Box 4. Mediterranean Spotted Fever (* controversial result due to the possibility of cross-reaction with other Rickettsia species).

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Sheryl Bell
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1 Mediterranean spotted fever Mediterranean spotted fever (MSF) (or Boutonneuse fever, or Marseilles fever) is a Mediterranean endemic tick-borne disease belonging to the rickettsiosis group (Box 4), the agents of various spotted fever diseases. MSF is the second (to malaria) most frequently identified febrile illness among travellers (2%) from Africa (Jensenius, Davis et al. 2009; Demeester, Claus et al. 2010; Beltrame, Angheben et al. 2012). MSF shares some of its tick vector species with CCHF but not all the CCHF vectors are MSF vectors (as wrongly assumed by (Arcos González and Escolano Escobar 2011)). Rhipicephalus sanguineus is the primary tick species involved in MSF transmission and hence is well studied with respect to its host preferences, pathogen transmission from host, and ecological habitats. Dogs are the preferred blood source of Rh. sanguineus and humans are rarely attacked (Parola, Socolovschi et al. 2008; Renvoise, Delaunay et al. 2012), although this preference changes with temperature; humans seem to be preferred in warmer climates. Recent studies confirmed that Rh. sanguineus can play the dual role of vector and reservoir because of its trans-stadial and trans-ovarial transmission of R. conorii conorii (the principal pathogen of MSF) (Parola, Socolovschi et al. 2009; Socolovschi, Gaudart et al. 2012). Laboratory temperatures lower than 4 C or higher than 37 C also have a negative effect on the viability of Rh. sanguineus infected with R. conorii conorii (Socolovschi, Gaudart et al. 2012) suggesting that infected ticks may not survive during winter (host ticks usually overwinter as engorged nymphs or unfed adults but not as eggs (Dantas-Torres, Giannelli et al. 2010)). Finally, (Socolovschi, Gaudart et al. 2012) reviewed the negative effect of the bacteria on the survival of the tick and found a decrease in fecundity in infected female ticks versus non-infected female ticks. A comprehensive review on the biology, epidemiology, distribution and control of Rh. sanguineus is given by (Dantas-Torres 2008). Apart from these, and a few other studies, the relationships between Rh. sanguineus and R. conorii conorii are still poorly understood (Socolovschi, Gaudart et al. 2012; Uchiyama 2012). This lack of information is probably due to the relative novelty of the disease and its low incidence. At present, the information is not enough for a full descriptive model because the ecological component of the disease transmission, the hosts contributing to the maintenance of the disease and the human population response (with a large asymptomatic incidence) are all unknown. In other words, this disease offers an exciting opportunity for epidemiologists, veterinarians, clinicians and modellers to work together to create a unique framework to understand Mediterranean Spotted Fever. Box 4. Mediterranean Spotted Fever (* controversial result due to the possibility of cross-reaction with other Rickettsia species). Topic Findings References Parasite Family Rickettsiaceae, genus Rickettsia systematic Parasite species Rickettsia conorii (and its subspecies: R conorii conorii and R. conorii Israeli), R. sibirica (Merhej and Raoult 2011; Uchiyama 2012)

2 mongolotimonae, R. slovaca, R. massiliae, R. africae and R. monacensis. Host species Transmission pathway Vector species R. sibirica mongolotimonae has been identified in Spain and in travellers from Egypt. R. slovaca and R. massiliae. In Sardinia and Spain MSF-like disease has been attributed to R. monacensis. R. conorii israeliensis has been detected in dogs in Portugal. Rickettsia conorii has been identified in Rhipicephalus evertsi evertsi for the first time in Senegal. R. monacensis in I. ricinus on migratory passerine birds captured in southern Sweden. Dogs, rodents and the tick Rhipicephalus sanguineus Tick bite Rhipicephalus sanguineus (brown dog tick), Rh. turanicus and Rh. evertsi evertsi. (Socolovschi, Barbarot et al. 2010; Ibarra, Portillo et al. 2012)) (Jado, Oteo et al. 2007; Madeddu, Mancini et al. 2012) (Alexandre, Santos et al. 2011) (Mediannikov, Diatta et al. 2010) (Elfving, Olsen et al. 2010) (Rovery, Brouqui et al. 2008) Parasite transmission parameters distribution Dogs naturally infected with R. conorii conorii and R. conorii israeli are infectious to Rh. sanguineus. Natural transmission of R. conorii conorii between Rh. sanguineus during co-feeding of uninfected nymphs and infected tick adults. In 2008 in Greece, Rh. sanguineus was the most abundant species (80%) collected from patients hospitalised for tick bite. Short life of antibodies in dogs and long in humans (antibodies are detectable for years). Incubation period of 6 days. Distributed in Africa, Asia and Europe. Endemic in the Mediterranean basin. (Levin, Killmaster et al. 2012) (Zemtsova, Killmaster et al. 2010) (Papa, Chaligiannis et al. 2011) (Levin, Killmaster et al. 2012) (Mediannikov, Diatta et al. 2010) for Africa. seasonality In Sicily 500 cases are reported yearly. In Canary Islands, where MSF has never been reported, R. conorii sero-prevalence was 4.4% in samples collected in 1998*. In Senegal R. conorii was found at very low prevalence in ticks, but still able to infect humans. The MSF-like disease, Israeli spotted fever, has recently been reported in Tunisia. In the Mediterranean basin, MSF is transmitted by ticks in spring and summer. (Colomba, Saporito et al. 2011) (Bolanos-Rivero, Santana-Rodriguez et al. 2011) (Mediannikov, Diatta et al. 2010) (Znazen, Hammami et al. 2011)

