Murine Typhus as a Cause of Fever in Travelers From Tunisia and Mediterranean Areas

Emmanouil Angelakis MD, PhD, Elizabeth Botelho MD, Cristina Socolovschi MD, PhD, Chantal Roure Sobas MD, Christophe Piketty MD, Philippe Parola MD, PhD, Didier Raoult MD, PhD
DOI: 310-315 First published online: 1 September 2010


Background Travelers are exposed to a variety of health risks in unfamiliar environments and fever is a common problem in patients returning from travel abroad. Rickettsial diseases are increasingly frequently being reported among international travelers. Here we present cases of Rickettsia typhi infection, the agent of murine typhus, that were identified in our laboratory the last year, in travelers from Tunisia.

Methods For each patient we tested an acute‐phase serum sample and for one patient we tested a convalescent‐phase serum sample. IgG and IgM antibody titers were estimated with use of the microimmunofluorescence (MIF) assay. Western blot (WB) assay was performed for all the patients.

Results We identified three cases of murine typhus after a travel in Tunisia. All cases were observed during late summer and early autumn and patients were suffering by persistent fever. None of them presented rash or inoculation eschar. MIF was positive for Rickettsia sp. in the acute‐phase serum samples of two patients. In one patient, two acute‐phase serum samples were Rickettsia sp. negative whereas a third convalescent‐phase serum sample that was obtained 2 weeks after was Rickettsia sp. positive. By WB assay we identified infection by R typhi. A treatment was immediately started and patients became apyretic.

Conclusions In the countries of North Europe, although autochthones cases of murine typhus have not been described, sporadic cases of R typhi infection are identified in travelers who visited murine typhus endemic areas. Murine typhus should be considered in the diagnosis of febrile illness without rash in travelers returning from disease endemic areas, like the south Mediterranean area.

International travel is now common worldwide for professional, social, recreational, and humanitarian purposes and has an increasingly important impact on health care. Travelers are exposed to a variety of health risks in unfamiliar environments and fever is a common problem in patients returning from travel abroad. 1 Fever is an important marker of potentially serious illness in returned travelers and a high percentage of the febrile returned travelers are categorized as having an unspecified febrile illness, meaning they did not have a confirmed or probable diagnosis. 2,3 Malaria remained the most common diagnosis in febrile travelers who presented at GeoSentinel clinics from March 1997 through March 2006. 2 Other causes of fever in returned travelers include typhoidal and nontyphoidal salmonellosis, dengue fever, viral hepatitis, and rickettsial infections. 2,3

Rickettsial infections in travelers are now of emerging importance as contact with the vectors, mainly ticks, but also fleas, is very common in several countries. 2,3 Spotted fever group (SFG) rickettsiae are the second most common diagnosis for systemic febrile illness in travelers to sub‐Saharan Africa. 4 In the last 15 years African tick bite fever caused by Rickettsia africae has been described as the most frequent rickettsioses acquired by travelers in sub‐Saharan Africa. 5 Other SFG rickettsioses such as Mediterranean spotted fever due to Rickettsia conorii have been reported as well as the flea‐borne murine typhus caused by Rickettsia typhi, and scrub typhus caused by Orienta tsutsugamushi are transmitted by trombiculid mites. Recently, epidemiological aspects of rickettsial diseases were analyzed in 280 international travelers reported to the GeoSentinel site from June 1996 through December 2008. 6 82.5% of these cases were tick‐borne rickettsioses, 5.7% were cases of scrub typhus, and 2.5% were cases of typhus group rickettsioses. 6 Most cases were associated with travel to sub‐Saharan Africa (75.1%). A European study by Bottieau and colleagues 7 in 1,743 patients with fever identified that 4% of the febrile patients returning from Africa presented a rickettsial infection. Rickettsia conorii and R africae were identified in 53 patients, R typhi in four, and O tsutsugamushi in three. 7 Here we report three cases of murine typhus infection after travel in Tunisia and we review the available data about this disease in the Mediterranean area.


