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African tick bite fever: Not a spotless rickettsiosis!
African tick bite fever: Not a spotless rickettsiosis! Laurence Toutous-Trellu, MD,a Olivier Pe´ter, PhD,b Pierre Chavaz, MD,a and Jean-Hilaire Saurat, MDa Geneva, Switzerland African tick bite fever is caused by Rickettsia africae, a newly recognized species from South Africa. We report the case of a patient with an unusual site of a tick bite and discuss cutaneous differences from other spotted fevers that may help dermatologists with clinical diagnosis. (J Am Acad Dermatol 2003;48:S18-9.)
S
everal rickettsial diseases have been described worldwide and are divided into 3 groups—spotted fever, typhus, and scrub typhus.1 One of the recently identified Rickettsia species is Rickettsia africae, which is transmitted by Amblyomma ticks from South Africa and Zimbabwe and causes spotted fever.2,3 African tick bite fever (ATBF) is the name given to R africae infection, which should be differentiated from Mediterranean spotted fever (MSF) caused by Rickettsia conorii infection transmitted by another tick, Rhipicephalus sanguineus. Both are endemic in the same regions of Africa. So far, few cases of ATBF have been reported in Europe, and most are imported cases. Because a rash is a hallmark of rickettsial infection, dermatologists sometimes are in the front line for diagnosis. Common clinical features exist for the different spotted fevers; however, distinctions can help the physician with diagnosis before laboratory confirmation. We report a case of ATBF in a traveler to South Africa.
CASE REPORT A 70-year-old man arrived in the emergency department with fever and asthenia. The fever had started 4 days after the patient returned from a 2-week trip to South Africa. He had been traveling in good conditions and taking antimalarial prophylaxis. He never felt or saw an insect such as a tick on his body. Two days after the beginning of fever, the patient noticed a few nonpruritic papules on both thighs. Clinical examination showed a high fever (40°C) and slight inguinal adenopathy. Neither splenomegaly nor hepatomegaly was found. Skin lesions were of 2 types. Each ankle bore a painless, large, hemorrhagic pustule with diameters of approximately 5 and 7 mm and with an inflammatory border, and approximately 10 purpuric papules were present on each leg (Fig 1). The rest of the skin and the mucous membranes were normal. Laboratory studies showed the following values: white blood cell count, 5.9 ⫻ 109/L (0.67 polymorphonuclear leukocytes and 0.17 lymphocytes); hemoglobin, 162 g/L; platelets, 184 ⫻ 109/L; erythrocyte sedimentation rate, 20 mm/h. Levels of alanine aminotransferThis supplement is made possible through an unrestricted educational grant from Stiefel Laboratories to the American Academy of Dermatology. From the Dermatology Department, Geneva University Hospital,a and the Infectious Diseases and Immunology Department, Central Institute of Valais Hospitalsb. Reprint requests: Dr Laurence Toutous-Trellu, Policlinique de dermatologic, Hoˆpital Universitaire de Gene`ve, rue Micheli-du-Crest, 24, 1211 Gene`ve-CH, Switzerland. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/mjd.2003.122
S18
ase, aspartate aminotransferase, and lactate dehydrogenase were normal. A blood sample was collected for specific serologic analysis, and a skin biopsy on a red papule was performed. The patient was immediately treated with doxycycline 200 mg/d for 2 weeks because rickettsial infection was clinically suspected. Follow-up evaluation showed apyrexia and flattening of the skin lesions after 48 hours. Healing of the eschars took longer (3 weeks), and there was no scar formation. Serial serologic tests for Rickettsia organisms by means of indirect immunofluorescence showed a significant 4-fold increase in IgM titer for R africae (from 32 to 256) in 2 weeks and an increase in IgG titer from 0 to 128. IgM and IgG titers for R conorii increased from 64 to 128 and 0 to 128, respectively. Histologic examination of a papule showed a perivascular lymphocytic infiltrate, necrotizing vasculitis, extravasation of erythrocytes, and eosinophiles in the dermis (Fig 2).
