Murine Typhus As a Common Cause of Fever of Intermediate Duration a 17-Year Study in the South of Spain

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. Pachoń, PhD; A. Alarcoń, PhD; L. F. Lo´pez-Corte´s, PhD; P. Viciana, PhD; M. E. Jimeńez-Mejıás, 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, prospectively, 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% Pachoń, Alarcoń, Lo´pez-Corte´s, real incidence is not known. of all patients with FID (n = 926). There Viciana, Jimeńez-Mejıás, 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 Rocıó, 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

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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 ϫ 109/L, leukopenia as a WBC count lower than interstitial in 3 cases, alveolar in 2 cases, and interstitial 5 ϫ 109/L, and thrombocytopenia as a platelet count with pleuropericarditis and pulmonary thromboembo- 9 lower than 100 ϫ 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 (Ն1:4096) 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 thrombopenia 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%

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 1. Yearly Percentage of Murine Typhus (MT) in Patients Who Were Treated for Fever of Intermediate Duration (FID)

Year Total No. 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 of Cases FID, No. 45 75 99 53 53 79 101 113 70 72 53 67 46 926 MT, No. (%) 8 (17.8) 6 (8) 7 (7) 1 (1.9) 5 (9.4) 5 (6.3) 7 (7) 5 (4.4) 6 (8.5) 2 (2.7) 2 (3.7) 4 (6) 4 (8.7) 62 (6.7)

of the patients had leukocytosis; and 18% of the patients had leukopenia. In 18.1% of the patients, lympho- Table 2. Cross-reactivity Between Rickettsia typhi and cytosis (Ͼ50% of total leukocytes) was present, and 19% Legionella bozemanii (Wiga Strain) Demonstrated by Immunofluorescence Antibody Assay of Serum Samples had thrombopenia. The erythrocyte sedimentation rate From Patients With Murine Typhus and High IgG Titers was higher than 20 mm/h (range, 5-111 mm/h) in 59.6% Against R typhi of the patients. Similarly, liver enzyme levels (aspartate aminotransferase and alanine aminotransferase) were el- Patient No. R typhi L bozemanii (Wiga Strain) evated in 67.3% of the patients, reaching hepatitis val- 1 1:1024 0 ues (aspartate aminotransferase, Ͼ185 IU/L; alanine 2 1:4096 0 aminotransferase, Ͼ200 IU/L) in 25% of them. Alka- 3 1:4096 0 line phosphatase levels were increased in 25% of the 4 1:16 384 1:128 patients. 5 1:8192 1:4096 The IFA method was used to establish the diagno- 6 1:4096 1:256 sis in all cases. Seventy-six cases (73%) were diagnosed 7 1:4096 0 8 1:16 384 1:1024 by a single titer of 1:512 or higher. The other 28 cases 9 1:2048 1:512 (27%) were diagnosed by a 4-fold increase of the initial 10 1:16 384 1:1024 titer. Agglutinations with Proteus OX-19 were per- 11 1:4096 0 formed in 88 cases, showing titers of 1:160 or higher in 12 1:4096 1:512 64 (72.7%) of them. 13 1:16 384 1:256 Twenty-two patients (21.1%) met serologic crite- 14 1:16 384 1:8192 15 1:16 384 1:8192 ria of boutonneuse fever (IFA IgG titer, Ն1:512 or sero- 16 1:8192 1:512 conversion). In 19 cases, the titers reached against R cono- 17 1:8192 1:512 rii were always lower than those reached against R typhi (14 differed in 2 or more dilutions, and 5 differed in 1 dilution). In the other 3 cases, the same titers were reached against both Rickettsia species. In these, the diagnosis duration, which lasts for up to 7 days and is often of vi- of MT was established clinically (absence of tache noire ral origin,14 and fever of unknown origin, which lasts for and distribution of rash). In all cases, antibodies against more than 21 days.15-17 In our environment, FID is caused C burnetii were nonreactive. by systemic infections in 69.5% of the cases (Q fever, 21%; Of the 17 serum samples with high antibody titers brucellosis, 19%; MT, 8.5%; boutonneuse fever, 6.9%; and against R typhi, 5 (29.4%) showed no antibodies against mononucleosis syndrome, 8.9%), localized infections in L bozemanii, and 12 demonstrated a positive reaction 7.7%, vasculitis in 1.6%, neoplasias in 0.2%, and miscel- against L bozemanni. However, titers reached against laneous causes in 12.4%. In 18.8% of the cases, the fever R typhi were always higher, and titers differed by fewer disappears without a specific diagnosis having been than 2 dilutions in only 3 cases (Table 2). established.18 Forty-four patients (42.3%) received treatment: 40 During the prospective period of study of FID in the received doxycyline hyclate, 2 received chlorampheni- south of Spain (1983-1995), MT was diagnosed in 62 cases col, 1 received ciprofloxacin, and 1 received sulfamethoxa- (6.7% of 926 cases of FID), which established the pres- zole-trimethoprim. The total duration of the fever was ence of this illness in Spain and supported previous ob- 12.5 ± 3.9 (mean ± SD) days (range, 8-27 days), with a servations over shorter periods.7,8 However, because of mean duration of 9.9 days prior to the first visit and 2.6 the benign outcome of this process and the characteris- days after the start of treatment. The total duration was tics of this study (which was hospital based), its real in- 12.7 days in untreated patients and 12.4 days in treated cidence in the community is not yet known. In Sala- patients. Cure was achieved in all cases. manca, in the north of Spain, the seroprevalence of R typhi was 12.8% among people living in urban and rural ar- 12 COMMENT eas. Data from the the southwestern area of Spain are scarce. In Seville, in 1984, the seroprevalence in per- Fever of intermediate duration is defined as a fever that sons older than 10 years using Rickettsia prowazekii lasts 7 to 28 days, in which no cause is identified after antigen was 0.6% to 2.0%,13 and, to our knowledge, no the initial evaluation, including physical examination, he- investigations have been carried out on rodents. mogram, plasma creatinine determination, urinalysis, and The monthly distribution of the cases in the pres- chest radiography. Chronologically, in clinical practice, ent study is similar to that reported by other investiga- this frequent syndrome is found between fever of short tors,1-10 most cases occurring in the summer and fall.

