Clinical and laboratory features of murine typhus in central Tunisia: a report of seven cases

International Journal of Infectious Diseases (2005) 9, 331—334

http://intl.elsevierhealth.com/journals/ijid

Clinical and laboratory features of murine typhus in central Tunisia: a report of seven cases A. Omezzine Letaı¨ef a,*, N. Kaabia a, M. Chakroun b, M. Khalifa a, N. Bouzouaia b, L. Jemni a a b

Infectious Diseases Unit, F. Hached University Hospital, Sousse, Tunisia Infectious Diseases Unit, F. Bourguiba University Hospital, Monastir, Tunisia

Received 3 January 2004; received in revised form 11 August 2004; accepted 14 September 2004 Corresponding Editor: Jon Cohen, Brighton, UK

KEYWORDS Rickettsia; Flea; Murine typhus; Tunisia

Summary Introduction: Murine or endemic typhus, caused by Rickettsia typhi, has been reported in all continents. In the 1970s, no cases of murine typhus were diagnosed in Tunisia. Methods: The clinico-epidemiological characteristics of seven cases of murine typhus diagnosed at our hospitals since 1993 are reported. Diagnosis was confirmed by indirect fluorescence assay detecting specific R. typhi antibodies. Results: Murine typhus occurred in all ages from 18—80 years during the hot season in rural areas. Clinical features were: sudden onset of fever and absence of eschar in all cases, with maculo-papular rash (five cases), prostration (four cases), meningism (three cases) and pneumonia (four cases). Frequent laboratory findings were moderate thrombopenia (four cases) and elevated transaminases (four cases). Before the results of serology, clinical diagnoses were Mediterranean Spotted Fever (four cases), Q fever (one case), pneumonia (one case), and lymphocytic meningitis (one case). Serology confirmed all diagnoses with cross-reactivity with Rickettsia conorii. Conclusion: Murine typhus exists in Tunisia and its prevalence is underestimated. Further, more specific studies are needed to evaluate the true prevalence. # 2005 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Introduction * Corresponding author. Present address: Service de Me ´decine Interne et Maladies Infectieuses, CHU F. Hached, 4000 Sousse, Tunisie. Tel.: +216 73 2111 83; fax: +216 73 2111 83. E-mail address: [email protected] (A.O. Letaı¨ef).

Murine typhus, caused by Rickettsia typhi, is an endemic zoonosis. Its main vector is the rat flea Xenopsylla cheopis, which maintains the microorganism in rodents. Flea bites and contamination

1201-9712/$30.00 # 2005 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2004.09.011

Doxycycline 21 days Ofloxacin 7 days 140 138 Maculo-papular Day 7 Maculo-papular Day 4

a

22/F 62/F 6 7

— 31/M 5

Macular Day 4 56/M 4

Reference ranges for lab values: sodium (136—142 mEq/l); ALAT/ASAT (37/40 U/l). MSF = Mediterranean Spotted Fever.

28/24 69/57 95 108 15.0 12.6 Q fever/MSF MSF

Doxycycline 21 days 124 28/24 98 10.0 Q fever

126 120/124 95 5.6

128 134 128 21/24 95/94 78/76 345 78 250 6.9 8.0 7.0

MSF Pneumonia Lymphocytic meningitis MSF

Interstitial pneumonia Pneumonia, prostration Meningitis, stupor, prostration Confusion, seizures, prostration, meningism Interstitial pneumonia, meningism, prostration Interstitial pneumonia Myalgia, acute renal failure 64/M 80/F 18/M

Maculo-papular Day 6 — —

Extra-cutaneous findings Rash

1 2 3

Murine typhus occurred in all ages from 18—80 years during the hot season from May to October in six cases and in January in one case. All patients were from rural or suburban areas; neither flea bites nor exposure to rats were mentioned. Sudden onset of fever and headache were reported in all cases. A rash, noted in four patients

Age/sex

Results

Case

Seven patients with a diagnosis of murine typhus identified between 1993 and 1998 were hospitalized in the infectious diseases unit of the University Hospital in central Tunisia. Clinical and epidemiological data were collected from the patients’ charts. Diagnosis was confirmed by a four-fold rise in antibody titer, or by a single high titer 128 to typhus group antigen by indirect fluorescent assay (IFA). All sera cross-reacted to Rickettsia conorii antigen at lower titer. Five of the seven cases were diagnosed in 1993 when a previous study (determining the prevalence of some infections among febrile patients) permitted retrospective diagnosis of murine typhus. Two other cases were thought to be MSF and complete serology of murine typhus confirmed the diagnosis.

Table 1 Clinical and biological findings in seven cases of murine typhus.

Patients and methods

Clinical diagnosis

Leucocyte count  106/L

Platelet count  106/L

ALAT/ASATa

Sodium mmol/l a

Treatment

of excoriated skin or the respiratory tract with inhalation of infected flea feces are the major sources of human infection.1 Often unrecognized, murine typhus occurs with high prevalence in the tropics and has been reported in travellers returning from coastal tropical and subtropical regions.2—4 In Africa, little recent reliable information is available on the prevalence of murine typhus infection. In Tunisia, a north African country where Mediterranean Spotted Fever (MSF) was first described by Conor in 1910, rickettsial diseases were largely described at the beginning of the century.5 Previous serosurveys indicating the absence of typhus in Tunisia in the 1970s used inappropriate methods.6 From 1984 to 1992, using a sensitive and specific test for the diagnosis of rickettsial infections, typhus was diagnosed in our hospitals7 and relatively high seroprevalence was detected among febrile patients and blood donors in the region (central Tunisia).8,9 In this study the epidemiological and clinical characteristics of murine typhus are reported with the aim of warning physicians of the persistence or re-emergence of the disease in Tunisia.