DISCUSSION ATBF develops several days after tick bite inoculation. In general, patients do not remember the bite. The incubation period varies between 1 and 2 weeks. The first clinical manifestations are high fever, arthralgia, myalgia, and fatigue. A rash appears after 2 to 3 days. Severe forms with the neurologic or visceral involvement of other rickettsial infections have not been described. The rash considered a distinct sign of spotted fever is not a major feature of ATBF.4-6 Careful skin examination is sometimes needed to find lesions and eschars. In MSF, only 1 black spot (tache noire), which appears as a crust with an inflammatory border and corresponds to the tick bite site, usually is present. In ATBF, however, several black spots, sometimes as many as 10,3 resemble those of MSF. This patient had 2 tick bite sites with 1 large hemorrhagic and necrotic pustule different from the usual crusty eschar. Among the few reported cases of ATBF, other cutaneous signs associated with the tick bite lesion have included limb lymphangitis on the draining area of the eschar, maculopapules, vesicles, and pustules. In comparison with the multiplicity of local signs, the systemic rash has been reported to be absent in ATBF. Because the course is more benign, discrete pinkish and transient macules can be underestimated. Buccal aphthoid lesions also have been found. The differential diagnosis of this disease is other rickettsial infections, such as MSF, Rocky Mountain spotted fever, and exanthematic typhus. For this reason, it is important to know the country from which the patient has traveled. Sepsis with gram-positive or gram-negative cocci also can be discussed. Cutaneous signs can resemble those of noninfectious vasculitis or insect bite reactions. Histopathologic analysis of rickettsial infection shows invasion of endothelial cells by microorganisms that cause vascular damage. In MSF, Rocky Mountain spotted fever, and typhus,
Toutous-Trellu et al S19
J AM ACAD DERMATOL VOLUME 48, NUMBER 2
Fig 1. Hemorrhagic pustule on ankle and few papules on thigh.
Fig 2. Lymphocytic vasculitis in dermis (papule). (Hematoxylin-eosin stain; original magnification ⫻40.)
rickettsial invasion and toxin delivery by the microorganism cause vasculitis in the central nervous system, heart, lung, spleen, or liver. Histopathologic examination of skin from the eschar, the tick bite site, shows necrotizing vasculitis in blood vessels of the dermis and subcutaneous fat with a perivascular inflammatory cell infiltrate composed mostly of lymphocytes and macrophages. Luminal thrombosis and microinfarcts also occur. The causative organism has a size of 0.3 to 1 mm, which is too small for light microscopic examination. Only blue coccoid intracellular forms can be seen with Giemsa stain.4,7 In this case, we analyzed a papular lesion far from a tick bite site that also showed necrotizing vasculitis. Standard histologic staining did not show microorganisms on the section. Direct immunohistochemical analysis by means of immunofluorescence was not performed on this sample. The diagnosis is confirmed with different laboratory methods. Culture of blood and tissue sampling are recommended for routine diagnosis. Direct immunofluorescence study of endothelial cells and tissue biopsy may be useful. Polymerase chain reaction analysis of endothelial cell, serum, and skin samples is highly specific. In serologic analysis, a microimmunofluorescence test with human isolates of concerned species, electrophoresis, and Western blotting are performed. Antibody crossreaction is usual among the same biogroup, as in our case.
Specific serum absorption for R africae confirms the diagnosis.1,4,6 When rickettsial infection is suspected, the country from which the patient have traveled should be determined so that specific methods can be used. Management of ATBF is the same as that of other rickettsial infections. These bacteria are sensitive to tetracyclines, quinolones, and chloramphenicol. Short courses of a single 200-mg dose of doxycycline have been used with success, although most patients are given 200 mg/d doxycycline for 7 to 10 days.3-5 Systemic and skin symptoms respond dramatically to the medication in a few days. Because the number of the persons who travel to foreign countries is quite high, recognition of new entities such as ATBF is important. Dermatologists should be aware of this entity and of its differentiation from other forms of rickettsial dermatosis. In 3 years, 6 patients, including one 4-member family and this patient, registered in our region; they all were travelers. We thank Prof Didier Raoult, WHO Collaborative Center for Rickettsial Reference and Research, Marseille, France, for help in identification of the diagnosis. REFERENCES 1. Walker DH. Rickettsia. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, editors. Manual of clinical microbiology. 7th ed. Washington, DC: ACM Press; 1999. p. 807-14. 2. Kelly PJ, Beati L, Matthewman LA, Mason PR, Dasch GA, Raoult D. A new pathogenic spotted fever group rickettsia from Africa. Am J Trop Med Hyg 1994;97:129-37. 3. Brouqui P, Harle JR, Delmont J, Frances C, Weiller PJ, Raoult D. African tick bite fever, an imported spotless rickettsiosis. Arch Intern Med 1997;157:119-24. 4. Combemale P, Dupin M, Bernard P, Guennoc B, Saccharin C, Tissot-Dupont H. Rickettsiose a` tique africaine: premie`re contamination autochtone? Ann Dermatol Veneorol 1998;125:601-3. 5. Quiles N, Brouqui P, Harle JR, Delmont J, Chosidow O, Frances C, et al. Fie`vre africaine apre`s piqure de tique: une nouvelle rickettsiose au sein des fie`vres boutonneuses—7 observations. Ann Dermatol Venereol 1996;123(Suppl 1):S21. 6. 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. 7. Sebastian L. Rocky Mountain spotted fever. In: Elder D, Elenitsas R, Jaworsky C, Johnson B Jr, editors. Lever’s histopathology of the skin. 8th ed. Philadelphia, PA: Lippincott-Raven; 1997. p. 490.
