67
BRIEF COMMUNICATION
Noneruptive Fever Revealing Murine Typhus in a Traveler Returning From Tunisia Laura Gastellier, MD,∗ Fanny Lanternier, MD, PhD,∗ Aurélie Renvoisé, MD,† Sébastien Rivière, MD,∗ Didier Raoult, MD, PhD,† Olivier Lortholary, MD, PhD,∗ and Marc Lecuit, MD, PhD∗‡ ∗ Université
Paris Descartes, Hôpital Universitaire Necker-Enfants Malades, Service des Maladies Infectieuses et Tropicales, Centre d’Infectiologie Necker-Pasteur, Institut Imagine, Assistance Publique-Hôpitaux de Paris, Paris, France ; † WHO Collaborative Center for Rickettsioses (UMR CNRS 6236–IRD 198), Marseille, France ; ‡ Biology of Infection Unit, Institut Pasteur, Paris, France DOI: 10.1111/jtm.12154
Rickettsia species are increasingly being recognized as a cause of infection among returning travelers. Murine typhus (MT) was mistakenly thought to have disappeared in the 1970s in Tunisia, yet recent serological data show that Rickettsia typhi, the causative agent of MT, still circulates in the Tunisian population. We report here a case of MT in a woman returning from Tunisia and hospitalized in France. Her presentation was nonspecific, with acute noneruptive fever. Diagnosis was confirmed by cross-adsorption and immunoblotting. Clinicians taking care of returning travelers with fever should be aware of MT, and know how to diagnose and treat it.
M
urine typhus (MT), also known as endemic typhus, belongs to the typhus group rickettsioses, together with epidemic typhus caused by Rickettsia prowazekii.1 Typhus group rickettsioses are louse- or flea-borne infections, whereas the main rickettsioses are tick-transmitted, such as Mediterranean spotted fever caused by Rickettsia conorii or African tick bite fever caused by Rickettsia africae.1 MT is caused by Rickettsia typhi (an obligate intracellular, Gram-negative bacterium) and its main vector is the rat flea Xenopsylla cheopis. Transmission of R. typhi to humans may occur by fleabite and by the feces of these fleas, whether inhaled or contaminating damaged skin. Nonetheless, more than half of the patients have no record of any contact with rats or fleas.2 MT incubation lasts from 7 to 14 days, and manifests usually as a mild disease, with nonspecific flu-like symptoms. It can occur worldwide, but most frequently in tropical coastal areas. The seasonal incidence seems to correlate with the abundance of fleas during late summer, and
Corresponding Author: Fanny Lanternier, MD, PhD, Hopital Necker-Enfants Malades, 149 rue de Sevres, Paris 75015, France. E-mail: [email protected]
most cases occur in August and September in endemic areas. Doxycycline is the treatment of choice.1 Without antimicrobial therapy, fever may last from 7 to 14 days, whereas it resolves within 48 hours when doxycycline is used. Case Report A 41-year-old woman with no past medical history was hospitalized in August 2010 at Necker Hospital, Paris, France, for acute fever, returning from a 5-week stay in Tunisia. She had stayed in Mahdia, a rural zone in the Tunisian Sahel in East Tunisia, approximately 15 km from the coast, where she had contacts with various domestic animals, but did not recall any fleabite. She reported a very abrupt onset of the first symptoms 7 days before admission: severe headache, vomiting, without fever. She became febrile with chills, sweating, nausea, myalgia and arthralgia, stiff neck, cough, and abdominal pain 2 days thereafter. Clinical examination did not show evidence of rash, fleabite mark, or inoculation eschar, but confirmed high fever (39∘ C). Cerebrospinal fluid analysis was normal, as well as results of chest and abdominal computed tomography scans, as well as standard biological analyses, except an increased C-reactive © 2014 International Society of Travel Medicine, 1195-1982 Journal of Travel Medicine 2015; Volume 22 (Issue 1): 67–69
68
Gastellier et al.
