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Murine typhus and leptospirosis as causes of acute undifferentiated fever, Indonesia.

Fever is one of the main reasons for seeking medical attention in Indonesia. The cause of fever usually remains obscure because of limited laboratory diagnostic facilities and expertise in performing laboratory confirmation. Favorable environmental conditions mean that both rickettsiosis rickettsiosis /rick·ett·si·o·sis/ (ri-ket?se-o´sis) infection with rickettsiae.

Infection with Rickettsia bacteria.
 and leptospirosis leptospirosis (lĕp'təspīrō`sĭs), febrile disease caused by bacteria of the genus Leptospirae. The disease occurs in dogs, cattle, pigs, sheep, goats, and horses and is transmissible to humans.  are considered endemic in Indonesia and may result in clinically indistinguishable cases of acute undifferentiated fever (AUF n. 1. A changeling or elf child, - that is, one left by fairies; a deformed or foolish child; a simpleton; an oaf. ). Serosurveys conducted on Java, Sumatra, and islands in eastern Indonesia identified antibodies to Rickettsia rickettsia (rĭkĕt`sēə), any of a group of very small microorganisms, many disease-causing, that live in vertebrates and are transmitted by bloodsucking parasitic arthropods such as fleas, lice (see louse), and ticks.  typhi (murine typhus murine typhus
A comparatively mild, acute, endemic form of typhus caused by the microorganism Rickettsia typhi, transmitted from rats to humans by fleas and characterized by fever, headache, and muscular pain. Also called endemic typhus.
), to Orientia tsutsugamushi Orientia tsutsugamushi

obligately intracellular bacteria that cause scrub typhus in humans and many small feral mammals, especially rodents and occasionally dogs.
 (scrub typhus scrub typhus: see rickettsia; typhus. ), and to members of the spotted fever group rickettsia (SFGR) in healthy persons (1-3). In addition, several investigations reported leptospirosis as cause of AUF in Indonesia (4,5).

Murine typhus and leptospirosis are likely to share routes of transmission in an urban setting where rats are abundant. The main vector for R. typhi is the Asiatic rat flea (Xenopsylla cheopsis). Humans usually become infected when R. typhi-infected flea feces contaminates excoriated skin or is inhaled. Leptospirosis is mainly spread by rats and other small mammals, which shed the bacteria through their urine into the environment. Humans are infected through mucous membranes, conjunctivae Conjunctivae
The clear membranes that line the inside of the eyelids and cover the white part (sclera) of the eyeballs.

Mentioned in: Exophthalmos, Kawasaki Syndrome
, or abraded skin.

The clinical features of mild leptospirosis and murine typhus are nonspecific nonspecific /non·spe·cif·ic/ (non?spi-sif´ik)
1. not due to any single known cause.

2. not directed against a particular agent, but rather having a general effect.


. Generally, patients with murine typhus exhibit fever, headache, and a rash, although the latter is often absent. Renal failure, jaundice jaundice (jôn`dĭs, jän`–), abnormal condition in which the body fluids and tissues, particularly the skin and eyes, take on a yellowish color as a result of an excess of bilirubin. , and hemorrhages are the classic symptoms of severe leptospirosis; fever, headache, and myalgia myalgia /my·al·gia/ (mi-al´jah) muscular pain.myal´gic

epidemic myalgia  see under pleurodynia.

 may be the only exhibited symptoms of mild disease. Dual infections with murine typhus are reported to occur in Southeast Asia and may complicate treatment and clinical course (6,7). In this study, we attempted to find evidence for acute rickettsial disease, leptospirosis, and dual infections among patients with AUF in Indonesia, where risk factors for both diseases are present.

The Study

The study was based in Semarang, a large harbor city in central Java. Consecutive outpatients were recruited at 2 primary healthcare centers and hospitalized patients at a governmental referral center (Dr. Kariadi University Hospital, Department of Internal Medicine). All eligible AUF patients ([greater than or equal to]5 years of age) were included who met the following criteria: fever [greater than or equal to]38[degrees]C (central) for <14 days with no apparent other disease. After informed consent was obtained, a blood sample was taken. A convalescent-phase sample was drawn after [approximately equal to]14 days. The study was approved by the local medical ethical committee.

