A souvenir from Africa
A 49-year-old Austrian woman attended the outpatient clinic of the Department of Dermatology in Graz complaining of fever, enlarged inguinal lymph nodes, and a skin lesion that appeared three days before on the right flank. Past medical history was unremarkable. She was not immunosuppressed and she had been taking only cephalexin 1000 mg three times a day for two days. The patient had returned from safaris in South Africa and in Botswana five days before this visit. She could not recall any insect bites or injuries. She had spent many vacations in Africa in the last 20 years. She was vaccinated for yellow fever and she did not take malaria prophylaxis.
General physical examination disclosed only enlarged right inguinal lymph nodes. The patient had a fever (38.5 C°), malaise, and headache. Cutaneous examination revealed on her right flank an almost 2 cm large round, erythematous, asymptomatic macule with a central crust (Figs. 1 and 2).
Figs. 1 and 2
A round, erythematous, asymptomatic macule with a central crust almost 2 cm in diameter. Note the enlarged right inguinal lymph node. The site of biopsy is marked.
The findings from routine radiologic and laboratory investigations, autoantibody screening, viral serologic analysis, and blood cultures were unremarkable except for a mild increase in neutrophils and erythrocyte sedimentation rate. Human immunodeficiency virus enzyme-linked immunosorbent assay (HIV/ELISA) was negative. Neurologic consultation was normal.
A skin biopsy was taken (Figs. 3-7). What is your diagnosis?
African tick-bite fever.
Skin biopsy showed epidermal hyperplasia with very discrete parakeratosis and focal vacuolar degeneration of basal keratinocytes (Fig. 4). In the dermis, edema with dilated vessels and a mainly perivascular superficial and deep lymphohistiocytic infiltrate were present (Figs. 3 and 6). Lymphocytic vasculitis and thrombosis of vessels were also observed (Figs. 5 and 6). IgM antibodies against Rickettsia africae were detected in blood.
Rickettsioses are a large group of arthropod-borne diseases caused by strictly intracellular gram-negative bacterias. [1-4] Nineteen bacterial species belonging to five genera (Rickettsia, Orientia, Ehrlichia, Anaplasma and Coxiella) are agents of human disease (see Table 1).  Rickettsial species are transmitted to humans by hematophagous arthropods including ticks, fleas, lice and mites (Table 1). [2,3] The incubation period ranges from 3 to 12 days. Rickettsial infection produces an acute febrile illness accompanied by headache, myalgia, arthralgia, malaise and morbidity. Cutaneous lesions are present in most rickettsial infections with the exception of Q fever (by Coxiella burnetii, that causes pneumonitis and hepatitis). Rocky Mountain spotted fever and other spotted fevers, murine typhus, and louse-borne typhus are characterized by a maculopapular rash that appears on the fourth day and becomes petechial after two to four days. The name typhus comes from the Greek typhos, meaning smoky or hazy, describing the state of mind of those affected with typhus (typhus should not be confused with typhoid fever, caused by Salmonella typhi). In fact, severe cases can develop a life-threatening disease with high fever, delirium, diffuse vasculitis and myocarditis. A maculo-papular-vesicular rash is typical of rickettsialpox. In most spotted fever rickettsioses and scrub typhus, bouttoneuse fever, Siberian tick typhus, Queensland tick typhus and murine typhus,  the tache noire at the site of the vector’s inoculation of organisms is an important physical sign. It appears as maculo-papular-vesicular lesion of 1-2 cm in diameter that in few days becomes necrotic, forming an eschar. Fever and lymphadenopathies are constantly present. After a few days, some patients can also develop a secondary maculopapular rash.
