that many patients do not seek medical attention.43,44,49 It is also difficult to see inoculation eschars in pigmented skin and this important clue might not be seen unless without thorough and extensive physical examinations. Moreover, definitive diagnosis of African tick bite fever requires sophisticated diagnostic tests that are not available in many African countries. Anecdotal reports indicate that African tick bite fever may pose a significant problem to local populations. During the Zimbabwean war of independence in the late 1970s, army medical authorities reported that several thousand cases of tick typhus had been treated. Both European and African soldiers were affected, although the infection rate seemed to be greater among the former. Zimbabwean cases occurred mainly among presumably non-immune soldiers of urban origin who were deployed to rural areas. No
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microbiological data are available; however, this period coincided with a major disruption of local cattle-dipping programmes and an ensuing extensive spread of A hebraeum.34 More recently, medical practitioners surveyed in Zimbabwe reported case incidence rates of African tick bite fever of 60–80 per 100 000 patients each year in areas where A hebraeum is endemic.49 International travellers
Traditionally, rickettsioses have been regarded as curiosities in international travel medicine. During the past few years, however, the number of travel-associated cases of African tick bite fever has increased significantly worldwide. Since 1983, 388 cases of spotted fever group rickettsioses acquired by international travellers to sub-Saharan Africa or the French West Indies have been reported in published material. Of these, 171 cases were microbiologically confirmed as African tick bite fever.11,12,50–57 Another 78 cases could, based on positive (but not species-specific) microbiological tests in combination with typical features (such as multiple inoculation eschars, a vesicular cutaneous rash, and/or clustering of cases), retrospectively be classified as probable African tick bite fever.52,54,58–75 The mean age of these 249 cases of African tick bite fever was 40 years; most patients (72%) were male, and most (64%) originated from Europe. Typically, more than 80% of the patients acquired the disease in South Africa, where many popular wildlife attractions are highly endemic for R africae infection76 and where the abolition of apartheid in the early 1990s was followed by a sixfold rise in international tourism.1 Any person who enters the tick vectors’ habitats in endemic areas is at risk of contracting African tick bite fever, and reported cases represent a wide range of travellers, including leisure safari tourists, backpackers, hunters, sports competitors, students, foreign aid workers, film crew staff, and deployed soldiers. Characteristically, up to 74% of travelassociated cases of African tick bite fever occur in clusters,12,56 which may seem spectacular and affect up to 100% of those exposed.11,50 Game hunting (an activity typically characterised by heavy exposure to ground vegetation, ungulates, and their hides), travel to southern Africa (where A hebraeum is the principal vector), and travel between November and April
(when tick activity peaks in many endemic areas) have recently been identified as independent risk factors of African tick bite fever.56 How common is African tick bite fever in international travellers to endemic areas? Three studies have addressed this question. In a seroepidemiological study of first-time Norwegian travellers to rural subequatorial Africa, specific antibodies to R africae were seen in 9% of the patients.77 Similarly, serological evidence of recent spotted fever group rickettsial infection was detected in 11% of returnees from southern Africa who presented at a German outpatient clinic with various medical complaints including fever.78 Finally, in a prospective cohort study of 940 Norwegian mostly short-term travellers to rural subequatorial Africa, the incidence-rates of African tick bite fever ranged from 4·0–5·3%,56—ie, estimates that widely exceed those reported for other tropical fevers in temporary visitors to sub-Saharan Africa, including malaria and typhoid fever.3,5,73,79,80 Thus, if the data from these three studies are extrapolated to the 6·4 million travellers to South Africa in 2002,1 as well as to the large annual numbers of tourists visiting other destinations in sub-Saharan Africa, it seems likely that thousands of cases of African tick bite fever should occur in international travellers each year.