A specific microimmunofluorescent antibody (IFA Immunofluorescent assay (IFA)
A blood test sometimes used to confirm ELISA results instead of using the Western blotting. In an IFA test, HIV antigen is mixed with a fluorescent compound and then with a sample of the patient's blood.
) assay for Rickettsia spp. was performed in Marseille, France, by using whole-cell antigens of O. tsutsugamushi, R. japonica japonica (jəpŏn`əkə): see quince; camellia. , R. heilongjiangensis, R. slovaca, R. honei, R. conorii subsp. indica, Rickettsia ATI (ATI Technologies Inc., Markham Ontario, A leading manufacturer of graphics chips and display adapters. Founded in 1985 by K. Y. Ho, Benny Lau and Lee Lau, ATI chips and boards are widely used by OEMs. , R. helvetica, R. felis, R. typhi, and R. prowazekii . The assay results were considered positive when 1) antibody titers were >256 for immunoglobulin (Ig) G and [greater than or equal to]64 for IgM, or 2) seroconversion seroconversion /se·ro·con·ver·sion/ (-con-ver´zhun) the change of a seronegative test from negative to positive, indicating the development of antibodies in response to immunization or infection.  was observed, or 3) a >4-fold increase in titers between the acute-phase and the convalescent-phase serum specimen was detected. Serologic se·rol·o·gy  
n. pl. se·rol·o·gies
1. The science that deals with the properties and reactions of serums, especially blood serum.

 analysis for leptospirosis was performed in Semarang, Indonesia. Crosschecks and PCR PCR polymerase chain reaction.

polymerase chain reaction

Polymerase chain reaction (PCR) 
 were performed in Amsterdam, the Netherlands. Convalescent-phase samples were screened with the LeptoTek Dri Dot (bioMerieux, Marcy l'Etoile, France). All positive samples were tested by the microscopic agglutination test (MAT) and IgG ELISA (8).

Additionally, a real-time PCR specifically targeting the secY gene of pathogenic Leptospira spp. (9) was performed on all samples. For the MAT, a panel of 31 serovars was used containing 28 pathogenic and 3 nonpathogenic serovars. For patient samples tested by ELISA ELISA (e-li´sah) Enzyme-Linked Immuno-Sorbent Assay; any enzyme immunoassay using an enzyme-labeled immunoreactant and an immunosorbent.

 or MAT, a titer [greater than or equal to]320 on a single sample was considered positive; also considered positive were those samples that showed sero-conversion or a [greater than or equal to]4-fold increase in titers between paired samples, as well as any patient sample with a positive PCR, irrespective of the serologic result. All samples were run in parallel.

From February 2005 through February 2006, 137 AUF patients were included: 67 hospitalized patients and 70 outpatients. A convalescent-phase sample was available for 106 (77%) patients. The main symptoms were headache (85%), myalgia (70%), nausea (64%), cough (44%), and abdominal pain (38%).

Murine typhus and leptospirosis were found to cause AUF in this clinical series (online Appendix Table, available from In total, 9 patients (7%) had evidence of an acute infection with R. typhi; none showed a rash. Murine typhus could be diagnosed in 6 (9%) of 67 hospitalized patients; 3 (4%) of 70 outpatients had acute murine typhus. Another 9 (7%) patients showed inconclusive R. typhi serologic results. One patient showed evidence of a past infection with R. typhi (IFA IgG/IgM titer 128/0 in both serum specimens). Evidence for acute infection with O. tsutsugamushi or SFGR was not found.

Leptospirosis was diagnosed in 13 (10%) of 137 patients; results for 2 of these patients were positive only by PCR. Eleven leptospirosis patients were recruited in the hospital; 2 patients were recruited outside the hospital. Consequently, the percentage of AUF caused by leptospirosis in hospitalized patients was 16% and in outpatients 3%. The most frequently identified serogroup by MAT was Bataviae (5 cases). No dual infections were detected; however, 3 (23%) leptospirosis patients showed titers in the R. typhi IFA assay.


We report that murine typhus and leptospirosis are important causes of AUF in Semarang, Indonesia. A previous study from rural Thailand identified both diseases in 2.8% and 36.9% of AUF cases, respectively (6,7). In Vientiane, the capital of Laos, R. typhi was reported to cause fever in 9.6% of investigated persons, results that closely resembling our data (10). Unfortunately, leptospirosis was not investigated.

In the present study, we expected leptospirosis to be a cause of AUF because the Dr. Kariadi University Hospital admits [approximately equal to]50 severe cases each year. These cases were not included in the study because of the high clinical suspicion of leptospirosis on admission with jaundice, azotemia azotemia /az·o·te·mia/ (az?o-te´me-ah) uremia; an excess of urea or other nitrogenous compounds in the blood.

