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Murine typhus in Tunisia: A neglected cause of fever as a single symptom
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www.sciencedirect.com Médecine et maladies infectieuses 43 (2013) 226–229
Original article
Murine typhus in Tunisia: A neglected cause of fever as a single symptom夽 Le typhus murin en Tunisie : cause négligée de fièvre isolée A. Znazen a,∗ , B. Hammami b , A. Ben Mustapha c , S. Chaari a , D. Lahiani b , I. Maaloul b , M. Ben Jemaa b , A. Hammami a a b
Laboratory of Microbiology, Habib Bourguiba University Hospital, Sfax, Tunisia Infectious Diseases Department, Hedi Chaker University Hospital, Sfax, Tunisia c Infectious Diseases Department, Djebeniana Regional Hospital, Sfax, Tunisia
Received 24 October 2012; received in revised form 17 December 2012; accepted 15 February 2013 Available online 22 April 2013
Abstract Objectives. – We had for aim to describe the epidemiologic and clinic characteristics of murine typhus in a series of 43 serologically confirmed cases, in our region. Patients and methods. – Serologic screening for IgG and IgM against Rickettsia typhi was performed in 1024 patients during three years (2006–2008). The characteristics of patients with a positive serology were examined retrospectively. One hundred and seventy sera obtained from blood donors were tested to detect IgG against R. typhi to determine the seroprevalence of the infection. Results. – There was evidence of recent R. typhi infection in 43 patients (4.2%) during the study period, and 3.7% of blood donors had IgG against R. typhi. The mean age of patients was 43.1 years and the sex-ratio was 1.04. Among the patients, 58.1% were from rural areas. No patient reported any exposure to rats or rat-fleas. There were more cases during the summer and fall. The most frequent complaint was fever as a single symptom (67.5%). A cutaneous rash was reported in 44.1% and headache in 60.5% of patients. Among the patients, 44.1% presented with thrombopenia and 47.2% with elevated liver enzymes. Conclusion. – Murine typhus seems to be frequent in Tunisia. This infection could be a threat for travellers. Serology should be performed systematically in patients with fever as a single symptom since its clinical presentation is non-specific. © 2013 Elsevier Masson SAS. All rights reserved. Keywords: Fever; Murine typhus; Rickettsiosis
Résumé Objectif. – Notre objectif était de décrire les caractéristiques épidémiologiques et cliniques du typhus murin dans notre région à travers une série de 43 cas confirmés par la sérologie. Patients et méthodes. – Durant une période de trois ans (2006–2008), 1024 patients ont bénéficié de la sérologie des rickettsioses avec la détection des IgM et des IgG anti-Rickettsia typhi. Les caractéristiques des patients ayant une sérologie positive ont été examinées rétrospectivement. Parallèlement, la séroprévalence de R. typhi a été déterminée chez 170 donneurs de sang. Résultats. – La séroprévalence de l’infection était de 3,7 %. Quarante-trois patients (4,2 %) avaient des marqueurs sérologiques d’une infection récente à R. typhi. La moyenne d’âge des patients et le sex-ratio étaient de 43,1 ans et 1,04 respectivement. Parmi les patients, 58,1 % étaient d’origine rurale. Aucun patient n’a rapporté une exposition aux rats ni à leurs puces. La distribution selon les mois a montré une nette prévalence de la maladie durant l’été et l’automne. La présentation clinique la plus importante était une fièvre isolée dans 67,5 % des cas. Le rash cutané était observé dans 44,1 % des cas et les céphalées dans 60,5 % des cas. Une thrombopénie et une élévation des transaminases étaient observées dans 44,1 % et 47,2 % des cas respectivement.
夽 ∗
This study was presented at the “6th international meeting on Rickettsiae and rickettsial diseases” from June 5 to 7, 2011, in Crete, Greece. Corresponding author. E-mail address: [email protected] (A. Znazen).
