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Mediterranean Spotted Fever in Travelers from the United States Leonavdo A. Palau and George A.Pankey Background: We wish to increase awareness by US. physicians of the clinical manifestations and diagnosis of Mediterranean spotted fever (MSF), and to determine the incidence of MSF among travelers returning to the United States from endemic areas. Methods: We report a case of a 56-year-old female physician from New Orleans who returned from a 3-week safari trip t o Zimbabwe and Zambia with clinical findings of MSFThe diagnosis was confirmed with a greater than fourfold rise i n titer of IgM and IgG antibody t o Rickettsia conoriion acute and convalescent sera (16 days apart) using indirect immunofluorescence technique. In addition, w e conducted a MEDLINE computer search of published MSF cases in U.S. travelers returning t o the United States and obtained the United States data over the past 20 years from the Centers for Disease Control and Prevention (CDC). Results: Less than 50 imported cases of MSF have been reported and confirmed by the CDC. Only seven cases have been published in the literature and none in the last 7 years. Conclusions: Despite the increasing incidence of MSF i n Europe, Asia and Africa, and the high number of U S . citizens traveling to these endemic areas, only a few imported cases of MSF i n travelers have been reported in the United States. Physicians in the United States are not familiar with the clinical findings and diagnosis of MSF; therefore this disease is underrecognized in the majority of cases. disease.The most common rickettsial disease in returning U.S. travelers is Mediterranean spotted fever. Mediterranean spotted fever (MSF) o r Boutonneuse fever is an acute infectious disease caused by Rickettsia conorii.This disease was first described by Conor and Bruch in Tunisia in 1910’ and the name MSF was adopted in 1932 at the First International Congress of Mediterranean Hygiene. It is transmitted to man by the bite of various European,AErican and Asian species of ixodid ticks, primarily the dog tick Rkipicepkalus sanguineu.q. Neither the Rickettsia conorii organism nor the ticks inhabit the North American continent. This disease is endemic to southern Europe (Italy, France, Spain, Portugal);subSaharan Africa; Middle Eastern areas adjacent to the Mediterranean, Black and Caspian Seas; and India. It occurs in urban areas as well as in the bush. In recent years a dramatically increased incidence of this disease in endemic areas has been noted.* Therefore, travelers visiting these countries are at risk for infection. Rickettsia1 infection is now the third most frequent cause of fever in travelers returning to Switzerland’; however, despite the increasing number of U.S. residents traveling to these endemic areas, only seven cases in travelers returning to the United States have been published,and none since 1990.&’This striking finding may be due to the lack of awareness by physicians in the United States of the clinical characteristics and epidemiology of this disease.The Centers for Disease Control and Prevention (CDC) Atlanta,Georgia, has clinically and serologically identified less than 50 cases of MSE The rickettsiae are obligate intracellular bacterial organisms. They are maintained in nature through a cycle involving vertebrate hosts (reservoir) and arthropod vectors. Humans become infected when they are incidentally bitten by an infected vector (tick, lice, etc.) and are not involved in maintaining or propagating the disease; with the exception of epidemic typhus, no transmission occurs from person to person. The rickettsiae are divided into spotted fever and typhus groups based on antigenic differences and intracellular growth. The spotted fevers have restrictive geographic distribution and affect different populations in different parts of the world, reflecting the existence of a particular reservoir and tick vector. Among the spotted fever group, only Rocky Mountain spotted fever and rickettsialpox are native to the United States. However, modern air travel has made it possible for a U.S. resident to return from any part of the world within the incubation period or with symptoms ofa spotted fever rickettsial Leonard0 A. Patau, MD, and George A. Pankey, MD: Department of Infectious Diseases, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana. This paper was presented at the 5th International Conference ofTrave1 Medicine in Geneva, Switzerland, 25 March 1997. Reprint requests: Dr. Pankey, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, LA 70121, USA. JTravel Med 1997; 4:179-182. 