The sera of patients returned from Tunisia were received at the WHO Collaborative Center for Rickettsioses and Other Arthropod‐Borne Bacterial Diseases in Marseille. For each patient, an acute‐phase serum sample was obtained within 2 weeks after the onset of symptoms and, when possible, a convalescent‐phase serum sample (ie, one collected more than 2 wk after onset of symptoms) was also obtained. IgG and IgM antibody titers were estimated with use of the microimmunofluorescence (MIF) assay, as reported elsewhere. 8 A MIF test was considered positive if (1) a single serum showed antibody titers of ≥1 : 64 for IgM and/or ≥1 : 128 for IgG antibodies; acute and convalescent sera showed (2) a seroconversion; or (3) a fourfold or greater increase in titers. On acute sera, Western blot (WB) assays were carried out for all the patients. 9 DNA was extracted from the sera using a QIAamp tissue kit (Qiagen, Hilden, Germany) and was used as a template in a previously described quantitative polymerase chain reaction (qPCR) assay. 10

Case Reports

Case 1

The first patient was a 59‐year‐old woman suffering from persistent fever (39°C) after a 1‐week trip in Tunisia during September. During the examination an inoculation eschar or a rash was not observed and she did not present other specific clinical findings. The patient was treated with doxycycline (14 d) and recovered.

Case 2

The second patient was a 19‐year‐old girl who presented persistent fever (40°C) and diarrhea during her stay in Djerba, Tunisia. The patient was living with relatives for about 2.5 months during the summer. The patient presented to the local hospital. During the examination, she presented hepatosplenomegaly. Neither rash nor inoculation eschar were observed. The patient mentioned contacts with rats. A treatment with penicillin was started. The patient returned to France and as symptoms remained, she presented at a hospital in Marseille, France. Fever, left hemiparesis, and hepatosplenomegaly were also observed. Blood analysis revealed anemia and thrombocytopenia. A treatment with doxycycline was immediately started and after 4 days the patient became apyretic.

Case 3

The third patient was a 48‐year‐old woman who stayed during July and August in a countryside village in Tunisia to visit relatives. The patient mentioned frequent contacts with dogs. During her stay in Tunisia she presented fever (40°C), myalgia, and chills and she presented to the local hospital. An inoculation eschar or a rash was not observed and she did not present other specific clinical findings. A leptospirosis infection was suspected and a treatment with intravenous (IV) cefotaxime for 7 days was started. After treatment the patient decided to return to France. However, symptoms remained and she presented at a hospital in Paris, France. A treatment with IV cefotaxime and doxycycline was immediately started. IV cefotaxime was stopped and doxycycline was continued. Fever was retreated 5 days after the beginning of doxycycline.


In these three travelers returned from Tunisia, murine typhus was confirmed by reference serological methods. Although all patients had a positive MIF for Rickettsia sp., the test did not allow differentiation of infection among Rickettsia sp. 11 WB assay definitely confirmed the diagnosis.

Murine typhus is usually mild with a group of symptoms that is shared with an array of other infectious diseases, including several bacterial and viral infections. As a result, many cases of murine typhus are overlooked without a laboratory‐confirmed diagnosis. 12 Most of the cases of murine typhus are mild and signs in untreated patients last for 7 to 14 days (Table 1). Patients usually present an abrupt onset of symptoms like fever, rash, cough, headaches, maculopapular exanthema on the trunk to the half‐patients, chills, as well as with myalgias and hepatomegaly. 11 Less common manifestations of murine typhus are lymphadenopathy (4%) and splenomegaly (5%). 12 In rare cases, aseptic meningitis, deafness, deep venous thrombosis, and even death have been reported with a fatality rate which may be as high as 4%. 13 Diagnosis may be missed because the rash is not always presented. The rash is nonspecific and its prevalence differs as 20% of patients from Thailand presented rash, 38% of patients from Laos, 49% of patients from Texas, 80% of patients from Greece, and 62.5% of patients from Spain. 12,14–17 None of our patient presented rash.

View this table:
Table 1

The cases of murine typhus identified in our laboratory

AgeSymptomsMicroimmunofluorescence assayPCR in the serumWestern blotTreatment
Patient 159Persistent fever (40°C)Acute serum, Rickettsia sp., IgG/IgM, 128/256NegativeR typhiDoxycycline (14 d)
Patient 219Persistent fever (40°C), diarrhea, and hepatosplenomegalyAcute serum negative, late (2 wk after) serum, Rickettsia sp., IgG/IgM, 0/512NegativeR typhiDoxycycline (10 d)
Patient 348Persistent fever (40°C), myalgia, and chillsAcute serum, Rickettsia sp., IgG/IgM, 32/128NegativeR typhiDoxycycline (14 d)

