ORIGINAL INVESTIGATION Murine Typhus as a Common Cause of Fever of Intermediate Duration A 17-Year Study in the South of Spain M. Bernabeu-Wittel, MD; J. Pacho´n, PhD; A. Alarco´n, PhD; L. F. Lo´pez-Corte´s, PhD; P. Viciana, PhD; M. E. Jime´nez-Mejı´as, PhD; J. L. Villanueva, PhD; R. Torronteras, PhD; F. J. Caballero-Granado, PhD Background: Fever of intermediate duration (FID), char- cluded, and MT was the cause in 6.7% of 926 cases of acterized by a febrile syndrome lasting from 7 to 28 days, FID. Insect bites were reported in only 3.8% of the cases is a frequent condition in clinical practice, but its epide- of MT previous to the onset of illness. Most cases (62.5%) miological and etiologic features are not well described. occurred in the summer and fall. A high frequency of rash Murine typhus (MT) is a worldwide illness; neverthe- (62.5%) was noted. Arthromyalgia (77%), headache less, to our knowledge, no studies describing its epide- (71%), and respiratory (25%) and gastrointestinal (23%) miological and clinical characteristics have been per- symptoms were also frequent. Laboratory findings were formed in the south of Spain. Also, its significance as a unspecific. Organ complications were uncommon (8.6%), cause of FID is unknown. but they were severe in 4 cases. The mean duration of fever was 12.5 days. Cure was achieved in all cases, al- Objective: To determine the epidemiological features, though only 44 patients received specific treatment. clinical characteristics, and prognosis of MT and, pro- spectively, its incidence as a cause of FID. Conclusions: Murine typhus is prevalent in the south of Spain and is a significant cause of FID. Clinical signs Design: Prospective study of cases of MT over 17 years are benign, but some patients may develop severe com- (1979-1995) and of all cases of FID treated in a tertiary plications. A high degree of clinical suspicion is re- teaching hospital in Seville, Spain. quired for diagnosis. Results: One hundred and four cases of MT were in- Arch Intern Med. 1999;159:872-876 URINE TYPHUS (MT), a 7 days,14 and fever of unknown origin zoonosis that is caused that lasts for more than 21 days.15-17 by Rickettsia typhi, oc- Fever that lasts from 7 to 28 days may be curs all over the world, classified as fever of intermediate dura- with endemic areas in tion (FID). This condition constitutes a North and South America, Southeast Asia, syndromic entity with well-defined etio- M 18 Africa, Australia, and some southern Eu- logic features. ropean countries.1-10 The importance of this The aim of the present study was to illness has been underestimated. It is more determine prospectively the incidence of frequent than is commonly believed and MT in patients with FID, as well as to de- represents a worldwide health prob- scribe their epidemiological, clinical, se- lem.11 Studies on its prevalence have shown rologic, and prognostic characteristics. that it also occurs in Spain.12,13 Sporadic cases have been reported in Seville, Huelva, RESULTS and Murcia,7-9 but, to our knowledge, no extensive studies have been per- One hundred four cases of MT were in- From the Service of Infectious formed to investigate its clinical and epi- cluded. Sixty-two cases occurred be- Diseases (Drs Bernabeu-Wittel, demiological characteristics. Therefore, its tween 1983 and 1995, representing 6.7% Pacho´n, Alarco´n, Lo´pez-Corte´s, real incidence is not known. of all patients with FID (n = 926). There Viciana, Jime´nez-Mejı´as, Febrile syndrome without a focal was a slight predominance of males (n = 57 Villanueva, and Caballero-Granado) and the condition is a common problem in out- [54.8%]) over females (n = 47 [45.2%]). Department of Microbiology patients who seek medical care in the com- The mean age was 37.9 years (age range, (Dr Torronteras), Hospital munity. Classically, there are 2 chrono- 12-81 years). The monthly distribution of Universitario Virgen del Rocı´o, logically distinct types of febrile syndrome: the cases is shown in the Figure; 62.5% Seville, Spain. fever of short duration that lasts for up to of the cases occurred in the summer. The ARCH INTERN MED/ VOL 159, APR 26, 1999 872 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 35 30 PATIENTS AND METHODS 30 28 25 The reference population included patients treated for FID at the Infectious Disease Unit of the Univer- 20 sity Hospital Virgen del Rocio in Seville, Spain, be- 16 tween 1983 and 1995. The hospital is a tertiary in- 15 No. of Cases stitution with 1474 adult beds, attending a population 9 10 of 640 000 persons, most (73.75%) of whom live in 7 urban areas. Included in the study were the patients 4 5 3 2 who fulfilled the diagnostic criteria of MT during this 