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 Murine typhus was also found to be predominantly ur- others.1-10 The patients with severe complications had no ban (63.5% of the cases) in this study. underlying illnesses; their mean age was similar to that of patients whose illness was noncomplicated; and none had received sulfonamides, factors that have been asso- N RECENT years, there has been a decrease in the ciated with a higher incidence of complications and se- number of cases diagnosed. This decrease may verity in rickettsiosis.37-39 be attributed to (1) campaigns of rat control that The easiest and most specific procedure for diag- were carried out in Seville between 1984 and nosis of MT is the detection of specific IgG antibodies 1986; (2) a better knowledge by general physi- by IFA.4,7,10 The results of Proteus OX-19 agglutination cians of the frequency of MT and other rickettsial in- were positive in only 72% of the cases. This low sensi- I 10,12,13 fections in our area, illnesses that are mainly treated tivity, along with its lower specificity, makes it a tech- outside the hospital; and (3) the introduction and fre- nique of poor value. quent use of fluoroquinolones in the outpatient set- Boutonneuse fever is endemic in Spain.12,40 Cross- ting,19-22 antibiotics that have a proven activity against Rick- reactions between R typhi and R conorii on IFA have been ettsia species.23-25 described previously.12,40,41 In the present study, they were Epidemiological data were not particularly useful for relatively frequent (21.1% of the patients). These cross- establishing diagnosis. In 81% of the cases, the source reactions may represent an important diagnostic prob- of transmission was not identified. Only 3.8% of the pa- lem for patients with FID in areas like ours, in which both tients involved remembered an insect bite in the days pre- Rickettsia species are present, and the problem becomes vious to the onset of illness. Because insect bites and the even more complicated when we consider the wide and presence of rodents often go unnoticed, their absence does unspecific clinical features of R typhi and R conorii in- not preclude the diagnosis. Two studies have shown that, fections. However, the rash of boutonneuse fever is also in some areas of the United States, cat fleas (Ctenoce- maculopapular, but the elements are bigger, more papu- phalides felis) and opossums are carriers of R typhi.26,27 lar, and often confluent, and it affects the palms and soles. However, opossums are not part of the fauna in Spain. Moreover, boutonneuse fever often (75% of cases) presents Other studies have demonstrated serologic evidence of with tache noire, a necrotic pustule in the site of the tick R typhi infection in cats28,29 but whether cats can serve bite.38,40 We used these clinical data to support the diag- as a reservoir for R typhi is still unknown.29 We do not nosis of MT in the 8 cases in which the antibody titers know if another reservoir or vector may be involved in against both Rickettsia were the same or differed in only the transmission of R typhi in Spain. 1 dilution. In these cases, new techniques in develop- Rickettsia felis (previously called ELB agent) has also ment, such as latex agglutination and enzyme immuno- been identified in C felis and opossums.30-32 Using poly- assays,42 and advances in molecular biology, such as polymerase chain reaction/restriction fragment length polymerase chain reaction,43 could represent qualitative morphism and partial sequencing of selected polymer- improvements because of their high specificity and be- ase chain reaction products, it was shown that more than cause they can lead to early diagnosis. 