0399-077X/$ – see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.medmal.2013.02.007
A. Znazen et al. / Médecine et maladies infectieuses 43 (2013) 226–229
227
Conclusion. – En Tunisie, le typhus murin parait une pathologie fréquente. Le risque de contracter l’infection peut se poser aussi pour les voyageurs. Vu la non-spécificité des signes cliniques, la sérologie devrait être indiquée systématiquement pour les patients se présentant avec une fièvre isolée. © 2013 Elsevier Masson SAS. Tous droits réservés. Mots clés : Fièvre ; Rickettsiose ; Typhus murin
1. Introduction Murine typhus is a flea born infection caused by Rickettsia typhi, a Gram-negative obligate intracellular bacterium. This common zoonotic disease has been reported in suburban settings where rats (Rattus sp.) and their fleas (Xenopsylla cheopis) coexist and it is maintained in a cycle involving these rodents as reservoir and the arthropod as vector. In fact, the rat-flea ingested blood from infected rat so that Rickettsiae multiply in the intestinal epithelial cells of the flea and are excreted in the feces. Humans are contaminated when the flea feces are inoculated at fleabite site or by skin abrasions [1]. This infection occurs in a variety of environments ranging from hot and humid to cold and mountains or semiarid [2]. In fact, murine typhus has been reported worldwide, in diverse geographic areas including the Mediterranean, Africa, South Asia and the USA [3]. In Tunisia, Letaief et al. reported seven cases from Sousse in 2005 showing that the infection still exists in Tunisia [4]. However, little is known about this infection and many clinicians do not suspect the diagnosis of murine typhus because of its nonspecific clinical presentations. In fact, patients do not present cutaneous rash in more than 50% of cases and they do not report a history of fleabite in general. In Sfax, the second town in Tunisia, we showed previously that the disease was diagnosed in our region [5]. But, no data regarding characteristics of the infection are available. In this paper, we reported the seroprevalence of R. typhi in our region among healthy people and we described clinical presentations and epidemiological characteristics of patients with murine typhus.
To assess the seroprevalence of R. typhi in healthy people, 170 blood donor sera were obtained from regional center of transfusion of Sfax collected during 2007. Sera were tested in the same manner for the presence of IgG against R. typhi. Sera with titers > 1:128 were considered as positive. Data were analyzed using SPSS 15.0 software. Student T-test was used to compare means and Chi2 test to compare proportions, P < 0.05 was considered as significant. 3. Results During a 3-year period, 1027 patients were tested by serology to Rickettsia infection. Forty-three patients (4.2%) were considered to have R. typhi infection. Among the patients, 7.5% with murine typhus presented with eruptive fever, and 13% with fever as a single symptom. Of blood donors, 3.7% were infected by R. typhi. R. typhi infection occurred in patients 8 to 83 years of age, with a median age of 41 years (IQ 27, 41, and 54) and a sexratio of 1.04. Patients came from rural areas in 25 cases (58.1%). No patient reported any exposure to rats. However, 27 patients (62.8%) reported contact with various animals: dogs (30.2%), cats (7%), sheep (27.9%), goats (18.6%), cows (4.7%), and birds (2.3%). Only one patient reported fleabites. The cases occurred mainly in the summer (37.3%) and fall (51.2%), between June and October (60.4%). We compared the occurrence of cases and temperature variations in our country; the cases occurred after the hottest period of the year and during period with high levels of humidity (Fig. 1). Patients had to be hospitalized in 36 cases (83.7%). The delay between initial symptoms and consultation ranged from 1 to 25 days with a median of 7 days (IQ 5, 7, and 9.75). The mean
2. Patients and methods Our study was retrospective and included all patients with positive R. typhi serology. Between 2006 and 2008, we received in our laboratory sera from 1027 patients to be tested for rickettsial serology. Serum samples were tested for the presence of antibodies against R. typhi, Rickettsia conorii and Rickettsia felis in a micro immunofluorescence assay as previously described using antigens provided by “Unité des Rickettsies Marseille France” [6]. In each series, sera tittered at the reference center, were included as controls. A recent R. typhi infection was considered if IgM titers to R. typhi were ≥ 1:32 or if a seroconversion on a convalescent serum was detected. Patients’ sera showing cross-reactions between R. typhi and R. conorii or R. felis were not included. A questionnaire form was created for all patients that fulfilled serologic criteria. We gathered demographic, epidemiologic, clinical, laboratory and treatment data.
Fig. 1. Monthly occurrence of murine typhus cases and monthly temperatures means during 2006 to 2008. Distribution mensuelle des cas de typhus murin avec les moyennes de température durant 2006 à 2008.
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Table 1 Clinical signs in cases with murine typhus. Les signes cliniques notés chez les patients ayant un typhus murin.