A major role for the early diagnosis of murine typhus is the epidemiologic investigation of patients. Murine typhus should be considered to patients from places with a high rat population like tropical countries, and also northern countries late in summer or early in autumn. When choosing a diagnostic method, one must take into account its specificity, sensitivity, cost, the amount of antigen required, and its commercial availability. The microorganisms can be isolated by inoculation of specimens onto conventional cell cultures (Vero cells). 18 The most recent technique is the centrifugation shell vial method, in which specimens are inoculated in Vero or L299 cells on a coverslip within the shell vial and the ensuing centrifugation enhances the attachment and penetration of rickettsiae into cells. 18 The technique allows the identification of new rickettsiae and ensures early diagnosis because it can give a positive result before the antibody titer rises. 19 The delay between sampling and inoculation in shell vials as well as the use of antibiotic therapy prior to sampling are important factors that limit the possibility of a positive culture. 18 However, culture and isolation of Rickettsia sp. must only be carried out in Biosafety Level 3 laboratories. PCR is a rapid, sensitive, and specific method and is considered the technique of choice for early diagnosis of the disease because it can give positive result before seroconversion. 18,20 It is a significant tool in detecting rickettsiae in blood, skin biopsies, and arthropods and it is also used for differentiating the various species of Rickettsia. 18 The genes that are specific of the typhus group Rickettsia are the rrs, gltA, ompB, and the gene D. 18 Serological tests are the most frequently used and widely available methods for the diagnosis of murine typhus. Indirect immunofluorescence assay (IFA) adapted to a micromethod format is the reference method for the serodiagnosis of Rickettsia in most laboratories. Because specific antibodies are frequently absent during the acute illness, serologic diagnosis can be made by obtaining acute and convalescent serum. IgM and IgG are usually both detected 7 to 15 days after disease onset. 20 The diagnosis of recent murine typhus can be established by demonstrating a four‐fold or greater rise in titer of antibody in properly collected acute and convalescent serum samples. 21

In Tunisia, rickettsioses have been described since the beginning of the 20th century, but cases are poorly documented and few records are available in the literature. 22 In 1995, Omezzine‐Letaief and colleagues 23 tested 500 sera from blood donors in Tunisia and identified that 3.6% had antibodies to R typhi. The same year, in a prospective study among 300 patients hospitalized with fever, infectious diseases were confirmed or suspected in 220 cases—in this group, when serology of rickettsial infections were performed systematically, 6% of patients had acute rickettsioses, and seroprevalence of R conorii and R typhi were 22.6 and 15.6%. 24 In 2005, seven cases of murine typhus were reported in Tunisia. 25 Sudden onset of fever and headache were reported in all cases, whereas a rash was noted in four patients. The rash began around the fifth day of the onset and was maculopapular and nonconfluent. Recently, nine consecutive patients with serologically confirmed murine typhus were reported. 26 These patients were examined for the ocular involvement that is frequently observed in acute murine typhus. 26

The typical cycle of R typhi involves the roof and Norway rats (Rattus rattus and Rattus norvegicus, respectively) and the rat flea (Xenopsylla cheopis). The rat reservoir not only serves as a host for the flea vector but also makes rickettsiae available in the blood for fleas, which transmit rickettsiae back to a rat host during subsequent feeding. 27 Most of the reported human cases of murine typhus have been associated in sites with large rat populations. Human infection is associated with the presence of rats and their fleas living in indoor urban environments. Fleas propagate most successfully in hot, dry environments. There is a seasonal incidence which appears to be correlated with the abundance of the vector fleas, which is in late summer and early autumn when X cheopis fleas are most abundant. 28 All our cases of murine typhus occurred in late summer and early autumn.

Cases of murine typhus have been identified in the countries around the Mediterranean area (Figure 1). Recently in Algeria two cases of R typhi infection were confirmed in patients with fever. 29 In Israel cases of murine typhus are frequently reported and Bishara and colleagues 30 published 406 cases of murine typhus in Jews and Arabs. Shalev and colleagues 31 identified that murine typhus is an important cause of febrile illnesses among Bedouin children as the 13.8% among 549 children with fever had serologically confirmed murine typhus. Murine typhus is also endemic in Cyprus and 21 children under 15 years of age were also identified from 2000 to 2006 with R typhi infection. 32 The most common symptoms were fever (100%), rash (57%), lymphadenopathy (37%), and severe headache (29%). R typhi infections are reported in Greece and mostly in the island of Crete. 12,33 The predominant clinical manifestations were fever (100%), headache (88%), chills (86.7%), and rash (79.5%). 12 In Italy, murine typhus was the most widespread rickettsioses, especially in Sicily during World War II. 34 Rickettsia typhi still exist, at least in Sicily; in particular, asymptomatic cases of murine typhus were reported in Sicily in the late 1980s. 34 In the south of Spain a prospective study over 17 years (1979–1995) identified 104 cases of murine typhus. 17 Rickettsia typhi infection was the cause in 6.7% of 926 cases of fever lasting for 7 to 28 days.