See uremia.
, and/ or bleeding. A definite diagnosis of murine typhus and leptospirosis co-infections could not be made, but in 3 cases this scenario was plausible. We did not find evidence for scrub typhus, which we expected, because O. tsutsugamushi transmission occurs primarily in rural areas (11). Although SFGR have been reported in Southeast Asia and proof for their presence in Indonesia is accumulating (2,12), these rickettsia were not identified as a cause of AUF in the present study.

From an epidemiologic point of view, Semarang, Indonesia, seems to encompass environmental circumstances that are prerequisites for R. typhi and leptospirosis transmission. Previous studies have shown that murine typhus is particularly prevalent in tropical port cities where rats are abundant (13,14). In the Indonesian urban situation, R. rattus and R. norvegicus rats are likely to be the main hosts harboring R. typhi-infected X. cheopsis fleas (12,15). These rats are also likely to be the maintenance hosts for pathogenic Leptospira spp. in Indonesia. In fact, the identified serogroups are commonly associated with rats.

Although serologic analysis might be hampered by cross-reactions and test sensitivity issues, we believe that our data are representative for the area. The chosen cutoff values are unlikely to cause false-positive results in a disease-endemic setting. In regard to leptospirosis serologic analysis, we used a wide panel for the MAT. This panel included serovars recommended by the World Health Organization and serovars that were previously isolated in Indonesia. Moreover, most serogroups were represented in our panel, and cross-reactions are likely to detect missing serovars.

Because of nonspecific clinical features, both diseases are difficult to diagnose on clinical grounds only. Misdiagnosis mis·di·ag·no·sis
n. pl. mis·di·ag·no·ses
An incorrect diagnosis.

 can lead to aberrant use of antimicrobial drugs and other pharmaceuticals. Therefore, rapid, cheap, and reliable diagnostic tests are needed to support clinical decision making.


We thank S.M.H. Faradz and personnel at the Center for Biomedical Research, Semarang, Indonesia, and the residents of the Department of Internal Medicine, Dr. Kariadi Hospital, Semarang, for their help and assistance during the study. We are also grateful to A.A. Ahmed for performing the leptospirosis PCR.

Dr Gasem is internist and acting head of Division of Infectious Disease, Department of Internal Medicine, Dr. Kariadi University Hospital. His research interests are typhoid fever typhoid fever acute, generalized infection caused by Salmonella typhi. The main sources of infection are contaminated water or milk and, especially in urban communities, food handlers who are carriers.  and leptospirosis.


(1.) Richards AL, Soeatmadji DW, Widodo MA, Sardjono TW, Yanuwiadi B, Hernowati TE, et al. Seroepidemiologic evidence for murine murine /mu·rine/ (mur´en) pertaining to, derived from, or characteristic of mice or rats.

 and scrub typhus in Malang, Indonesia. Am J Trop Med Hyg. 1997;57:91-5.

(2.) Richards AL, Ratiwayanto S, Rahardjo E, Kelly DJ, Dasch GA, Fryauff DJ, et al. Serologic evidence of infection with ehrlichiae and spotted fever group rickettsiae among residents of Gag Island, Indonesia. Am J Trop Med Hyg. 2003;68:480-4.

(3.) Van Peenen PF, Koesharjono C, See R, Bourgeois AL, Irving GS. Antibodies against murine typhus in sera from Indonesians. Trans R Soc Trop Med Hyg. 1977;71:297-9. DOI (Digital Object Identifier) A method of applying a persistent name to documents, publications and other resources on the Internet rather than using a URL, which can change over time. : 10.1016/0035-9203-(77)90103-1

(4.) Light RH, Nasution R, Van Peenen PF. Leptospirosis in febrile febrile /feb·rile/ (feb´ril) pertaining to or characterized by fever.

Of, relating to, or characterized by fever; feverish.
 hospital patients in Djakarta. Southeast Asian J Trop Med Public Health. 1971;2:493-5.

(5.) Laras K, Cao BV, Bounlu K, Nguyen TK, Olson JG, Thongchanh S, et al. The importance of leptospirosis in Southeast Asia. Am J Trop Med Hyg. 2002;67:278-86.

(6.) Ellis RD, Fukuda MM, McDaniel P, Welch K, Nisalak A, Murray CK, et al. Causes of fever in adults on the Thai-Myanmar border. Am J Trop Med Hyg. 2006;74:108-13.