The two most common imported rickettsioses in Europe are Mediterranean spotted fever (bouttoneuse fever, caused by Rickettsia conorii) and African tick-bite fever. [1,2] African tick-bite fever is a newly described spotted fever rickettsiosis caused by Rickettsia africae, and is an endemic disease in rural areas of sub-Saharan Africa and in the French West Indies. [1,5] Amblyomma hebraeum and Amblyomma variegatum are the hard ticks that can carry Rickettsia africae. [3,6,7] It is now recognized as the predominant rickettsial disease in sub-Saharan Africa and in Europe is a frequent cause of travel-associated rickettsial disease (4%-5.3% among tourists returning from sub-Saharan Africa contract African tick-bite fever). [1,3]
The incubation period of African tick-bite fever is usually 5-7 days with a maximum reported of 10 days. The disease has usually different mild-to-moderate clinical manifestations that include general symptoms like fever, chills, myalgias, asthenia, anorexia, weight loss, somnolence, headache and lymphadenopathy. A nonpruriginous rash consisting of macular or maculopapular lesions, vesicular lesions, maculovesicular lesions or purpuric lesions (10-20 lesions smaller than 1 cm in diameter on the trunk, abdomen, back, face and thighs) is reported in only 41% of cases. The cutaneous eschar is characteristic (that in some cases can be multiple), and aphthoid stomatitis and a purpuric enantema have also been described. On rare occasions complications like prolonged fever, reactive arthritis, lymphangitis, conjunctivitis, peripheral nerve involvement, encephalitis, neuropsychiatric disorders and myocarditis have been reported. The most severe course of the disease has been reported in the advance-age population with underlying chronic diseases, but no deaths have been described. [1-5]
In the blood tests of infected patients mild elevation of the inflammatory parameters, moderate elevation of hepatic proofs and mild elevation of creatinine levels have been described. 
Rickettsia africae can be detected in blood samples and in cutaneous eschar biopsy specimens by culture and/or PCR in reference laboratories. The disease can be diagnosed with Rickettsia africae detection by culture and/or PCR or by suggestive clinical and epidemiological data together with a serologic result positive for spotted fever group of rickettsiae. The antibody titers against Rickettsia africae are positive with IgG titer greater than/equal to 1:64 and/or IgM titer greater than/equal 1:32, but significant antibody titers may be detected only 3-4 weeks after symptoms onset and may not be detected in mild cases or in patients receiving tetracycline. A pronounced cross reactivity exists within the different species of Rickettsiae. [1-5]
Histopathology of rickettsial infection is not specific. The most common finding (as in our case) is a lymphocytic vasculitis with dermal hemorrhages and with thrombosis and some fibrinoid necrosis of the vessels. Lymphocytes predominate, but also few neutrophils may be present. Some cases may show basal vacuolar degeneration with exocytosis of inflammatory cells in the epidermis. The histopathological differential diagnosis is within the large group of conditions that may present with lymphocytic vasculitis (i.e., viral exanthema, perniosis, pityriasis lichenoides, polymorphous light eruption, polymorphous eruption of pregnancy, etc.). If the eschars are biopsied, necrosis of the epidermis and dermis is seen. 
Treatment has not been defined specifically. In the literature doxycycline 200 mg daily for one to four weeks, tetracycline 500 mg four times per day for 7-14 days or until 48 hours of apyrexia are obtained is described. Fluoroquinolones are an affective alternative too. [1,2,4] Our patient presented with a classic African tick-bite fever. The main clinical differential diagnoses included anthrax, tularaemia, arthropod reaction, leishmaniasis and ecthyma. Our patient received doxycycline 200 mg a day for two weeks. The fever disappeared within two days; she did not develop cutaneous rash. The eschar healed with an atrophic scar within 2 weeks. In most cases reported in the literature, the recovery is slow (15 days to 1 month after diagnosis) but with a favorable course, like our patient. Complete healing of the eschars generally is obtained in 2-4 weeks. 
Ecotourism in sub-Saharan Africa is expanding, so imported cases of rickettsioses are playing an important role in travel medicine and should not be underestimated. Rickettsioses are the second cause of imported feverish infections in Europe after malaria. [1-3,7]
Recommendations advising personal prophylactic measures to prevent tick bites in travelers to endemic regions are important too. No human vaccines for rickettsial diseases are available and prophylactic antibiotic therapy is not usually recommended [1,2].
We decided to report this case because of the increasing number of European tourists who travel to the endemic zones of the disease and, therefore, the increasing number of cases. 