Pathogenesis Recent studies have given insights into the pathophysiology of African tick bite fever. The first step of infection, rickettsial invasion of endothelial cells, occurs with an increased secretion of endothelium-associated mediators such as von Willebrand factor and soluble E-selectin.81 Subsequent damage to the endothelium is followed by perivascular infiltration of T cells and macrophages resulting in a lymphohistiocytic vasculitis, the histopathological hallmark of rickettsial disease.57 Finally, the clearance of R africae, which is believed to involve complex interactions between T cells, macrophages, natural killer cells, B lymphocytes, and antibodies, is characterised by increased circulating concentrations of cytokines (eg, tumour necrosis factor alpha, interleukin 6, and interleukin 10), as well as CC-chemokines (eg, RANTES and macrophage inflammatory protein 1 alpha), and CXC-chemokines (eg, interleukin 8).81 There are no convincing data that secreted toxins are involved in the pathogenesis of African tick bite fever.
Clinical features
Figure 4. Inoculation eschar in groin with large red halo.
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The modern clinical description of African tick bite fever is mainly based on four studies (table): one consecutive series of an outbreak affecting 39 US soldiers deployed to Botswana in 1992,54 one consecutive series describing an outbreak affecting 13 French sports competitors infected in South Africa in 1997,11 one consecutive series of 38 Norwegian cases diagnosed in 1999–2001,56 and one retrospective series of 119 cases diagnosed in ten European and North American countries from 1996–2000.12 The time lag from tick bite to symptom onset is usually 5–7 days but may be as long as 10 days. Most patients present with abrupt flu-like symptoms such as fever, nausea, fatigue, headache, and myalgia. Of note is a prominent neck muscle myalgia with subjective neck THE LANCET Infectious Diseases Vol 3 September 2003
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stiffness that is reported by four of five cases. This symptom, which has also been described in Rocky Mountain spotted fever caused by Rickettsia rickettsii,82 probably indicates central nervous system affection. An inoculation eschar, a black crust surrounded by a red halo at the site of the tick bite (figure 4), is present in most cases but may easily be overlooked, particularly on dark skin, in the hair, or in the anogenital region. Sometimes, nontypical eschars mimicking acne are seen. Up to 54% of patients with African tick bite fever have multiple eschars, a pathognomonic clinical sign which indicates the aggressive behavior of the implicated tick vectors (figure 5). The number of skin lesions may be impressive, as was seen during the investigation of an outbreak among Italian safari tourists to South Africa, where five patients presented with a total of 34 eschars.50 Regional lymphadenitis is common and may be seen also in the absence of a frank eschar. A generalised cutaneous rash, sometimes vesicular and usually best seen close to the eschar, is present in 15–46% of the patients. Less common signs of African tick bite fever include aphthous stomatitis, which was reported in six patients infected in South Africa,10,56,72 and lymphangitis, which was recorded in one case from Zimbabwe and one case from South Africa.10,50 Complications seem to be rare in African tick bite fever. A fever of more than 3 weeks’ duration was reported in one case from Zimbabwe and one case from the French West Indies71,83 These reports suggest that African tick bite fever should be considered when assessing travellers from endemic areas with prolonged fevers. Reactive arthritis has occasionally been seen in cases infected in South Africa.56 Most important, and by contrast with other spotted fever group rickettsioses, life-threatening complications have never been reported in African tick bite fever, and there are no known fatal cases. The sequential kinetics of haematological and biochemical parameters during the acute phase of African tick bite fever mimic those reported in other spotted fever group rickettsioses.82,84 During the first 10 days of illness, when most patients are likely to present, increased concentrations of serum C-reactive protein and moderate lymphopenia are seen in most cases. Elevated serum liver enzymes and thrombocytopenia are also common, and are detected in 40% and 20% of patients, respectively.85 Signs and symptoms in African tick bite fever Characteristic Fever
Frequency (%) 59–100
Headache
62–83
Myalgia Neck muscle myalgia
63–87 81
Inoculation eschar Multiple eschars
53–100 21–54
Regional lymphadenitis
43–100
Cutaneous rash Maculopapular Vesicular Aphthous stomatitis
15–46 15–26 0–21 11
Data compiled from four studies (references 11,12,54,56)
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Figure 5. Patient with multiple inoculation eschars on ankles.