Figure 1 Cross-adsorption and immunoblotting. Western blot following cross-adsorption with Rickettsia typhi, Rickettsia prowazekii, and Rickettsia felis antigens. When cross-adsorption is performed with R. typhi antigens, the specific antigen-corresponding line disappears. This demonstrates the presence of anti-R. typhi antibodies in the tested serum sample. NA, nonadsorbed; Rt, R. typhi; Rp, R. prowazekii; Rf , R. felis.
protein serum level (81 mg/L). Treatment with ceftriaxone was started 2 days after admission because typhoid fever was first suspected. It was stopped on day 5 when no improvement was observed, and blood and stool cultures were negative. Two weeks after the onset of symptoms, a decrease in fever was observed and the patient was discharged. Serum was sampled 2 weeks after the onset of symptoms and sent to the WHO Collaborative Center for Rickettsioses in Marseille, France. Serum sample testing for Rickettsia species was performed using a multiple-antigen immunofluorescent assay. There were elevated IgG and IgM antibody titers, which were the highest for Typhus group rickettsioses. As frequently observed in Rickettsia species, there were serological cross-reactions, but the most elevated antibody titers at the convalescent phase were for R. prowazekii, R. typhi, and Rickettsia felis (IgG = 256; IgM = 256); for the other Rickettsia species (R. conorii subsp. conorii, Rickettsia slovaca, Rickettsia mongolitimonae, Rickettsia helvetica, R. conorii subsp. israelensis, Rickettsia massiliae, Rickettsia aeschlimannii, Rickettsia africae), antibodies were at a lower titer (IgG = 256; IgM = 16). Total blood sample was tested via real-time polymerase chain reaction (PCR) targeting typhus group rickettsioses,1,3 and were negative. Cross-adsorption and Western blot analysis of a serum sample identified antibodies directed against R. typhi but not against R. prowazekii or against R. felis, establishing the diagnosis of MT (Figure 1).4 Discussion Fever in returned travelers is often caused by common cosmopolitan infections, such as pneumonia and pyelonephritis, which should not be overlooked in the search for more exotic diagnoses. Travel-related causes J Travel Med 2015; 22: 67–69
of systemic infections need to be screened in febrile, returned travelers, especially those back from tropical regions. Although malaria and arboviroses remain, by far, the most important exotic cause of fever in returned travelers, rickettsioses, in particular African tick bite fever, is of emerging importance in this setting.1,2,5,6 Yet, very often the diagnosis is overlooked, either because the clinical presentation is nonspecific or because no specific diagnostic tool is available to the clinician. Despite its global distribution, R. typhi has been primarily identified in coastal urban regions among rats and their fleas. Yet, this classic cycle has broadened to peridomestic animals including cats, dogs, opossums, and their fleas. MT is usually a mild disease with nonspecific symptoms including fever, headache, maculopapular rash, arthralgia, and myalgia. These nonspecific symptoms also have a relatively poor sensitivity (except for fever): in a recent study, rash was present only in 47% and headache in 34% of patients with MT.7 Therefore, the classic so-called triad of fever, headache, and skin rash is in fact quite rare, found in less than 20% of patients with MT.7,8 Serology should therefore be performed more systematically and preferably in paired serum samples to assess dynamic rises in titers in febrile patients returning from endemic areas.9 Our patient did not present the triad of fever, headache, and skin rash. In a recent series of 32 patients with MT, all presented with fever, but only 12% of patients presented with classical triad, 47% with exanthema, 34% with headache, 37% with digestive signs, 16% with hepato/splenomegaly, 28% with arthralgia/myalgia, 9% with confusion, 1 patient with septic shock, and 1 with myocarditis.7 Therefore, the physician should be aware that the absence of rash and/or headache does not allow excluding the diagnosis of MT. Fever seems to be the only clinical sign in MT that is consistently observed.
69
Murine Typhus From Tunisia
In recent years, a wide array of rickettsioses has been reported throughout the world, because of improved clinician awareness and development of modern diagnostic tools (cross-adsorption and Western blot assays, cell-based cultures, and molecular methods such as PCR).7 Because results of serological testing allow a presumptive diagnosis, more sophisticated and direct methods are critical for the diagnosis and description of new rickettsial diseases, especially in atypical cases.7 A positive immunofluorescence assay for Rickettsia sp. can determine the genus but not the species, which can be determined by cross-adsorption followed by Western blot analysis. Therefore, in febrile, returning travelers, once major cosmopolitan infections as well as malaria and arboviroses have been eliminated, rickettsioses (including MT) should be considered and the appropriate diagnostic tools be used in order to come up with a positive diagnosis ruling out other causes of fever, and help manage potential severe cases with appropriate doxycycline therapy. Mortality in the absence of antibiotic therapy has been reported in up to 4% of cases.8 Given the disease’s potential severity (in an extensive study, 2% of the patients with MT experienced life-threatening conditions, three deaths being recorded8 ; besides, a recent article reports the first known case of a hemophagocytic syndrome associated with MT7 ) and given the limited availability of appropriate diagnostic tools in common medical practice, a case could be made in favor of the use of empirical treatments (assuming other major causes of fever in returned travelers have been ruled out) such as doxycycline,1,10 which presents the benefit of being easy to administer, inexpensive, and with limited side effects.