3 clinical features Fever and flu-like symptoms appear and within 3-5 days a general maculopapular rash is evident, especially on palms and soles. The black eschar at the inoculation site is the sign of this disease (but is not always present). Neurological complications (MSF encephalitis) may occur in up to 10% of cases. The disease can eventually lead to multi-organ failure. The mortality rate is generally between 1-7% and rarely higher (32% in one Portuguese village in 1997). Asymptomatic cases are quite common. (de Sousa, Nobrega et al. 2003; Rovery and Raoult 2008; Botelho-Nevers, Rovery et al. 2011) diagnosis Permanent brain lesions are described in different cases in Portugal and Morocco. In Italy MSF was complicated by acute renal failure associated with herpetic oesophagitis. MSF clinical differences were found between adults and young children, with the latter presenting less severe symptoms. A fatal case has been reported from Greece. MSF due to R. conorii conorii is less severe than that caused by R. conorii israelensis which has an almost three-fold higher mortality Clinical features, PCR. IgM and IgG can be detected 7-15 days after the onset of the disease. (Bougteba, Basir et al. 2011; Rafik, Hachimi et al. 2011; Duque, Ventura et al. 2012) (Saporito, Giammanco et al. 2010) (Colomba, Saporito et al. 2011) (Papa, Dalla et al. 2010) reviewed by (Figueira-Coelho, Martins et al. 2010) (Brouqui, Bacellar et al. 2004; Beltrame, Angheben et al. 2012) treatment prophylaxis prevention Coinfection Screening by Raoult Diagnostic Criteria and IFA tests are advised. Use of doxycycline, although how this works against MSF has been only poorly studied. The use of fluoroquinolone is not recommended. NA (Yilmaz, Akalin et al. 2009) (Botelho-Nevers and Raoult 2011; Botelho-Nevers, Rovery et al. 2011) Measures against tick bite. Pet Travel scheme in Europe. (Gover, Kirkbride et al. 2011) NA References Alexandre, N., A. S. Santos, et al. (2011). "Detection of Rickettsia conorii strains in Portuguese dogs (Canis familiaris)." Ticks Tick Borne Dis 2(2):

4 Arcos González, P. and C. Escolano Escobar (2011). "Potentially emergent vector-borne diseases in the Mediterranean and their possible relationship with climate change." Enfermedades de transmisión vectorial potencialmente emergentes en la cuenca mediterránea y su posible relación con el cambio climático 23(5): Beltrame, A., A. Angheben, et al. (2012). "Imported rickettsioses in Italy." Travel Med Infect Dis 10(4): Bolanos-Rivero, M., E. Santana-Rodriguez, et al. (2011). "Seroprevalence of Rickettsia typhi and Rickettsia conorii infections in the Canary Islands (Spain)." Int J Infect Dis 15(7): e Botelho-Nevers, E. and D. Raoult (2011). "Host, pathogen and treatment-related prognostic factors in rickettsioses." Eur J Clin Microbiol Infect Dis 30(10): Botelho-Nevers, E., C. Rovery, et al. (2011). "Analysis of risk factors for malignant Mediterranean spotted fever indicates that fluoroquinolone treatment has a deleterious effect." J Antimicrob Chemother 66(8): Bougteba, A., A. Basir, et al. (2011). "[Meningoencephalitis caused by Rickettsia conorii in a young infant]." Rev Neurol (Paris) 167(2): Brouqui, P., F. Bacellar, et al. (2004). "Guidelines for the diagnosis of tick-borne bacterial diseases in Europe." Clin Microbiol Infect 10(12): Colomba, C., L. Saporito, et al. (2011). "[Mediterranean spotted fever in paediatric and adult patients: two clinical aspects of the same disease]." Infez Med 19(4): Dantas-Torres, F. (2008). "The brown dog tick, Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae): from taxonomy to control." Vet Parasitol 152(3-4): Dantas-Torres, F., A. Giannelli, et al. (2010). "Effects of prolonged exposure to low temperature on eggs of the brown dog tick, Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae)." Vet Parasitol 171(3-4): de Sousa, R., S. D. Nobrega, et al. (2003). "Mediterranean spotted fever in Portugal: risk factors for fatal outcome in 105 hospitalized patients." Ann N Y Acad Sci 990: Demeester, R., M. Claus, et al. (2010). "Diversity of life-threatening complications due to Mediterranean spotted fever in returning travelers." J Travel Med 17(2): Duque, V., C. Ventura, et al. (2012). "Mediterranean spotted fever and encephalitis: a case report and review of the literature." J Infect Chemother 18(1): Elfving, K., B. Olsen, et al. (2010). "Dissemination of spotted fever rickettsia agents in Europe by migrating birds." PLoS One 5(1): e8572. Figueira-Coelho, J., T. Martins, et al. (2010). "Atypical case of Mediterranean spotted fever." Braz J Infect Dis 14(3): Gover, L., H. Kirkbride, et al. (2011). "Public health argument to retain current UK national controls for tick and tapeworms under the Pet Travel Scheme." Zoonoses Public Health 58(1): Ibarra, V., A. Portillo, et al. (2012). "Septic shock in a patient infected with Rickettsia sibirica mongolitimonae, Spain." Clin Microbiol Infect 18(8): E Jado, I., J. A. Oteo, et al. (2007). "Rickettsia monacensis and human disease, Spain." Emerg Infect Dis 13(9): Jensenius, M., X. Davis, et al. (2009). "Multicenter GeoSentinel analysis of rickettsial diseases in international travelers, " Emerg Infect Dis 15(11): Levin, M. L., L. F. Killmaster, et al. (2012). "Domestic dogs (Canis familiaris) as reservoir hosts for Rickettsia conorii." Vector Borne Zoonotic Dis 12(1): Madeddu, G., F. Mancini, et al. (2012). "Rickettsia monacensis as cause of Mediterranean spotted fever-like illness, Italy." Emerg Infect Dis 18(4): Mediannikov, O., G. Diatta, et al. (2010). "Tick-borne rickettsioses, neglected emerging diseases in rural Senegal." PLoS Negl Trop Dis 4(9). Merhej, V. and D. Raoult (2011). "Rickettsial evolution in the light of comparative genomics." Biol Rev Camb Philos Soc 86(2):