Fever Chills Asthenia Anorexia Arthralgia Myalgia Headache Confusion Dry cough Rash Lymphadenopathy Conjunctivitis Uveitis Nausea/vomiting Abdominal pain Diarrhea Splenomegaly Hepatomegaly
n = 43 (%)
Frequencies in literature (%) [13,23–27]
42 (97.7) 14 (32.6) 19 (44.2) 4 (9.3) 14 (32.6) 16 (37.2) 26 (60.5) 2 (2.3) 5 (11.6) 19 (44.1) 6 (14) 2 (4.6) 1 (2.3) 13 (30.2) 7 (16.3) 4 (9.3) 4 (9.3) 1 (2.3)
98–100 66–87 29–89 35–81 23–77 46–88 41–90 2–13 15–40 20–80 3.6–15 12–25 2 3–48 11–60 5–40 5–24 24–29
delay before consultation was significantly lower among hospitalized patients (2.3 days, SD 2.5) than among those treated in day care (5.8 days with standard deviation of 3.7, P = 0.006). Patients consulted for fever in 29 cases (67.5%), fever associated to a cutaneous rash in five cases (11.6%), fever associated to headache in five cases (11.6%), urinary symptoms in three cases (7%), and fever after a flea bite in only one case (2.3%). The incidence of reported clinical symptoms are listed in Table 1. The usual triad of fever, cutaneous rash and headache was noted in 11 cases (25.6%). Fever, noted in 42 cases (97.7%), was the most frequent symptoms. Headache was noted in 26 patients (60.5%). The cutaneous rash, observed in 19 patients (44.1%), was macular in 12 cases (63.1%), maculopapular in six cases (31.5%), and purpuric in one case (8.3%). Neurologic disorders were observed in five patients (11.6%), most often consciousness disorders. However, cerebrospinal fluid analysis was normal in every case. Chest radiography was performed in 39 cases. An alveolar syndrome was noted in two cases (4.6%), and an interstitial syndrome in ten cases (23.2%). Abdominal ultrasonography, was performed in only 13 cases; it revealed splenomegaly in four cases (9.3%). Biological abnormalities included an elevated sedimentation rate in 33 patients (58.1%) with a rate above 100 mm/h in only one case. None of our patients presented with renal failure. The serological diagnosis was based on IgM detection in 32 cases. IgG antibodies were reported among 16 patients in their first serum sample. Seroconversion or a significant elevation of antibody titers was observed in 11 cases. The first serological tests were performed after a mean infection duration of 10.4 days (SD 6.8) and the second serological tests were performed after a mean infection duration of 26.3 days (SD 15.2). Forty patients were treated with antibiotics. Three patients were not treated because fever resolved within the first 24 hours of hospitalization. These patients had received antibiotics before
being hospitalized. Antibiotics active on R. typhi, such as doxycycline and ciprofloxacin, were prescribed in 35 cases: in 28 cases at hospitalization and in seven cases after confirmation of diagnosis by serological tests. In the remaining five patients, the non-effective antibiotics prescribed initially were not modified, since confirmation by serological tests was given after a favorable outcome. Our patients were finally dived into two groups: • group 1 (n = 35) patients who received effective antibiotherapy; • group 2 (n = 8) patients who received non-effective antibiotherapy or no antibiotherapy. The two groups were compared; the mean delays before apyrexia were 2.5 days (SD 1.1) in group one and 8.3 days (with standard deviation of 3) in group 2 (P = 0.06); the mean delay before clinical sign resolution were 4 days (SD 1.9) and 9.8 days (SD 3.8) (P = 0.08) respectively. The outcome was favorable in every case. However, four patients in group 1 reported persistent asthenia, headaches, coughing, and arthralgia. 4. Discussion Murine typhus is a common zoonotic disease prevalent worldwide in various environments; but cases are concentrated in tropical, subtropical, and seaside regions [3,7,8]. The infection has been reported in Mediterranean countries, Asia, and in the USA [3,9–14]. Most cases diagnosed in European countries, were imported [15–17]. The real incidence has been never determined in Tunisia. Since Charles Nicolle studies on rickettsial diseases, the Pasteur institute has notified annually the incidence of positive Rickettsia serological tests, and reported a decreasing trend of positive R. typhi serological tests from 1966 to 1975 [18]. No case of murine typhus has been reported since then. This is probably due to inappropriate diagnostic methods. The high seroprevalence (3.7%) reported in our study among healthy blood donors suggests that the disease occurs frequently in our country. Similar or higher seroprevalence rates have been reported in other countries. Rates ranged from 1.1% in Brazil to 14% in Mexico [19]. The authors of a multicenter study made in China, reported a seroprevalence rate of 4.1%, with the highest rate (18.8%) reported in a coastal area at the lowest altitude, in a harbor [20]. The R. typhi cycle includes rats (Rattatus rattatus) and its flea (Xenopsylla cheopis). Climatic conditions are known to influence flea activity [3]. The seasonal distribution of cases revealed a higher number of cases just after the hottest period of the year and when the humidity was maximal. Fleas are more infected at 30 ◦ C [21]. The rat-flea-rat cycle could be maintained all year round and cases could occur in winter when temperatures range around 18 ◦ C; this accounts for cases diagnosed in December and January. This standard cycle, described mostly in urban regions, needs to be reevaluated. The disease is known to be frequent in urban regions, but many authors report an extension of the infection to foothills, suburban, and rural areas [3]. Our cases came from urban or rural regions. No patient reported any contact with