50% of the cat fleas obtained from vertebrate hosts, in- Immunofluorescence antibody assay has been used cluding dogs and a bobcat, were infected with R felis.29 to demonstrate a cross-reaction between R typhi and The pathogenetic role of this new agent has been dem- L bozemanii in serum samples obtained from patients with onstrated in a patient with an acute febrile illness mim- febrile syndrome.44,45 In the present study, we found cross- icking MT.33 In Spain, the presence of R felis has never reactivity in 12 of 17 serum samples with a high titer of been demonstrated. IgG anti–R typhi, but in all cases, the IgG titer against The clinical features in our study were similar to L bozemanii was between 1 and 7 dilutions lower than those in other studies,1-10 except that the frequency of rash that reached against R typhi. Therefore, it did not repre- was higher (62.5% of the cases), the rash was noncon- sent a diagnostic problem. fluent and subtle in all but 3 patients, and the palms and Only 44 patients received specific treatment for MT. soles were not affected at all. Characteristics and fre- This small number can be explained by the frequent un- quency of rash are important data that may be clues to specific clinical picture of MT, the subtleness of the signs the diagnosis of MT. Respiratory (25%) and digestive that could make the physicians suspect MT, and the com- symptoms (23%) were also frequent in our study, but oc- mon benign presentation. A high degree of suspicion and curred less often than in other studies.1 The analytical the use of knowledge-based medical decision support sys- alterations, which were nonspecific, were the result of tems have recently led to a reduction in the number of the infection of endothelial cells in multiple organs,34 lead- days from initial visit to diagnosis.46 ing to a diversity of clinical and laboratory findings. Both The duration of fever after treatment was 2.6 days, anemia, which was infrequent and mild, and thrombo- similar to the 3 days previously reported.4 The total du- cytopenia, which was present in only 19% of the pa- ration of fever was the same in treated and untreated patients, occurred less frequently than in other studies.1 tients. This lack of difference in fever duration may be However, we did find a frequent increase in hepatic en- explained by the relative lateness of the first visit (mean, zyme levels (in 67.3% of the cases). 9.9 days) and therefore the late start of specific treat- Murine typhus is generally a benign illness, but it ment. Another reason may be that physicians pre- may result in potentially severe complications.34-36 The scribed empirical treatment most frequently in patients frequency of such complications in the present study was with the most severe symptoms. Some authors have shown 3.8% (4 cases), a percentage similar to that reported by that early and effective treatment against R typhi may con-

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 siderably reduce morbidity and mortality.1,4 However, be- Fernańdez MV. Consumo extrahospitalario de antiinfecciosos en dosis diaria cause the treatment was not randomized in our study, definida por mil habitantes y dıá. Aten Primaria. 1996;18:357-361. 21. Yań˜ezGo´mez P. Grado de utilizacioń de anti-infecciosos de accioń siste´mica en we can draw no conclusions about the reduction of mor- un a´rea de salud rural de Asturias: comparacioń de los anõs 1994 y 1995. Aten bidity and mortality with specific and early treatment. Primaria. 1997;19:243-249. In summary, MT, which is prevalent in the south 22. Llop JC. Evolucioń en la utilizacioń de antibacterianos en Catalunã: impacto de of Spain, is a significant cause of FID and is usually a be- los nuevos fa´rmacos comercializados. Aten Primaria. 1997;19:230-236. nign illness. A high degree of clinical suspicion is nec- 23. Raoult D, Gallais H, de Micco P, Casanova P. 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