Table 1. Rickettsioses, transmitting agent and geographical distribution 
|Rickettsial species||Disease||Transmitting agent||Geographical distribution|
|R. prowazekii*||Epidemic typhus||Clothes lice||Africa, Asia, Central and South America|
|R. prowazekii*||Endemic typhus||Clothes lice||Africa, Asia, Central and South America|
|R. typhi*||Endemic typhus||Fleas||Worldwide|
|R. africae||African tick-bite fever||Ticks||Sub-Saharan Africa, Caribbean|
|R. helvetica||Uneruptive tick-bite fever||Ticks||Eurasia|
|R. conorii||Mediterranean spotted fever||Ticks||Mediterranean, Middle East, India|
|R. monacensis||Tick-bite fever||Ticks||Europe|
|R. massiliae||Tick-bite fever||Ticks||Europe|
|R. aeschlimannii||Tick-bite fever||Ticks||Africa|
|R. rickettsii||Rocky Mountain spotted fever||Ticks||North and South America|
|R. parkeri||Macular fever||Ticks||North and South America|
|R. marmionii||Australian spotted fever||Ticks||Australia|
|R. felis||Flea-borne spotted fever||Fleas||Worldwide (presumed)|
|R. heilongjiangensis||Far east tick-borne spotted fever||Ticks||Far East of Russia, Northern China|
|R. japonica||Japanese spotted fever||Ticks||Japan|
|R. honei||Flinders Island tick bite fever; Thailand tick bite fever||Ticks||Australia, Thailand|
|R. sibirica subsp. mongolotimonae||Tick-borne lymphangitis||Ticks||Southern Europe, Asia, Africa|
|R. australis||Queensland||Ticks||Australia, Tasmania|
|R. sibirica||Siberian tick typhus||Ticks||Russia, China, Mongolia|
|R. slovaca||TIBOLA (tick-borne lymphadenitis)||Ticks||Eurasia|
|R. akari||Rickettsialpox||Mites||Worldwide (presumed)|
|Orientia tsutsugamushi||Scrub typhus||Mites||Southern and eastern Asia|
|Ehrlichia chaffeensis||Human monocytotropic ehrlichiosis||Ticks||Southeastern and south-central US|
|Ehrlichia ewingii||Ehrlichia ewingii infection||Ticks||Southeastern and south-central US|
|Anaplasma phagocyticum||Human granulocytotropic anaplasmosis||Ticks||US, Europe, Eurasia|
|Coxiella burnetii||Q fever||Aerosol||Worldwide|
Background: Rickettsioses are a large group of arthropod-borne diseases caused by strictly intracellular gram-negative bacteria. The two most important imported rickettsioses in Europe are Mediterranean spotted fever and African tick-bite fever. Objectives: To demonstrate the clinical and histopathologic characteristics of a patient with African tick-bite fever. Patients/Methods: A 49-year-old Austrian woman attended the outpatient clinic of the Department of Dermatology in Graz complaining of fever, enlarged right inguinal lymph nodes, and an almost 2 cm round erythematous asymptomatic macule with a central crust on the right flank. Histopathology showed epidermal hyperplasia with very discrete parakeratosis and focal vacuolar degeneration of basal keratinocytes. In the dermis, edema with dilated vessels and a mainly perivascular superficial and deep lymphohistiocytic infiltrate were present. Lymphocytic vasculitis and thrombosis of vessels were also observed. Conclusion: We decided to report this case because of the increasing number of European tourists who travel to the endemic zones of the disease and the increasing number of cases.
Katherine Droppelmann, M.D., Silvia Koller, M.D., and Cesare Massone, M.D., are from the Department of Dermatology, Medical University of Graz in Austria. Katherine Droppelmann also works at the Pontificia Universidad Católica de Chile, Santiago, Chile. Alexandra Maria Giovanna Brunasso, M.D., is from the Department of Environmental Dermatology and Venereology, Medical University of Graz, in Austria, and Andrea Gulia, M.D., is from the Department of Dermatology, University of L’Aquila in Italy. This article was reviewed by Almut Böer, M.D. Contact corresponding author via email: firstname.lastname@example.org .
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