A. Znazen et al. / Médecine et maladies infectieuses 43 (2013) 226–229
rats. The role of other animals should be investigated. Indeed, the bacterium has been detected in the USA in cat and opossum fleas; cats and opossums have a higher seroprevalence rates than rats [22]. The clinical features of murine typhus were similar to published data in many other series (Table 1) [12,13,23–27]. However, the usual triad of fever, headache, and cutaneous rash [7,13,28], were noted in only 25% of our patients. Among the patients, 65.1% consulted for fever of unknown origin. Patients presented with various clinical signs and fleabite was reported in only one case. This stresses the heterogeneity of reported symptoms for this disease. Nevertheless, our study was retrospective and this could account for a lack of information. Our serological test data revealed a seroconversion or a significant elevation of antibody titers in only 11 cases. A low antibody kinetics was already reported in other rickettsial infections, such as for R. africae [29]. Serological tests were frequently negative during the first week, especially if patients had been previously treated [29]. A second serological test should be performed two and even 3 weeks after hospitalization to confirm or rule out the infection. In conclusion, murine typhus is a not a rare infectious disease in our country and its true frequency remains to be determined. Its epidemiology is directly related to its vector and reservoir. More environmental studies, investigating animals and arthropods, should be performed. These investigations should determine the bacterium’s cycle and its main reservoir in our region. This would allow developing preventive actions. Travelers should also be informed on the risk of infection. Clinicians should be warned of the polymorphic and non-specific characters of clinical signs, and specifically understand that that the disease often presents as fever only. Thus, serological tests for the diagnosis of rickettsiosis should be considered in the differential diagnosis of fever of unknown origin. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments We thank Pr. Didier Raoult (Unité des rickettsies, Marseille, France) for providing Rickettsia antigens. We thank Sajiaa Hachicha, Radhia Turiki and Dalenda Charfeddine for their technical assistance. References [1] Azad AF, Radulovic S, Higgins JA, Noden BH, Troyer JM. Flea-borne rickettsioses: ecologic considerations. Emerg Infect Dis 1997;3:319–27. [2] Azad AF. Epidemiology of murine typhus. Annu Rev Entomol 1990;35:553–69. [3] Civen R, Ngo V. Murine typhus: an unrecognized suburban vectorborne disease. Clin Infect Dis 2008;46:913–8. [4] Letaief AO, Kaabia N, Chakroun M, Khalifa M, Bouzouaia N, Jemni L. Clinical and laboratory features of murine typhus in central Tunisia: a report of seven cases. Int J Infect Dis 2005;9:331–4.
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[5] Znazen A, Rolain JM, Hammami N, Jemaa MB, Raoult D. Rickettsia felis infection. Tunisia Emerg Infect Dis 2006;12:138–40. [6] Rolain JM, Gouriet F, Brouqui P, Larrey D, Janbon F, Vene S, et al. Concomitant or consecutive infection with Coxiella burnetii and tickborne diseases. Clin Infect Dis 2005;40:82–8. [7] Raoult D, Roux V. Rickettsioses as paradigms of new or emerging infectious diseases. Clin Microbiol Rev 1997;10:694–719. [8] Tselentis Y, Gikas A. Murine Typhus. In: Raoult D, Parola P, editors. Rickettsial Diseases. New York: Informa Healthcare; 2007. p. 37–49. [9] Mouffok N, Parola P, Raoult D. Murine typhus, Algeria. Emerg Infect Dis 2008;14:676–8. [10] Parola P, Vogelaers D, Roure C, Janbon F, Raoult D. Murine typhus in travelers returning from Indonesia. Emerg Infect Dis 1998;4: 677–80. [11] Centers for Disease Control and, Prevention. Outbreak of Rickettsia typhi infection – Austin, Texas. MMWR Morb Mortal Wkly Rep 2009;58:1267–70. [12] Bernabeu-Wittel M, del Toro MD, Nogueras MM, Muniain MA, Carde˜nosa N, Márquez FJ, et al. Seroepidemiological study of Rickettsia felis, Rickettsia typhi, and Rickettsia conorii infection among the population of southern Spain. Eur J Clin Microbiol Infect Dis 2006;25:375–81. [13] Gikas A, Doukakis S, Pediaditis J, Kastanakis S, Psaroulaki A, Tselentis Y. Murine typhus in Greece: epidemiological, clinical, and therapeutic data from 83 cases. Trans R Soc Trop Med Hyg 2002;96:250–3. [14] Hidalgo M, Salguero E, de la Ossa A, Sánchez R, Vesga JF, Orejuela L, et al. Murine typhus in Caldas, Colombia. Am J Trop Med Hyg 2008;78: 321–2. [15] Wilson ME, Brush AD, Meany MC. Murine typhus acquired during shortterm urban travel. Am J Med 1989;87:233–4. [16] Estève V, Maisonneuve L, Porcheret H, Bellaiche G, Le Pennec MP. Fièvre éruptive au retour du Maroc: penser au typhus murin. Med Mal infect 2000;30:722–4. [17] Da Costa P, Brigatte ME, Greco DB. Antibodies to Rickettsia rickettsii, Rickettsia typhi, Coxiella burnetii, Bartonella henselae, Bartonella quintana, and Ehrlichia chaffeensis among healthy population