Declaration of Interests The authors state that they have no conflicts of interest to declare. References 1. Jensenius M, Davis X, von Sonnenburg F, et al. Multicenter GeoSentinel analysis of rickettsial diseases in international travelers, 1996-2008. Emerg Infect Dis 2009; 15:1791–1798. 2. Angelakis E, Botelho E, Socolovschi C, et al. Murine typhus as a cause of fever in travelers from Tunisia and Mediterranean areas. J Travel Med 2010; 17:310–315. 3. Renvoise A, Rolain JM, Socolovschi C, Raoult D. Widespread use of real-time PCR for rickettsial diagnosis. FEMS Immunol Med Microbiol 2012; 64:126–129. 4. La Scola B, Raoult D. Laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases. J Clin Microbiol 1997; 35:2715–2727. 5. Blanton LS. Rickettsial infections in the tropics and in the traveler. Curr Opin Infect Dis 2013; 26:435–440. 6. Wilson ME, Weld LH, Boggild A, et al. Fever in returned travelers: results from the GeoSentinel Surveillance Network. Clin Infect Dis 2007; 44:1560–1568. 7. Walter G, Botelho-Nevers E, Socolovschi C, Raoult D, Parola P. Murine typhus in returned travelers: a report of thirty-two cases. Am J Trop Med Hyg 2012; 86:1049–1053. 8. Dumler JS, Taylor JP, Walker DH. Clinical and laboratory features of murine typhus in south Texas, 1980 through 1987. JAMA 1991; 266:1365–1370. 9. Znazen A, Hammami B, Mustapha AB, et al. Murine typhus in Tunisia: a neglected cause of fever as a single symptom. Med Mal Infect 2013; 43:226–229. 10. Botelho-Nevers E, Socolovschi C, Raoult D, Parola P. Treatment of Rickettsia spp. infections: a review. Expert Rev Anti Infect Ther 2012; 10:1425–1437.
J Travel Med 2015; 22: 67–69
Copyright of Journal of Travel Medicine is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
BRIEF COMMUNICATION
Noneruptive Fever Revealing Murine Typhus in a Traveler Returning From Tunisia Laura Gastellier, MD,∗ Fanny Lanternier, MD, PhD,∗ Aurélie Renvoisé, MD,† Sébastien Rivière, MD,∗ Didier Raoult, MD, PhD,† Olivier Lortholary, MD, PhD,∗ and Marc Lecuit, MD, PhD∗‡ ∗ Université
Paris Descartes, Hôpital Universitaire Necker-Enfants Malades, Service des Maladies Infectieuses et Tropicales, Centre d’Infectiologie Necker-Pasteur, Institut Imagine, Assistance Publique-Hôpitaux de Paris, Paris, France ; † WHO Collaborative Center for Rickettsioses (UMR CNRS 6236–IRD 198), Marseille, France ; ‡ Biology of Infection Unit, Institut Pasteur, Paris, France DOI: 10.1111/jtm.12154
Rickettsia species are increasingly being recognized as a cause of infection among returning travelers. Murine typhus (MT) was mistakenly thought to have disappeared in the 1970s in Tunisia, yet recent serological data show that Rickettsia typhi, the causative agent of MT, still circulates in the Tunisian population. We report here a case of MT in a woman returning from Tunisia and hospitalized in France. Her presentation was nonspecific, with acute noneruptive fever. Diagnosis was confirmed by cross-adsorption and immunoblotting. Clinicians taking care of returning travelers with fever should be aware of MT, and know how to diagnose and treat it.