S
everal rickettsial diseases have been described worldwide and are divided into 3 groups—spotted fever, typhus, and scrub typhus.1 One of the recently identified Rickettsia species is Rickettsia africae, which is transmitted by Amblyomma ticks from South Africa and Zimbabwe and causes spotted fever.2,3 African tick bite fever (ATBF) is the name given to R africae infection, which should be differentiated from Mediterranean spotted fever (MSF) caused by Rickettsia conorii infection transmitted by another tick, Rhipicephalus sanguineus. Both are endemic in the same regions of Africa. So far, few cases of ATBF have been reported in Europe, and most are imported cases. Because a rash is a hallmark of rickettsial infection, dermatologists sometimes are in the front line for diagnosis. Common clinical features exist for the different spotted fevers; however, distinctions can help the physician with diagnosis before laboratory confirmation. We report a case of ATBF in a traveler to South Africa.
CASE REPORT A 70-year-old man arrived in the emergency department with fever and asthenia. The fever had started 4 days after the patient returned from a 2-week trip to South Africa. He had been traveling in good conditions and taking antimalarial prophylaxis. He never felt or saw an insect such as a tick on his body. Two days after the beginning of fever, the patient noticed a few nonpruritic papules on both thighs. Clinical examination showed a high fever (40°C) and slight inguinal adenopathy. Neither splenomegaly nor hepatomegaly was found. Skin lesions were of 2 types. Each ankle bore a painless, large, hemorrhagic pustule with diameters of approximately 5 and 7 mm and with an inflammatory border, and approximately 10 purpuric papules were present on each leg (Fig 1). The rest of the skin and the mucous membranes were normal. Laboratory studies showed the following values: white blood cell count, 5.9 ⫻ 109/L (0.67 polymorphonuclear leukocytes and 0.17 lymphocytes); hemoglobin, 162 g/L; platelets, 184 ⫻ 109/L; erythrocyte sedimentation rate, 20 mm/h. Levels of alanine aminotransferThis supplement is made possible through an unrestricted educational grant from Stiefel Laboratories to the American Academy of Dermatology. From the Dermatology Department, Geneva University Hospital,a and the Infectious Diseases and Immunology Department, Central Institute of Valais Hospitalsb. Reprint requests: Dr Laurence Toutous-Trellu, Policlinique de dermatologic, Hoˆpital Universitaire de Gene`ve, rue Micheli-du-Crest, 24, 1211 Gene`ve-CH, Switzerland. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/mjd.2003.122
S18
ase, aspartate aminotransferase, and lactate dehydrogenase were normal. A blood sample was collected for specific serologic analysis, and a skin biopsy on a red papule was performed. The patient was immediately treated with doxycycline 200 mg/d for 2 weeks because rickettsial infection was clinically suspected. Follow-up evaluation showed apyrexia and flattening of the skin lesions after 48 hours. Healing of the eschars took longer (3 weeks), and there was no scar formation. Serial serologic tests for Rickettsia organisms by means of indirect immunofluorescence showed a significant 4-fold increase in IgM titer for R africae (from 32 to 256) in 2 weeks and an increase in IgG titer from 0 to 128. IgM and IgG titers for R conorii increased from 64 to 128 and 0 to 128, respectively. Histologic examination of a papule showed a perivascular lymphocytic infiltrate, necrotizing vasculitis, extravasation of erythrocytes, and eosinophiles in the dermis (Fig 2).
DISCUSSION ATBF develops several days after tick bite inoculation. In general, patients do not remember the bite. The incubation period varies between 1 and 2 weeks. The first clinical manifestations are high fever, arthralgia, myalgia, and fatigue. A rash appears after 2 to 3 days. Severe forms with the neurologic or visceral involvement of other rickettsial infections have not been described. The rash considered a distinct sign of spotted fever is not a major feature of ATBF.4-6 Careful skin examination is sometimes needed to find lesions and eschars. In MSF, only 1 black spot (tache noire), which appears as a crust with an inflammatory border and corresponds to the tick bite site, usually is present. In ATBF, however, several black spots, sometimes as many as 10,3 resemble those of MSF. This patient had 2 tick bite sites with 1 large hemorrhagic and necrotic pustule different from the usual crusty eschar. Among the few reported cases of ATBF, other cutaneous signs associated with the tick bite lesion have included limb lymphangitis on the draining area of the eschar, maculopapules, vesicles, and pustules. In comparison with the multiplicity of local signs, the systemic rash has been reported to be absent in ATBF. Because the course is more benign, discrete pinkish and transient macules can be underestimated. Buccal aphthoid lesions also have been found. The differential diagnosis of this disease is other rickettsial infections, such as MSF, Rocky Mountain spotted fever, and exanthematic typhus. For this reason, it is important to know the country from which the patient has traveled. Sepsis with gram-positive or gram-negative cocci also can be discussed. Cutaneous signs can resemble those of noninfectious vasculitis or insect bite reactions. Histopathologic analysis of rickettsial infection shows invasion of endothelial cells by microorganisms that cause vascular damage. In MSF, Rocky Mountain spotted fever, and typhus,
Toutous-Trellu et al S19
J AM ACAD DERMATOL VOLUME 48, NUMBER 2
Fig 1. Hemorrhagic pustule on ankle and few papules on thigh.