in Minas Gerais, Brazil. Mem Inst Oswaldo Cruz 2005;100:853–9. [18] Kennou MF, Edlinger E. Données actuelles sur les rickettsioses en Tunisie. Arch Inst Past Tun 1984;61:427–33. [19] Acuna-Soto R, Calderon-Romero L, Romero-Lopez D, Bravo-Lindoro A. Murine typhus in Mexico City. Trans R Soc Trop Med Hyg 2000;94: 45. [20] Zhang L, Shan A, Mathew B, Yin J, Fu X, Zhang J, et al. Rickettsial Seroepidemiology among farm workers, Tianjin, People’s Republic of China. Emerg Infect Dis 2008;14:938–40. [21] Valbuena G, Walker DH. Infection of the endothelium by members of the order Rickettsiales. Thromb Haemost 2009;102:1071–9. [22] Adjemian J, Parks S, McElroy K, Campbell J, Eremeeva ME, Nicholson WL, et al. Murine typhus in Austin, Texas, USA. Emerg Infect Dis 2010;16:412–7. [23] Purcell K, Fergie J, Richman K, Rocha L. Murine typhus in children, South Texas. Emerg Infect Dis 2007;13:926–7. [24] Dumler JS, Taylor JP, Walker DH. Clinical and laboratory features of murine typhus in South Texas, 1980 through 1987. JAMA 1991;266:1365–70. [25] Hernandez CM, ngel-Moreno A, Santana E, Bola˜nos M, Francès A, MartínSánchez MS, et al. Murine typhus with renal involvement in Canary Islands, Spain. Emerg Infect Dis 2004;10:740–3. [26] Whiteford SF, Taylor JP, Dumler JS. Clinical, laboratory, and epidemiologic features of murine typhus in 97 texas children. Arch Pediatr Adolesc Med 2001;155:396–400. [27] Silpapojakul K, Chayakul P, Krisanapan S. Murine typhus in Thailand: clinical features, diagnosis and treatment. Q J Med 1993;86:43–7. [28] Toumi A, Loussaief C, Ben Yahia S, Ben Romdhane F, Khairallah M, Chakroun M, et al. Meningitis revealing Rickettsia typhi infection. Rev Med Interne 2007;28:131–3. [29] 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;9:324–8.
www.sciencedirect.com Médecine et maladies infectieuses 43 (2013) 226–229
Original article
Murine typhus in Tunisia: A neglected cause of fever as a single symptom夽 Le typhus murin en Tunisie : cause négligée de fièvre isolée A. Znazen a,∗ , B. Hammami b , A. Ben Mustapha c , S. Chaari a , D. Lahiani b , I. Maaloul b , M. Ben Jemaa b , A. Hammami a a b
Laboratory of Microbiology, Habib Bourguiba University Hospital, Sfax, Tunisia Infectious Diseases Department, Hedi Chaker University Hospital, Sfax, Tunisia c Infectious Diseases Department, Djebeniana Regional Hospital, Sfax, Tunisia
Received 24 October 2012; received in revised form 17 December 2012; accepted 15 February 2013 Available online 22 April 2013
Abstract Objectives. – We had for aim to describe the epidemiologic and clinic characteristics of murine typhus in a series of 43 serologically confirmed cases, in our region. Patients and methods. – Serologic screening for IgG and IgM against Rickettsia typhi was performed in 1024 patients during three years (2006–2008). The characteristics of patients with a positive serology were examined retrospectively. One hundred and seventy sera obtained from blood donors were tested to detect IgG against R. typhi to determine the seroprevalence of the infection. Results. – There was evidence of recent R. typhi infection in 43 patients (4.2%) during the study period, and 3.7% of blood donors had IgG against R. typhi. The mean age of patients was 43.1 years and the sex-ratio was 1.04. Among the patients, 58.1% were from rural areas. No patient reported any exposure to rats or rat-fleas. There were more cases during the summer and fall. The most frequent complaint was fever as a single symptom (67.5%). A cutaneous rash was reported in 44.1% and headache in 60.5% of patients. Among the patients, 44.1% presented with thrombopenia and 47.2% with elevated liver enzymes. Conclusion. – Murine typhus seems to be frequent in Tunisia. This infection could be a threat for travellers. Serology should be performed systematically in patients with fever as a single symptom since its clinical presentation is non-specific. © 2013 Elsevier Masson SAS. All rights reserved. Keywords: Fever; Murine typhus; Rickettsiosis
Résumé Objectif. – Notre objectif était de décrire les caractéristiques épidémiologiques et cliniques du typhus murin dans notre région à travers une série de 43 cas confirmés par la sérologie. Patients et méthodes. – Durant une période de trois ans (2006–2008), 1024 patients ont bénéficié de la sérologie des rickettsioses avec la détection des IgM et des IgG anti-Rickettsia typhi. Les caractéristiques des patients ayant une sérologie positive ont été examinées rétrospectivement. Parallèlement, la séroprévalence de R. typhi a été déterminée chez 170 donneurs de sang. Résultats. – La séroprévalence de l’infection était de 3,7 %. Quarante-trois patients (4,2 %) avaient des marqueurs sérologiques d’une infection récente à R. typhi. La moyenne d’âge des patients et le sex-ratio étaient de 43,1 ans et 1,04 respectivement. Parmi les patients, 58,1 % étaient d’origine rurale. Aucun patient n’a rapporté une exposition aux rats ni à leurs puces. La distribution selon les mois a montré une nette prévalence de la maladie durant l’été et l’automne. La présentation clinique la plus importante était une fièvre isolée dans 67,5 % des cas. Le rash cutané était observé dans 44,1 % des cas et les céphalées dans 60,5 % des cas. Une thrombopénie et une élévation des transaminases étaient observées dans 44,1 % et 47,2 % des cas respectivement.