M
urine typhus (MT), also known as endemic typhus, belongs to the typhus group rickettsioses, together with epidemic typhus caused by Rickettsia prowazekii.1 Typhus group rickettsioses are louse- or flea-borne infections, whereas the main rickettsioses are tick-transmitted, such as Mediterranean spotted fever caused by Rickettsia conorii or African tick bite fever caused by Rickettsia africae.1 MT is caused by Rickettsia typhi (an obligate intracellular, Gram-negative bacterium) and its main vector is the rat flea Xenopsylla cheopis. Transmission of R. typhi to humans may occur by fleabite and by the feces of these fleas, whether inhaled or contaminating damaged skin. Nonetheless, more than half of the patients have no record of any contact with rats or fleas.2 MT incubation lasts from 7 to 14 days, and manifests usually as a mild disease, with nonspecific flu-like symptoms. It can occur worldwide, but most frequently in tropical coastal areas. The seasonal incidence seems to correlate with the abundance of fleas during late summer, and
Corresponding Author: Fanny Lanternier, MD, PhD, Hopital Necker-Enfants Malades, 149 rue de Sevres, Paris 75015, France. E-mail: [email protected]
most cases occur in August and September in endemic areas. Doxycycline is the treatment of choice.1 Without antimicrobial therapy, fever may last from 7 to 14 days, whereas it resolves within 48 hours when doxycycline is used. Case Report A 41-year-old woman with no past medical history was hospitalized in August 2010 at Necker Hospital, Paris, France, for acute fever, returning from a 5-week stay in Tunisia. She had stayed in Mahdia, a rural zone in the Tunisian Sahel in East Tunisia, approximately 15 km from the coast, where she had contacts with various domestic animals, but did not recall any fleabite. She reported a very abrupt onset of the first symptoms 7 days before admission: severe headache, vomiting, without fever. She became febrile with chills, sweating, nausea, myalgia and arthralgia, stiff neck, cough, and abdominal pain 2 days thereafter. Clinical examination did not show evidence of rash, fleabite mark, or inoculation eschar, but confirmed high fever (39∘ C). Cerebrospinal fluid analysis was normal, as well as results of chest and abdominal computed tomography scans, as well as standard biological analyses, except an increased C-reactive © 2014 International Society of Travel Medicine, 1195-1982 Journal of Travel Medicine 2015; Volume 22 (Issue 1): 67–69
68
Gastellier et al.
Figure 1 Cross-adsorption and immunoblotting. Western blot following cross-adsorption with Rickettsia typhi, Rickettsia prowazekii, and Rickettsia felis antigens. When cross-adsorption is performed with R. typhi antigens, the specific antigen-corresponding line disappears. This demonstrates the presence of anti-R. typhi antibodies in the tested serum sample. NA, nonadsorbed; Rt, R. typhi; Rp, R. prowazekii; Rf , R. felis.
protein serum level (81 mg/L). Treatment with ceftriaxone was started 2 days after admission because typhoid fever was first suspected. It was stopped on day 5 when no improvement was observed, and blood and stool cultures were negative. Two weeks after the onset of symptoms, a decrease in fever was observed and the patient was discharged. Serum was sampled 2 weeks after the onset of symptoms and sent to the WHO Collaborative Center for Rickettsioses in Marseille, France. Serum sample testing for Rickettsia species was performed using a multiple-antigen immunofluorescent assay. There were elevated IgG and IgM antibody titers, which were the highest for Typhus group rickettsioses. As frequently observed in Rickettsia species, there were serological cross-reactions, but the most elevated antibody titers at the convalescent phase were for R. prowazekii, R. typhi, and Rickettsia felis (IgG = 256; IgM = 256); for the other Rickettsia species (R. conorii subsp. conorii, Rickettsia slovaca, Rickettsia mongolitimonae, Rickettsia helvetica, R. conorii subsp. israelensis, Rickettsia massiliae, Rickettsia aeschlimannii, Rickettsia africae), antibodies were at a lower titer (IgG = 256; IgM = 16). Total blood sample was tested via real-time polymerase chain reaction (PCR) targeting typhus group rickettsioses,1,3 and were negative. Cross-adsorption and Western blot analysis of a serum sample identified antibodies directed against R. typhi but not against R. prowazekii or against R. felis, establishing the diagnosis of MT (Figure 1).4 Discussion Fever in returned travelers is often caused by common cosmopolitan infections, such as pneumonia and pyelonephritis, which should not be overlooked in the search for more exotic diagnoses. Travel-related causes J Travel Med 2015; 22: 67–69
of systemic infections need to be screened in febrile, returned travelers, especially those back from tropical regions. Although malaria and arboviroses remain, by far, the most important exotic cause of fever in returned travelers, rickettsioses, in particular African tick bite fever, is of emerging importance in this setting.1,2,5,6 Yet, very often the diagnosis is overlooked, either because the clinical presentation is nonspecific or because no specific diagnostic tool is available to the clinician. Despite its global distribution, R. typhi has been primarily identified in coastal urban regions among rats and their fleas. Yet, this classic cycle has broadened to peridomestic animals including cats, dogs, opossums, and their fleas. MT is usually a mild disease with nonspecific symptoms including fever, headache, maculopapular rash, arthralgia, and myalgia. These nonspecific symptoms also have a relatively poor sensitivity (except for fever): in a recent study, rash was present only in 47% and headache in 34% of patients with MT.7 Therefore, the classic so-called triad of fever, headache, and skin rash is in fact quite rare, found in less than 20% of patients with MT.7,8 Serology should therefore be performed more systematically and preferably in paired serum samples to assess dynamic rises in titers in febrile patients returning from endemic areas.9 Our patient did not present the triad of fever, headache, and skin rash. In a recent series of 32 patients with MT, all presented with fever, but only 12% of patients presented with classical triad, 47% with exanthema, 34% with headache, 37% with digestive signs, 16% with hepato/splenomegaly, 28% with arthralgia/myalgia, 9% with confusion, 1 patient with septic shock, and 1 with myocarditis.7 Therefore, the physician should be aware that the absence of rash and/or headache does not allow excluding the diagnosis of MT. Fever seems to be the only clinical sign in MT that is consistently observed.