Figure 1

Cases of murine typhus in countries around the Mediterranean area. Yellow stars: areas where autochthones cases of murine typhus have been described Red stars: areas where only sero‐epidemiological evidence for the presence of murine typhus exists.

Sero‐epidemiological studies reveal that murine typhus probably exists in other Mediterranean countries. In Morocco indirect immunofluorescence test on human sera obtained from 300 donors and 126 patients from clinical laboratories identified R typhi antibodies in 1.7 and 4%, respectively. 35 In France R typhi antibodies were identified in homeless patients from Marseille. 36 An R typhi‐positive serology was identified in 68.1% of the residents in the northern Dalmatian islands of Croatia in an epidemiological study. 37 Rickettsia typhi has also identified and cultivated from Monopsyllus sciurorum sciurorum fleas collected in southern Slovenia. 38 There is evidence that murine typhus also exists in North Spain as the R typhi seroprevalence was in 7.6% of the people living in urban, 8.5% in semirural, and 21.4% in rural areas. 39 In Malta, contrary to current belief, R typhi did not account for any of the cases seen. 40 Finally, there have not been any studies to determine if murine typhus is endemic in Libya, Lebanon, Syria, Turkey, Albania, Serbia, and Montenegro.

In the countries of North Europe autochthones cases of murine typhus have not been described. However, sporadic cases are identified in travelers who visited endemic areas like the countries of the south Mediterranean area. As a result, R typhi infection was found in a Norwegian tourist with fever, chills, and severe headache who had visited the island of Crete. 41 The patient did not present a rash and recovered without sequelae. The diagnosis of murine typhus was based on the detection of IgM antibodies against R typhi in serum samples during reconvalescence. 41 Murine typhus was also identified in a traveler from the UK after her return from Spain. 42 The patient presented fever (39.5°C), chills, severe headache, photophobia, a sore throat, neck stiffness, purpuric rash, and she was passing very little urine. Unfortunately, murine typhus was not considered from the beginning of the symptoms and she was treated with IV cefotaxime. The patient died although antibiotic was changed to doxycycline, and at necropsy a generalized macular skin rash with larger areas of hemorrhage over the legs and trunk was noted. 42 Murine typhus was also confirmed in a Czech traveler after his return from Egypt. 43 The patient was suffering from fever lasting for 4 days, strong headache, dry cough, and on the 7th and 8th day he appeared with transient maculopapular rash. The fever dropped after 15 days when doxycycline was given and no response was observed to the previously administered antibiotics—amoxicillin/clavulanate, clarithromycin, and ofloxacin. This was the first documented case of R typhi infection in Egypt and confirmed the previous sero‐epidemic studies which proposed that murine typhus was probably endemic in this country. 44 Moreover, in Cyprus, although to date many cases of murine typhus have been described, the first identification was done in a Swede who developed fever, severe headache, myalgia, and rash. 45 Three weeks before the onset of the symptoms she had stayed in a hotel in Cyprus where she got numerous bites from insects in her bed. The patient was treated with ciprofloxacin; her condition improved remarkably within 24 hours after the start of the treatment and was afebrile within 3 days. 45 A case of murine typhus was reported in Florence in 1991 in a person who was reportedly bitten by an unidentified insect during a trip to Sicily about 2 weeks before the onset of symptoms. 34

Besides tropical areas where murine typhus is known as a frequent cause of fever of unknown origin, the Mediterranean area has also been considered as a risk area for travelers. As a result, clinicians who may see patients returning from the Mediterranean area should be aware that murine typhus is present in this area and considered as an R typhi infection in differential diagnosis of patients with febrile illnesses.

Declaration of interests

The authors state they have no conflicts of interest to declare.


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