夽 ∗
This study was presented at the “6th international meeting on Rickettsiae and rickettsial diseases” from June 5 to 7, 2011, in Crete, Greece. Corresponding author. E-mail address: [email protected] (A. Znazen).
0399-077X/$ – see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.medmal.2013.02.007
A. Znazen et al. / Médecine et maladies infectieuses 43 (2013) 226–229
227
Conclusion. – En Tunisie, le typhus murin parait une pathologie fréquente. Le risque de contracter l’infection peut se poser aussi pour les voyageurs. Vu la non-spécificité des signes cliniques, la sérologie devrait être indiquée systématiquement pour les patients se présentant avec une fièvre isolée. © 2013 Elsevier Masson SAS. Tous droits réservés. Mots clés : Fièvre ; Rickettsiose ; Typhus murin
1. Introduction Murine typhus is a flea born infection caused by Rickettsia typhi, a Gram-negative obligate intracellular bacterium. This common zoonotic disease has been reported in suburban settings where rats (Rattus sp.) and their fleas (Xenopsylla cheopis) coexist and it is maintained in a cycle involving these rodents as reservoir and the arthropod as vector. In fact, the rat-flea ingested blood from infected rat so that Rickettsiae multiply in the intestinal epithelial cells of the flea and are excreted in the feces. Humans are contaminated when the flea feces are inoculated at fleabite site or by skin abrasions [1]. This infection occurs in a variety of environments ranging from hot and humid to cold and mountains or semiarid [2]. In fact, murine typhus has been reported worldwide, in diverse geographic areas including the Mediterranean, Africa, South Asia and the USA [3]. In Tunisia, Letaief et al. reported seven cases from Sousse in 2005 showing that the infection still exists in Tunisia [4]. However, little is known about this infection and many clinicians do not suspect the diagnosis of murine typhus because of its nonspecific clinical presentations. In fact, patients do not present cutaneous rash in more than 50% of cases and they do not report a history of fleabite in general. In Sfax, the second town in Tunisia, we showed previously that the disease was diagnosed in our region [5]. But, no data regarding characteristics of the infection are available. In this paper, we reported the seroprevalence of R. typhi in our region among healthy people and we described clinical presentations and epidemiological characteristics of patients with murine typhus.