Microbiological diagnosis Culture and antigen detection
Isolation of R africae from clinical specimens, the ultimate confirmation of African tick bite fever, poses several inherent limitations and should be reserved to specialised laboratories equipped with biohazard facilities. Cell culture is currently the most widely used system for primary isolation, with human embryonic lung fibroblast (HEL) cell being one of the most useful cell lines. Shipment of specimens should be done in dry ice and be swift, since inoculation of cell cultures should ideally take place within 24 h after sampling. The sensitivity of isolation of R africae in African tick bite fever is generally poor, less than 15% in heparinised blood and 44% in skin-biopsy specimens.12 Detection of R africae antigen may be done either by immunohistochemistry using monoclonal antibodies86 or by PCR. The former method is reserved to reference centres but the latter technique may be used by any laboratory equipped for molecular diagnosis. PCR may be applied to an array of samples including blood, skin biopsy samples, and arthropod tissues. Detection strategies based on recognition of sequences within the genes encoding the 16S rRNA, outer membrane proteins rOmpA, rOmpB, and PS120 have effectively been used for R africae.87–90 The best human specimen is undoubtedly the inoculation eschar biopsy. With use of standard PCR, R africae DNA can be detected in 48% of skin-biopsy specimens, whereas the sensitivity approaches 100% when suicide PCR, a nested PCR using single-use primers targeting a gene never amplified previously in the laboratory, is used.12,91 However, eschar specimens may not be easy to obtain, and during the
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investigation of an outbreak of African tick-bite fever among French sports competitors, 12 of 13 patients refused to undergo skin biopsy.11 Serology
In addition to the archaic and poorly specific Weil-Felix test, which continues to be used as a first-line test in many countries, immunofluorescence assay is the most widely used microbiological test in rickettsial diseases worldwide.92 No immunofluorescence assay for African tick bite fever is commercially available but due to extensive cross-reactions, commercial kits based on R conorii or R rickettsii antigens can be used. When testing, however, it is important to note that diagnostic antibody titres are seen late in African tick bite fever, frequently more than 3 weeks after the onset of symptoms, or not at all in mild cases or in patients treated early with doxycycline.93 More specific serological tests for African tick bite fever are laborious and expensive, and at present are only available at reference centres. Such tests include multiple-antigen immunofluorescence assay (where reactions to several spotted fever group rickettsial antigens, including R africae, can be compared directly), western blotting (where speciesspecific antibodies directed to high-molecular-weight proteins [rOmpA, rOmpB and PS120] are detected), and cross-adsorption assays (where the infecting species may be determined by removing non-specific antibodies).11,12
focally very abundant on vegetation, they are highly aggressive feeders and are usually active 24 h a day. During bush walks, travellers should be recommended to wear protective clothing, preferably impregnated or sprayed with acaricides. They should also use topical insect repellents on any exposed skin97 and regularly examine themselves for ticks. Unfortunately, most commercially available insect repellents based on diethyl-3methylbenzamide (DEET), piperidine compounds, or citronella oil have only short-lasting efficacy against Amblyomma spp ticks, typically for less than 2 h.98–100 US authorities advocate the use of DEET products containing 33% DEET against biting arthropods,101 but lotions containing more than 19·5% are not widely available in Europe and Africa. A hebraeum and A variegatum ticks should be removed carefully as they have long mouth parts and are often very firmly attached. The minimum attachment time needed for transmission of R africae to people is unknown. In the only feeding study done with this pathogen, A hebraeum ticks were allowed to feed until fully engorged and all feeding stages transmitted infections to rabbits.27 There are also few data for the other spotted fever group rickettsiae. Dermacentor andersonii ticks may transmit R rickettsii, the agent of Rocky Mountain spotted fever, after only 6 h of attachment although it usually requires 10 to 24 h, and R sanguineus requires more than 20 h to transmit R conorii, the agent of Mediterranean spotted fever.102
Treatment There are only limited data on the optimal antibiotic treatment of African tick bite fever, including indication, drug of first choice, and proper dosing. No reliable randomised clinical trials have been done. Certainly, one study describes the inefficacy of erythromycin in six of 17 hospitalised patients with tick bite fever in South Africa,94 but in this series many cases did probably represent Mediterranean spotted fever and not African tick bite fever. Of the 249 aforementioned published cases of African tick bite fever and for whom data on antibiotic treatment were provided, 149 of 179 (83%) were treated with antibiotics. In virtually all of these cases, the prescribed treatment was doxycycline, usually as 100 mg twice daily for 7 to 10 days, or, rarely for 1 to 5 days.64,95 Possible treatment failures occurred in only three cases, two treated with doxycycline56,83 and one treated with azithromycin.50 In most cases, symptoms were reported to resolve within 24–48 h after start of treatment. Currently, then, doxycycline 100 mg twice daily for 7 days or until 48 h after defervescence can be recommended in cases of African tick bite fever with high fever, intense headache, or other more pronounced symptoms. Fluoroquinolones may also be of benefit. The use of chloramphenicol or josamycin, the recommended regimen for pregnant women with spotted fever group rickettsioses,96 has never been reported in African tick bite fever.