1 1 2 1 period. Cases of MT that presented as FID between 0 1979 and 1982, when prospective etiologic studies JanFebMar Apr May Jun Jul Aug Sep Oct Nov Dec were not yet performed in all cases of FID, were also Months included. Fever of intermediate duration was de- Monthly distribution of cases of murine typhus. fined as a temperature higher than 38°C lasting 7 to 28 days in patients who remained without diagnosis or without findings that prompted a diagnostic proce- (19%) had seen rats at home, and only 4 (3.8%) re- dure after anamnesis, physical examination, hemo- ported insect bites in the days immediately previous to gram, serum creatinine determination, urinalysis, and radiography of the chest. the onset of fever. In all patients with FID, the following param- The patients with MT presented with the following eters were studied: hemoglobin level, white blood symptoms: cell (WBC) count, platelet count, erythrocyte sedi- Symptom No. (%) of Patients mentation rate, glycemia, urinary sediment, chest x- Fever 104 (100) ray film, and serologic studies of Brucella (rose of Arthromyalgia 81 (77.8) bengal and immunofluorescence antibody assay Headache 74 (71.1) [IFA]), Rickettsia conorii, R typhi, and Coxiella bur- Rash 65 (62.5) netii (IFA as well as agglutination against Proteus Odynophagia 31 (29.8) OX-19 and OX-2 between 1979 and 1990). In some Hepatomegaly 31 (29.8) cases, depending on the clinical features, proteinol- Cough/expectoration 26 (25) ogy; serologic studies for Leptospira, Legionella, Chla- Splenomegaly 25 (24) mydia, and Yersinia species, Toxoplasma gondii, Ep- Nausea, vomiting 24 (23) stein-Barr virus, and hepatitis B virus; tuberculin Diarrhea 6 (5.7) testing with2Uofpurified protein derivative using Somnolence 5 (4.8) trichloroacetic acid (PPD-RT23); and acid-fast stain- Adenopathies 2 (1.9) ing of sputum and urine samples were performed. The diagnostic criteria of MT were a compat- On physical examination, the most noteworthy finding ible clinical picture and serological confirmation by was rash, which was noted in 62.5% of the patients. The determination of IgG antibodies by IFA. Titers of 1: rash, which began around the fifth day after the onset of 512 or higher, or a 4-fold rise between the results of the illness (mean, 4.7 days; range, 2-12 days), was macu- 2 successive assays performed at least 14 days apart, lopapular, nonconfluent, and subtle, except in 3 cases, were considered diagnostic.7 For IFA, R typhi anti- in which it was petechial. It was distributed over the trunk gen for complement fixation test fixed with acetone and limbs, sparing the palms and soles. The mean dura- (Diagnostic Pasteur Laboratories, Marnes, la Co- tion of rash was 4 days (range, 1-12 days). quette, France) was used as a reagent until 1986, and Nine patients (8.6%) developed organ complica- R typhi antigen cultivated in Vero cells (bioMe´rieux Laboratories, Marcy-l’Eoile, France) was used as a re- tions, which were severe in 4 (3.8%). The mean age of agent from 1986 to 1995. these patients was 43 years, and none had any underly- Anemia was defined as a hemoglobin level lower ing illnesses. Five of them received specific treatment. than 117 g/L in females and lower than 130 g/L in There were 6 cases of pneumonitis, with infiltrates dem- males, leukocytosis as a WBC count higher than onstrated on the chest x-ray film; the pneumonitis was 10 3 109/L, leukopenia as a WBC count lower than interstitial in 3 cases, alveolar in 2 cases, and interstitial 5 3 109/L, and thrombocytopenia as a platelet count with pleuropericarditis and pulmonary thromboembo- 9 lower than 100 3 10 /L. To evaluate possible cross- lism in 1 case. One 79-year-old patient developed cer- reactivity between R typhi and Legionella bozemanii, ebellitis with ataxia, intention tremor, and adiadocho- 17 serum samples from patients with high titers of kinesis, with diffuse cerebral involvement demonstrated IgG against R typhi ($1:4096) were used. The IgG against L bozemanii (Wiga strain ATCC 35292) was on the electroencephalogram. The last 2 patients devel- determined by IFA. oped multiorgan failure, with hypotension and throm- bopenia in both cases; pneumonitis, hepatitis, and peri- carditis in the first one, and adult respiratory distress syndrome plus acute renal failure and disseminated in- yearly distribution of the cases is shown in Table 1. The travascular coagulation in the second one. percentage of cases from urban areas was 63.5%; the rest Only one patient had anemia (hemoglobin, 111 g/L). of the cases were from rural settings. Only 20 patients The WBC count was normal in 62% of the patients; 20% ARCH INTERN MED/ VOL 159, APR 26, 1999 873 ©1999 American Medical Association.