Ofloxacin 10 days

A.O. Letaı¨ef et al.

Doxycycline 10 days Cefotaxime 10 days Doxycycline 10 days

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Clinical and laboratory features of murine typhus in central Tunisia

Table 2 Results of indirect fluorescent assay testing for antibodies against Rickettsia typhi, Rickettsia conorii. Case

1 2 3 4 5 6 7

R. conorii

R. typhi

S1 (IgG/M)

S2 (IgG/M)

S1 (IgG/M)

S2 (IgG/M)

0/0 64/0 128/16 32/0 32/0 0/0 40/20

64/32 128/0 256/32 ND ND 40/20 80/40

128/64 64/32 128/256 1024/128 256/512 160/20 160/40

1024/256 512/64 2048/512 ND ND 1280/160 1280/320

S1, S2: early serum and convalescent serum; ND: not done.

(57%), began around the fifth day of the onset and was maculopapular and non-confluent. It was distributed over the trunk and limbs, sparing the face, palms and soles. There were four cases of pneumonia, with interstitial infiltrates on chest X-ray film in three cases and alveolar infiltrates in one case. Meningitis was suspected in three cases and cerebrospinal fluid showed lymphocytic meningitis in one case. Clinical and biological features are summarised in Table 1. Routine laboratory tests showed a normal white blood cell count in five cases and thrombocytopenia in four cases. The erythrocyte sedimentation rate was higher than 40 mm/h in all cases. Liver enzyme levels were elevated in five cases. Hyponatremia was present in four cases and hypokalemia in three cases. In two cases, murine typhus was diagnosed by a single titer of 512 or higher by IFA. The other five cases were diagnosed by a four-fold increase of the initial titer. In all cases, the titers reached against R. conorii were always lower than those reached against R. typhi (Table 2). All patients received antibiotics: four received doxycycline, two received ciprofloxacin or ofloxacin and one received cefotaxime. Complications of murine typhus were infrequent and included neuropsychiatric abnormalities, meningitis and renal failure. All cases were cured.

Discussion Rickettsia typhi is found world-wide, but the number of reported cases does not reflect the current prevalence. The mild and non-specific features of infection suggest that its incidence is probably largely underestimated in tropical countries. However, the disease is prevalent in Texas, USA, in the Mediterranean area (recently reported in Greece, Spain,

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Portugal, Croatia, Cyprus, and Israel), and in Asia (Thailand, Vietnam, Japan, Indonesia, China) and in Africa.3,10,11 Tissot-Dupont noted that the prevalence of antibodies reactive with R. typhi varied from 1—20% in seven African countries and it was higher in coastal areas where rats are prevalent.12 In Tunisia, MSF occurs more frequently during the hot season and is well documented by isolation of R. conorii from eschar in two patients (in Unite ´ des Rickettsies, Professor D. Raoult; unpublished data), whereas typhus infection is thought to have disappeared in the 1970s. Previous studies, however, have suggested persistence of the infection,7—9 which is underestimated in Tunisia due to the lack of specificity of symptoms and of physician awareness of murine typhus. In fact, when systematic serology was performed for acute fever in 1993, five cases of murine typhus were diagnosed during only one year. Murine typhus is re-emerging in Tunisia, both amongst the indigenous population and travellers, and physicians need to be aware that some of the classical epidemiological and clinical features may differ here. Epidemiological features noted in patients in this study were the association with a rural area and occurrence during the hot season. So in that respect it is similar to MSF. However, one important difference from MSF was the lack of patient contact with infected fleas, along with the fact that there was no direct contact with rats. Such contact was, however, noted in 54% of patients in a prospective study in Greece.10 The variability in the clinical presentation of the patients in this study was reflected in difficulties with the diagnosis. This was evidenced by two patients who presented with an initial diagnosis of pneumonia and one with viral meningitis. The clinical diagnosis of murine typhus is particularly difficult when the patient is seen early on in the course of the disease with only isolated fever and non-specific clinical abnormalities, or the absence of a rash. This last presentation (3/7 cases in this study) has been reported in 20—80% of cases, according to the stage of illness at consultation.3,11 In a recent review in the United States, 22 different diagnoses were proposed for 80 patients with murine typhus.13 When eruptive fever is observed, the main differential diagnosis in the region is MSF without identified eschar. So, in the absence of criteria for clinical diagnosis, it is believed that murine typhus should be considered routinely in unspecified acute febrile illness and eruptive fever during the hot season, especially when associated with thrombocytopenia and elevated aminotransferases. The definitive diagnosis of murine typhus, like other rickettsial infections, requires laboratory confirmation based on serologic testing by IFA, the

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reference method. Latex test, dot blot enzymelinked immunosorbent assay and immunoperoxidase assay have also been described.14 However, detected antibodies are cross-reactive within the spotted fever or typhus group and particularly between Rickettsia typhi and Rickettsia prowazekii.15 Rickettsia felis, recently isolated from patients with murine typhus-like illness and from cat fleas in many European and American countries, should also be considered.16—18 Cross-adsorption studies and Western blotting are useful serological tools for confirmation.15 In this study, cross-adsorption was only performed in five cases. However, differentiation between murine and epidemic typhus could be made based on epidemiological and clinical criteria. As for R. felis, prospective studies should determine its implication in spotted fever group rickettsial infection in the central Tunisian region. In conclusion, it is recommend that physicians should be alert for murine typhus in Tunisia, where more specific studies are needed to evaluate the true prevalence and the epidemiological features of this disease.

Acknowledgments We thank Dr Didier Raoult (Unite ´ des Rickettsies, Faculte ´ de Me ´decine, Marseille, France) for confirming diagnosis of murine typhus in his laboratory. Conflict of interest: No conflict of interest to declare.

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