Prevention Travellers to sub-Saharan Africa should be informed that they are very likely to encounter the tick vectors of African tick bite fever if they visit rural areas. The ticks may be
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Unsolved issues Although a substantial body of information has been collected since the description of R africae as a human pathogen in 1992, several central aspects of African tick bite fever still need to be elucidated. Most importantly, the precise geographical distribution of R africae, as well as those of other spotted fever group rickettsiae endemic to sub-Saharan Africa (eg, R conorii,12,103 Rickettsia aeschlimanii,104 and “Rickettsia mongolotimonae”24) is largely unknown and warrant further epidemiological studies in human beings, mammals, and ticks. Moreover, the apparent paucity of African tick bite fever in indigenous populations, even in regions highly endemic to R africae, is puzzling.49 Co-infection with HIV and R africae is probably common throughout sub-Saharan Africa, as is indicated by a study at five gold-panning communities in rural Gabon,105 but so far no studies on possible interactions between these two pathogens have been reported. The issue is interesting, since scrub typhus, a rickettsial disease with widespread distribution in southeast Asia, may suppress HIV-1 viral load in co-infected patients,106 and since some rickettsioses may cause clinical relapse several years after the primary infection in immunocompromised subjects.107 The incidence of travel-associated African tick bite fever is clearly increasing, and further studies on risk factors in travellers would be welcomed, as would assessments of personal protective measures against Amblyomma tick bites. The diagnostic armamentarium of R africae infection is limited in many areas92 and better availability of the current
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Search strategy and selection criteria We did a computer-aided search of Pubmed from 1983 through to March 2003 using the key words “Rickettsia africae”, “Rickettsia conorii” and “rickettsial infection”. We also surveyed relevant doctoral theses, textbook chapters, and conference proceedings in English.
microbiological tests, as well as development of new, sensitive and easy-to-perform tests, are of crucial importance. Finally, and as mentioned above, current recommendations of antibiotic treatment of African tick bite fever are largely based on extrapolations from case reports, and no randomised clinical trials have been published.
travellers to sub-Saharan Africa, and should now be considered along with malaria, typhoid fever, and other tropical fevers when assessing febrile returnees from this region. The clinical diagnosis is not always straightforward, but several signs and symptoms, including inoculation eschars and neck muscle myalgia, are important clues. Anti-rickettsial chemotherapy seems to shorten the clinical course, and is recommended in cases with more pronounced symptoms. Travellers to endemic areas should be informed about the risk of contracting African tick bite fever, and should be encouraged to protect themselves against tick bites. Conflicts of interest
Conclusion African tick bite fever has recently emerged as one of the most common causes of flu-like illness in international References 1 2 3 4 5 6 7
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None declared. Funding was received from the Research Council of Norway (grant No. 136239/320), Research Forum at Aker University Hospital, and Centre for Imported and Tropical Diseases, Ullevål University Hospital, Oslo, Norway.
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