To assess the seroprevalence of R. typhi in healthy people, 170 blood donor sera were obtained from regional center of transfusion of Sfax collected during 2007. Sera were tested in the same manner for the presence of IgG against R. typhi. Sera with titers > 1:128 were considered as positive. Data were analyzed using SPSS 15.0 software. Student T-test was used to compare means and Chi2 test to compare proportions, P < 0.05 was considered as significant. 3. Results During a 3-year period, 1027 patients were tested by serology to Rickettsia infection. Forty-three patients (4.2%) were considered to have R. typhi infection. Among the patients, 7.5% with murine typhus presented with eruptive fever, and 13% with fever as a single symptom. Of blood donors, 3.7% were infected by R. typhi. R. typhi infection occurred in patients 8 to 83 years of age, with a median age of 41 years (IQ 27, 41, and 54) and a sexratio of 1.04. Patients came from rural areas in 25 cases (58.1%). No patient reported any exposure to rats. However, 27 patients (62.8%) reported contact with various animals: dogs (30.2%), cats (7%), sheep (27.9%), goats (18.6%), cows (4.7%), and birds (2.3%). Only one patient reported fleabites. The cases occurred mainly in the summer (37.3%) and fall (51.2%), between June and October (60.4%). We compared the occurrence of cases and temperature variations in our country; the cases occurred after the hottest period of the year and during period with high levels of humidity (Fig. 1). Patients had to be hospitalized in 36 cases (83.7%). The delay between initial symptoms and consultation ranged from 1 to 25 days with a median of 7 days (IQ 5, 7, and 9.75). The mean
2. Patients and methods Our study was retrospective and included all patients with positive R. typhi serology. Between 2006 and 2008, we received in our laboratory sera from 1027 patients to be tested for rickettsial serology. Serum samples were tested for the presence of antibodies against R. typhi, Rickettsia conorii and Rickettsia felis in a micro immunofluorescence assay as previously described using antigens provided by “Unité des Rickettsies Marseille France” [6]. In each series, sera tittered at the reference center, were included as controls. A recent R. typhi infection was considered if IgM titers to R. typhi were ≥ 1:32 or if a seroconversion on a convalescent serum was detected. Patients’ sera showing cross-reactions between R. typhi and R. conorii or R. felis were not included. A questionnaire form was created for all patients that fulfilled serologic criteria. We gathered demographic, epidemiologic, clinical, laboratory and treatment data.
Fig. 1. Monthly occurrence of murine typhus cases and monthly temperatures means during 2006 to 2008. Distribution mensuelle des cas de typhus murin avec les moyennes de température durant 2006 à 2008.
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Table 1 Clinical signs in cases with murine typhus. Les signes cliniques notés chez les patients ayant un typhus murin.
Fever Chills Asthenia Anorexia Arthralgia Myalgia Headache Confusion Dry cough Rash Lymphadenopathy Conjunctivitis Uveitis Nausea/vomiting Abdominal pain Diarrhea Splenomegaly Hepatomegaly
n = 43 (%)
Frequencies in literature (%) [13,23–27]
42 (97.7) 14 (32.6) 19 (44.2) 4 (9.3) 14 (32.6) 16 (37.2) 26 (60.5) 2 (2.3) 5 (11.6) 19 (44.1) 6 (14) 2 (4.6) 1 (2.3) 13 (30.2) 7 (16.3) 4 (9.3) 4 (9.3) 1 (2.3)
98–100 66–87 29–89 35–81 23–77 46–88 41–90 2–13 15–40 20–80 3.6–15 12–25 2 3–48 11–60 5–40 5–24 24–29
delay before consultation was significantly lower among hospitalized patients (2.3 days, SD 2.5) than among those treated in day care (5.8 days with standard deviation of 3.7, P = 0.006). Patients consulted for fever in 29 cases (67.5%), fever associated to a cutaneous rash in five cases (11.6%), fever associated to headache in five cases (11.6%), urinary symptoms in three cases (7%), and fever after a flea bite in only one case (2.3%). The incidence of reported clinical symptoms are listed in Table 1. The usual triad of fever, cutaneous rash and headache was noted in 11 cases (25.6%). Fever, noted in 42 cases (97.7%), was the most frequent symptoms. Headache was noted in 26 patients (60.5%). The cutaneous rash, observed in 19 patients (44.1%), was macular in 12 cases (63.1%), maculopapular in six cases (31.5%), and purpuric in one case (8.3%). Neurologic disorders were observed in five patients (11.6%), most often consciousness disorders. However, cerebrospinal fluid analysis was normal in every case. Chest radiography was performed in 39 cases. An alveolar syndrome was noted in two cases (4.6%), and an interstitial syndrome in ten cases (23.2%). Abdominal ultrasonography, was performed in only 13 cases; it revealed splenomegaly in four cases (9.3%). Biological abnormalities included an elevated sedimentation rate in 33 patients (58.1%) with a rate above 100 mm/h in only one case. None of our patients presented with renal failure. The serological diagnosis was based on IgM detection in 32 cases. IgG antibodies were reported among 16 patients in their first serum sample. Seroconversion or a significant elevation of antibody titers was observed in 11 cases. The first serological tests were performed after a mean infection duration of 10.4 days (SD 6.8) and the second serological tests were performed after a mean infection duration of 26.3 days (SD 15.2). Forty patients were treated with antibiotics. Three patients were not treated because fever resolved within the first 24 hours of hospitalization. These patients had received antibiotics before