Fig 2. Lymphocytic vasculitis in dermis (papule). (Hematoxylin-eosin stain; original magnification ⫻40.)
rickettsial invasion and toxin delivery by the microorganism cause vasculitis in the central nervous system, heart, lung, spleen, or liver. Histopathologic examination of skin from the eschar, the tick bite site, shows necrotizing vasculitis in blood vessels of the dermis and subcutaneous fat with a perivascular inflammatory cell infiltrate composed mostly of lymphocytes and macrophages. Luminal thrombosis and microinfarcts also occur. The causative organism has a size of 0.3 to 1 mm, which is too small for light microscopic examination. Only blue coccoid intracellular forms can be seen with Giemsa stain.4,7 In this case, we analyzed a papular lesion far from a tick bite site that also showed necrotizing vasculitis. Standard histologic staining did not show microorganisms on the section. Direct immunohistochemical analysis by means of immunofluorescence was not performed on this sample. The diagnosis is confirmed with different laboratory methods. Culture of blood and tissue sampling are recommended for routine diagnosis. Direct immunofluorescence study of endothelial cells and tissue biopsy may be useful. Polymerase chain reaction analysis of endothelial cell, serum, and skin samples is highly specific. In serologic analysis, a microimmunofluorescence test with human isolates of concerned species, electrophoresis, and Western blotting are performed. Antibody crossreaction is usual among the same biogroup, as in our case.
Specific serum absorption for R africae confirms the diagnosis.1,4,6 When rickettsial infection is suspected, the country from which the patient have traveled should be determined so that specific methods can be used. Management of ATBF is the same as that of other rickettsial infections. These bacteria are sensitive to tetracyclines, quinolones, and chloramphenicol. Short courses of a single 200-mg dose of doxycycline have been used with success, although most patients are given 200 mg/d doxycycline for 7 to 10 days.3-5 Systemic and skin symptoms respond dramatically to the medication in a few days. Because the number of the persons who travel to foreign countries is quite high, recognition of new entities such as ATBF is important. Dermatologists should be aware of this entity and of its differentiation from other forms of rickettsial dermatosis. In 3 years, 6 patients, including one 4-member family and this patient, registered in our region; they all were travelers. We thank Prof Didier Raoult, WHO Collaborative Center for Rickettsial Reference and Research, Marseille, France, for help in identification of the diagnosis. REFERENCES 1. Walker DH. Rickettsia. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, editors. Manual of clinical microbiology. 7th ed. Washington, DC: ACM Press; 1999. p. 807-14. 2. Kelly PJ, Beati L, Matthewman LA, Mason PR, Dasch GA, Raoult D. A new pathogenic spotted fever group rickettsia from Africa. Am J Trop Med Hyg 1994;97:129-37. 3. Brouqui P, Harle JR, Delmont J, Frances C, Weiller PJ, Raoult D. African tick bite fever, an imported spotless rickettsiosis. Arch Intern Med 1997;157:119-24. 4. Combemale P, Dupin M, Bernard P, Guennoc B, Saccharin C, Tissot-Dupont H. Rickettsiose a` tique africaine: premie`re contamination autochtone? Ann Dermatol Veneorol 1998;125:601-3. 5. Quiles N, Brouqui P, Harle JR, Delmont J, Chosidow O, Frances C, et al. Fie`vre africaine apre`s piqure de tique: une nouvelle rickettsiose au sein des fie`vres boutonneuses—7 observations. Ann Dermatol Venereol 1996;123(Suppl 1):S21. 6. 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. 7. Sebastian L. Rocky Mountain spotted fever. In: Elder D, Elenitsas R, Jaworsky C, Johnson B Jr, editors. Lever’s histopathology of the skin. 8th ed. Philadelphia, PA: Lippincott-Raven; 1997. p. 490.