179 180 However, this disease is not reportable in the United States, and the CDC,Atlanta, Georgia, does not keep track of the number of new cases ( K u s d l Regnery, PhD, CDC,personal coniniunication, November 1996),making it difficult to establish its incidence in travelers returning froni endemic areas. We report a case of MSF in a New Orleans resident who contracted this disease during a safari trip to Africa. Case Report A 56-year-old, previously healthy female physician presented to the Ochsner Travel Clinic on 24 June 1996, 2 days after returning from a 3-week safari trip to Africa. She complained of fever, chills, malaise, a maculopapular rash, and a necrotic skin lesion on the right side of the abdomen. She had arrived in the city of Harare in Zimbabwe on 4 June 1996 and immediately started taking doxycycline 100 mg daily for malaria prophylaxis, but discontinued 3 days later due to a vaginal yeast infection. Much of the time in Africa was spent in the bush, including canoeing in the Zambesi River (between Zimbabwe and Zambia) and camping in sandy and grassy areas along the shore of the river. O n 15June, she noticed an erythematous lesion in the right lower abdomen consistent with a tick bite,although she did not recall renioving any ticks from her skin. O n 16June, she noticed the onset of high fever (38.2 to 39.4”C),chills, and malaise. She did not have diaphoresis,headache, myalgia or tachycardia.A maculopapular rash was observed on the left arm and both thighs.These symptoms persisted and on 19 June, she flew to Capetown, South Africa, seeking medical attenti0n.A clinical diagnosis of malaria was excluded, and empiric treatment with doxycycline 100 nig twice daily was begun o n 20 June. She returned to the United States o n 22 June. At the time of presentation, she was symptoniatically much improved, though the skin lesion and the rash persisted. She was alert and in no distress. Her temperature was 37OC, heart rate 62 beats per minute and regular, and blood pressure 138/76 niinHg. There was no lymphadenopathy, and cardiac, pulmonary, and abdominal examinations were normal. There was a nontender 3x3 cm erythematous skin lesion with a dark center over the right lower abdomen and a maculopapular nonpruritic rash over both thighs and left arm.The rash did not involve the palms and soles. Laboratory studies revealed the following values; white cell count, 3.3X10’/nim3, with 64% segmented neutrophils, 28%)lymphocytes and 8% monocytes; hemoglobin, 12.6 g/dL; hernatocrit, 36%; platelet count, 235 X I 0‘/uim3;and erythrocyte sedimentation, 5 mni/h. Blood chemistry profile was normal. Liver function tests Journal o f Travel Medicine, Volume 4, N u m b e r 4 were mildly elevated:aspartate aminotransferase,53 U/L; alanine aminotransferase 47 U/L; and lactate dehydrogenase (LDH), 281 U/L. Serologic tests performed at Specialty Laboratories, Los Angeles, showed a rise in indirect fluorescent IgM antibody titers to Rickettsia ronorii from less than I :20 o n 26 June to greater than 1:320 on I2 July (normal range less than 1:20). IgG antibody rose from 1 5 4 to greater than 1:1024 (normal range less than 1:16) in the same period of time. The patient received a total of 10 days ofdoxycycline and fully recovered. Discussion The incubation period of MSF is about 6-1 0 days, and the natural duration of illness is froni 12-21) days. The disease begins with fever, malaise, headache, niyalgia and conjunctival injection.’The niajority of patients (80%) have a primary lesion at the site of the tick bite (“tache noire”).This lesion is usually present at the onset of fever and consists of a small ulcer with a black center and a red areola (Fig. l ) . A maculopapular rash appears around the fourth day and involves most of the body including palms and soles (Fig. 2).This rash is hndamental for the diagnosis. Five percent of the patients develop a severe form of the disease, and 2.7%)die. The laboratory findings are nonspecific. The total leukocyte count may be low. Elevation of liver function tests and LDH levels occur in more than 75% of cases. Hyponatremia and thrombocytopenia are common. MSF must be differentiated from African tick-bite fever (ATBF) (Table I ) , a recently described disease caused by Rickettsia nfYicae and transmitted by Amblyomma ticks (buffalo ticks).”’” Unlike MSF, this disease is characterized by multiple “taches noire,” lymphadenopathy, lymphangitis, eschar edema, the absence of rash, and the production of increased IgA serum levels.‘(I MSF should be suspected in any traveler returning tiom an endemic area with fever, maculopapular rash, and the distinctive “tache noire.”Traditionally the causative organism has been identified from epideniiologic, clinical, and serologic data. Indirect inimunofluorescence antibody assay of acute and convalescent sera is the most widely used diagnostic test.This serologic test can be nude species-specific. However, these antibodies may cross-react with the antigens of the other members of the spotted group, especially R. rirkettsii and R. akari, making this test unreliable to identify the causative agent with certainty. Other tests can be performed to confirm the diagnosis, such as isolation of R. cunorii from blood culture with the use of the shell vial culture technique’ and demonstration of R. ctinorii in cutaneous lesions by immunofluorescence staining” or polynierase chain reaction amplification.’3 ’ Palau and Pankey, Mediterranean Spotted Fever 181 Figure 1 Typical "tache noire" skin