5 Papa, A., I. Chaligiannis, et al. (2011). "Ticks parasitizing humans in Greece." Vector Borne Zoonotic Dis 11(5): Papa, A., V. Dalla, et al. (2010). "Fatal Mediterranean spotted fever in Greece." Clin Microbiol Infect 16(6): Parola, P., C. Socolovschi, et al. (2008). "Warmer weather linked to tick attack and emergence of severe rickettsioses." PLoS Negl Trop Dis 2(11): e338. Parola, P., C. Socolovschi, et al. (2009). "Deciphering the relationships between Rickettsia conorii conorii and Rhipicephalus sanguineus in the ecology and epidemiology of Mediterranean spotted fever." Ann N Y Acad Sci 1166: Rafik, R., M. Hachimi, et al. (2011). "[Acute polyradiculoneuropathy and Rickettsia conorii infection]." Med Mal Infect 41(10): Renvoise, A., P. Delaunay, et al. (2012). "Urban family cluster of spotted fever rickettsiosis linked to Rhipicephalus sanguineus infected with Rickettsia conorii subsp. caspia and Rickettsia massiliae." Ticks Tick Borne Dis 3(5-6): Rovery, C., P. Brouqui, et al. (2008). "Questions on Mediterranean spotted fever a century after its discovery." Emerg Infect Dis 14(9): Rovery, C. and D. Raoult (2008). "Mediterranean spotted fever." Infect Dis Clin North Am 22(3): , ix. Saporito, L., G. M. Giammanco, et al. (2010). "Severe Mediterranean spotted fever complicated by acute renal failure and herpetic oesophagitis." J Med Microbiol 59(Pt 8): Socolovschi, C., S. Barbarot, et al. (2010). "Rickettsia sibirica mongolitimonae in traveler from Egypt." Emerg Infect Dis 16(9): Socolovschi, C., J. Gaudart, et al. (2012). "Why are there so few Rickettsia conorii conorii-infected Rhipicephalus sanguineus ticks in the wild?" PLoS Negl Trop Dis 6(6): e1697. Uchiyama, T. (2012). "Tropism and pathogenicity of rickettsiae." Front Microbiol 3: 230. Yilmaz, E., H. Akalin, et al. (2009). "Mediterranean Spotted Fever: Retrospective Evaluation Of 16 Cases." Medical Journal of Trakya University. Zemtsova, G., L. F. Killmaster, et al. (2010). "Co-feeding as a route for transmission of Rickettsia conorii israelensis between Rhipicephalus sanguineus ticks." Exp Appl Acarol 52(4): Znazen, A., B. Hammami, et al. (2011). "Israeli spotted fever, Tunisia." Emerg Infect Dis 17(7):

Three patients with fever and rash after a stay in Morocco: infection with Rickettsia conorii

Three patients with fever and rash after a stay in Morocco: infection with Rickettsia conorii Stylemans D 1, Mertens R 1, Seyler L 1, Piérard D 2, Lacor P 1 1. Department of Internal Medicine, UZ Brussel