(7.) Suttinont C, Losuwanaluk K, Niwatayakul K, Hoontrakul S, Intaranongpai W, Silpasakorn S, et al. Causes of acute, undifferentiated, febrile illness in rural Thailand: results of a prospective observational study. Ann Trop Med Parasitol. 2006;100:363-70. DOI: 10.1179/136485906X112158

(8.) Terpstra WJ, Ligthart GS, Schoone GJ. Serodiagnosis serodiagnosis /se·ro·di·ag·no·sis/ (-di?ag-no´sis) diagnosis of disease based on serologic tests.serodiagnos´tic

n. pl.
 of human leptospirosis by enzyme-linked-immunosorbent-assay (ELISA). Zentralbl Bakteriol A. 1980;247:400-5.

(9.) Victoria B, Ahmed A, Zuerner RL, Ahmed N, Bulach DM, Quinteiro J, et al. Conservation of the S10-spc-alpha locus within otherwise highly plastic genomes provides phylogenetic phy·lo·ge·net·ic
1. Of or relating to phylogeny or phylogenetics.

2. Relating to or based on evolutionary development or history.
 insight into the genus Leptospira. PLoS One. 2008;3:e2752. DOI: 10.1371/journal. pone See pwn. .0002752

(10.) Phongmany S, Rolain JM, Phetsouvanh R, Blacksell SD, Soukkhaseum V, Rasachack B, et al. Rickettsial infections and fever, Vientiane, Laos. Emerg Infect Dis. 2006;12:256-62.

(11.) Watt G, Parola P. Scrub typhus and tropical rickettsioses Rickettsioses

Often severe infectious diseases caused by several diverse and specialized bacteria, the rickettsiae and rickettsia-like organisms. The best-known rickettsial diseases infect humans and are usually transmitted by parasitic arthropod vectors.
. Curr Opin Infect Dis. 2003;16:429-36. DOI: 10.1097/00001432-200310000-00009

(12.) Ibrahim IN, Okabayashi T, Ristiyanto, Lestari EW, Yanase T, Muramatsu Y, et al. Serosurvey of wild rodents for rickettsioses (spotted fever, murine typhus and Q fever) in Java Island, Indonesia. Eur J Epidemiol. 1999;15:89-93. DOI: 10.1023/A:1007547721171

(13.) Richards AL, Rahardjo E, Rusjdi AF, Kelly DJ, Dasch GA, Church CJ, et al. Evidence of Rickettsia typhi and the potential for murine typhus in Jayapura, Irian Jaya, Indonesia. Am J Trop Med Hyg. 2002;66:431-4.

(14.) Dupont HT, Brouqui P, Faugere B, Raoult D. Prevalence of antibodies to Coxiella burnettii, Rickettsia conorii, and Rickettsia typhi in seven African countries. Clin Infect Dis. 1995;21:1126-33.

(15.) Jiang J, Soeatmadji DW, Henry KM, Ratiwayanto S, Bangs MJ, Richards AL. Rickettsia felis in Xenopsylla cheopis, Java, Indonesia. Emerg Infect Dis. 2006;12:1281-3.

DOI: 10.3201/eid1506.081405

M. Hussein Gasem, [1] Jiri F.P. Wagenaar, [1] Marga Marga can refer to:
  • Marga (Indian Philosophy)
  • Marga, a commune in Caraş-Severin County, Romania
  • Magga, one of the Four Noble Truths, in Buddhism
  • Marga (Batak), a family name in Batak society
  • Efraín Abdiel Alveo a.k.a.
 G.A. Goris, Mateus S. Adi, Bambang B. Isbandrio, Rudy A. Hartskeerl, Jean-Marc Rolain, Didier Raoult, and Eric C.M. van Gorp

[1] These authors equally contributed to this article.

Address for correspondence: Jiri F.P. Wagenaar, Department of Internal Medicine (9B), Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands; email:

Author affiliations: Diponegoro University, Semarang, Indonesia (M.H. Gasem, M.S. Adi, B.B. Isbandrio); Slotervaart Hospital, Amsterdam, the Netherlands (J.F.P. Wagenaar, E.C.M. van Gorp); Royal Tropical Institute, Amsterdam (M.G.A. Goris, R.A. Hartskeeri); and Universite de la Mediterranee, Marseille, France (J.M. Rolain, D. Raoult)
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Title Annotation:DISPATCHES
Author:Gasem, M. Hussein; Wagenaar, Jiri F.P.; Goris, Marga G.A.; Adi, Mateus S.; Isbandrio, Bambang B.; Ha
Publication:Emerging Infectious Diseases
Article Type:Report
Geographic Code:4EUFR
Date:Jun 1, 2009
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