lesion on the abdomen of a patient with Mediterranean spotted fever. Figure2 Maculopapular rash overthe legs of a patientwith Mediterranean spotted fever. When travelers return with equivocal clinical manifestations from areas where rickettsia species overlap (MSF and ATBF in Africa),specificWestern ininiunoblot analysis against a specific protein antigen can identify the species.l o infection; therefore, it is contraindicated for therapy of MSF."' Treatment Therapy with doxycycline, ciprofloxacin, or chloraniphenicol is effective.Antibiotics shorten the duration of symptoms and prevent possible coinplications and recurrences. T h e optimal duration of treatment is unknown.Although most authorities recommend I- or 2-week courses of antibiotics, a single dose of 200 nig of doxycycline or two single doses over a 24-hour period have been shown to be effective as well.14 Ciprofloxacin (750 mg q32h PO for 1 week) may be more effective than doxycycline, since it is bactericidal, has fewer side effects, and is at lower risk than doxycycline for development of resistance." Trimethoprim-sulfamethoxazole increases the pathogenic potential of R. ronovii and the severity of the Prevention U.S. travelers to endemic areas should avoid contact with ticks by the use of repellents and protective clothing.The body should be searched regularly for ticks, and the ticks should be promptly removed. Malaria prophylaxis with doxycycline may abort or prevent this disease. Summary Modern transportation enables U.S. residents to travel to regions where R. conorii is common and to return harboring Mediterranean spotted fever.This is particularly true for tourists visiting subSaharan Africa countries and southern Europe where the incidence of MSF is increasing. Our case illustrates the need for physicians in the United States to be familiar with the epideiniology and clinical characteristics of MSF and to advise travelers of the risk of acquiring this disease. Table 1 Clinical Differences between Mediterranean Spotted Fever and African 5ck-Bite Fever Characteristic Agent Tick vector Skin rash Tache noire Lymphadenopathy Lymphangitis Eschar rdenia Serum IgA fljican Tick- Bite Fever Rickettsia conorii Rliipicephalus sanguineus present usually one unconiiiion absent uncommon normal Rickettsia afrirae Amhlyonirnn Iiebrawrr absent nlultlple coninion common common sometinier elevated J o u r n a l o f T r a v e l M e d i c i n e , V o l u m e 4, Number 4 182 References 1. ConorJD, Uruch M. Une fievre Pruptive observke enTunisie. Bull Soc Pathol Exo Filiales 1910;8:139-142. 2. Segura F, Font B. Resurgence of Mediterranean spotted fever in Spain [Letter]. Lancet 1982;2:280. 3. Raeber PA, Winteler S,Paget J. Fever in the returned traveller: rrmmibrr rickettsia1 diseases (Letter]. Lancet 1994;344: 331. 4. TreadwellTL, Phillips SD,Jablonski WJ. Mediterranean spotted fever in children returning from France.Arn J IXs Child 1990;144:1037-1038. 5. Harris ILL, Kaplari SL, Bradshaw MW,WillianisTW Jr. Boutonneuse fever in American travelers. J Infect Dis l986;153: 126-128. 6. Barrett-Connor E, Ginsberg M M . Imported South African tick typhus.West J Med 1983;138:264-266. 7 . Anderson JF, Magnarelli LA, Burgdorier W, et a]. Importation into the United States from Africa of Rhipiqphalus sirnus on a Boutonneuse fever patient.Ani JTrop Med Hyg 1981;30: 897-899. 8. Font-Creus B, BeUa-Cueto F, Espejo-Arenas E, et al. Mediterranean spotted fever:a cooperative study of 227 cases. Rev Infect I>is 1985;7:635-642. 9. Kelly PJ, Beati L, Matthewman LA, et al. A new pathogenic spotted fever group rickettsia froni Africa. J Trop Med Hyg 1994;97:129-137. 10. Urouqui P, Hark JR,Ilelniont J,et al.African tick-bite fever. An imported spotless rickettsiosis.Arch Intern Med 1997;157: 119-1 24. 1 1. Marrero M , Raoult D. Centrifugation-shell vial technique for rapid detection of Mediterranean spotted fever rickettsia in blood culture. Am J Trop Med Hyg 1989;40:197-199. 12. Raoult D, de Micco C, Gallais H,Toga M. Laboratory diagnosis of Mediterranean spotted fever by inimunofluorescent demonstration of Rickettsia cunorii in cutaneous lesions. J Infect Dis 1984;150:145-148. 13. RouxV, Fournier PE, Raoult D. Differentiation of spotted fever group rickettsiae by sequencing and analysis of restriction fiagnient length polymorphism of PCK-amplified DNA of the gene encoding the protein rOmpA. J Clin Microbiol 1996;34:2058-2065. 14. Bella-Cueto F, Font-Creus 8, Segura-Porta F, et al. Coniparative, randomized trial of one-day doxycycline versus 1 0-day tetracycline therapy for Mediterranean spotted fever. J Infect Dis 1987;155:1056-1058. 15. Ruiz Beltran K, Herrero Herrero JI. Evaluation of ciprofloxacin and doxycycline in the treatment of Mediterranean spotted fever. Eur J Clin Microbiol Infect IXs 1 9 9 2 ; l l : 427-431. 16. Ruiz Beltran I<, Herrero Herrero JI. Deleterious effect of triniethopritii/sulfatiiethoxazole in Mediterranean spotted fever [Letter, Comment]. Antiniicrob Agents Chemother 1992;36:1342-1343. Tourists canoeing on the Zambesi river. Submitted by the authors.