69
Murine Typhus From Tunisia
In recent years, a wide array of rickettsioses has been reported throughout the world, because of improved clinician awareness and development of modern diagnostic tools (cross-adsorption and Western blot assays, cell-based cultures, and molecular methods such as PCR).7 Because results of serological testing allow a presumptive diagnosis, more sophisticated and direct methods are critical for the diagnosis and description of new rickettsial diseases, especially in atypical cases.7 A positive immunofluorescence assay for Rickettsia sp. can determine the genus but not the species, which can be determined by cross-adsorption followed by Western blot analysis. Therefore, in febrile, returning travelers, once major cosmopolitan infections as well as malaria and arboviroses have been eliminated, rickettsioses (including MT) should be considered and the appropriate diagnostic tools be used in order to come up with a positive diagnosis ruling out other causes of fever, and help manage potential severe cases with appropriate doxycycline therapy. Mortality in the absence of antibiotic therapy has been reported in up to 4% of cases.8 Given the disease’s potential severity (in an extensive study, 2% of the patients with MT experienced life-threatening conditions, three deaths being recorded8 ; besides, a recent article reports the first known case of a hemophagocytic syndrome associated with MT7 ) and given the limited availability of appropriate diagnostic tools in common medical practice, a case could be made in favor of the use of empirical treatments (assuming other major causes of fever in returned travelers have been ruled out) such as doxycycline,1,10 which presents the benefit of being easy to administer, inexpensive, and with limited side effects.
Declaration of Interests The authors state that they have no conflicts of interest to declare. References 1. Jensenius M, Davis X, von Sonnenburg F, et al. Multicenter GeoSentinel analysis of rickettsial diseases in international travelers, 1996-2008. Emerg Infect Dis 2009; 15:1791–1798. 2. Angelakis E, Botelho E, Socolovschi C, et al. Murine typhus as a cause of fever in travelers from Tunisia and Mediterranean areas. J Travel Med 2010; 17:310–315. 3. Renvoise A, Rolain JM, Socolovschi C, Raoult D. Widespread use of real-time PCR for rickettsial diagnosis. FEMS Immunol Med Microbiol 2012; 64:126–129. 4. La Scola B, Raoult D. Laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases. J Clin Microbiol 1997; 35:2715–2727. 5. Blanton LS. Rickettsial infections in the tropics and in the traveler. Curr Opin Infect Dis 2013; 26:435–440. 6. Wilson ME, Weld LH, Boggild A, et al. Fever in returned travelers: results from the GeoSentinel Surveillance Network. Clin Infect Dis 2007; 44:1560–1568. 7. Walter G, Botelho-Nevers E, Socolovschi C, Raoult D, Parola P. Murine typhus in returned travelers: a report of thirty-two cases. Am J Trop Med Hyg 2012; 86:1049–1053. 8. Dumler JS, Taylor JP, Walker DH. Clinical and laboratory features of murine typhus in south Texas, 1980 through 1987. JAMA 1991; 266:1365–1370. 9. Znazen A, Hammami B, Mustapha AB, et al. Murine typhus in Tunisia: a neglected cause of fever as a single symptom. Med Mal Infect 2013; 43:226–229. 10. Botelho-Nevers E, Socolovschi C, Raoult D, Parola P. Treatment of Rickettsia spp. infections: a review. Expert Rev Anti Infect Ther 2012; 10:1425–1437.
J Travel Med 2015; 22: 67–69
Copyright of Journal of Travel Medicine is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