being hospitalized. Antibiotics active on R. typhi, such as doxycycline and ciprofloxacin, were prescribed in 35 cases: in 28 cases at hospitalization and in seven cases after confirmation of diagnosis by serological tests. In the remaining five patients, the non-effective antibiotics prescribed initially were not modified, since confirmation by serological tests was given after a favorable outcome. Our patients were finally dived into two groups: • group 1 (n = 35) patients who received effective antibiotherapy; • group 2 (n = 8) patients who received non-effective antibiotherapy or no antibiotherapy. The two groups were compared; the mean delays before apyrexia were 2.5 days (SD 1.1) in group one and 8.3 days (with standard deviation of 3) in group 2 (P = 0.06); the mean delay before clinical sign resolution were 4 days (SD 1.9) and 9.8 days (SD 3.8) (P = 0.08) respectively. The outcome was favorable in every case. However, four patients in group 1 reported persistent asthenia, headaches, coughing, and arthralgia. 4. Discussion Murine typhus is a common zoonotic disease prevalent worldwide in various environments; but cases are concentrated in tropical, subtropical, and seaside regions [3,7,8]. The infection has been reported in Mediterranean countries, Asia, and in the USA [3,9–14]. Most cases diagnosed in European countries, were imported [15–17]. The real incidence has been never determined in Tunisia. Since Charles Nicolle studies on rickettsial diseases, the Pasteur institute has notified annually the incidence of positive Rickettsia serological tests, and reported a decreasing trend of positive R. typhi serological tests from 1966 to 1975 [18]. No case of murine typhus has been reported since then. This is probably due to inappropriate diagnostic methods. The high seroprevalence (3.7%) reported in our study among healthy blood donors suggests that the disease occurs frequently in our country. Similar or higher seroprevalence rates have been reported in other countries. Rates ranged from 1.1% in Brazil to 14% in Mexico [19]. The authors of a multicenter study made in China, reported a seroprevalence rate of 4.1%, with the highest rate (18.8%) reported in a coastal area at the lowest altitude, in a harbor [20]. The R. typhi cycle includes rats (Rattatus rattatus) and its flea (Xenopsylla cheopis). Climatic conditions are known to influence flea activity [3]. The seasonal distribution of cases revealed a higher number of cases just after the hottest period of the year and when the humidity was maximal. Fleas are more infected at 30 ◦ C [21]. The rat-flea-rat cycle could be maintained all year round and cases could occur in winter when temperatures range around 18 ◦ C; this accounts for cases diagnosed in December and January. This standard cycle, described mostly in urban regions, needs to be reevaluated. The disease is known to be frequent in urban regions, but many authors report an extension of the infection to foothills, suburban, and rural areas [3]. Our cases came from urban or rural regions. No patient reported any contact with
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rats. The role of other animals should be investigated. Indeed, the bacterium has been detected in the USA in cat and opossum fleas; cats and opossums have a higher seroprevalence rates than rats [22]. The clinical features of murine typhus were similar to published data in many other series (Table 1) [12,13,23–27]. However, the usual triad of fever, headache, and cutaneous rash [7,13,28], were noted in only 25% of our patients. Among the patients, 65.1% consulted for fever of unknown origin. Patients presented with various clinical signs and fleabite was reported in only one case. This stresses the heterogeneity of reported symptoms for this disease. Nevertheless, our study was retrospective and this could account for a lack of information. Our serological test data revealed a seroconversion or a significant elevation of antibody titers in only 11 cases. A low antibody kinetics was already reported in other rickettsial infections, such as for R. africae [29]. Serological tests were frequently negative during the first week, especially if patients had been previously treated [29]. A second serological test should be performed two and even 3 weeks after hospitalization to confirm or rule out the infection. In conclusion, murine typhus is a not a rare infectious disease in our country and its true frequency remains to be determined. Its epidemiology is directly related to its vector and reservoir. More environmental studies, investigating animals and arthropods, should be performed. These investigations should determine the bacterium’s cycle and its main reservoir in our region. This would allow developing preventive actions. Travelers should also be informed on the risk of infection. Clinicians should be warned of the polymorphic and non-specific characters of clinical signs, and specifically understand that that the disease often presents as fever only. Thus, serological tests for the diagnosis of rickettsiosis should be considered in the differential diagnosis of fever of unknown origin. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments We thank Pr. Didier Raoult (Unité des rickettsies, Marseille, France) for providing Rickettsia antigens. We thank Sajiaa Hachicha, Radhia Turiki and Dalenda Charfeddine for their technical assistance. References [1] Azad AF, Radulovic S, Higgins JA, Noden BH, Troyer JM. Flea-borne rickettsioses: ecologic considerations. Emerg Infect Dis 1997;3:319–27. [2] Azad AF. Epidemiology of murine typhus. Annu Rev Entomol 1990;35:553–69. [3] Civen R, Ngo V. Murine typhus: an unrecognized suburban vectorborne disease. Clin Infect Dis 2008;46:913–8. [4] Letaief AO, Kaabia N, Chakroun M, Khalifa M, Bouzouaia N, Jemni L. Clinical and laboratory features of murine typhus in central Tunisia: a report of seven cases. Int J Infect Dis 2005;9:331–4.
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