AJTMH Transactions of the Royal Society of Tropical Medicine and Hygiene
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Am. J. Trop. Med. Hyg., 68(1), 2003, pp. 89-91
Copyright © 2003 by The American Society of Tropical Medicine and Hygiene

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POSSIBLE SCRUB TYPHUS COINFECTIONS IN THAI AGRICULTURAL WORKERS HOSPITALIZED WITH LEPTOSPIROSIS

GEORGE WATT, KRISADA JONGSAKUL, AND CHUANPIT SUTTINONT
Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; Department of Internal Medicine, Maharaj Nakhon Ratchasima Hospital, Nakhon Ratchasima, Thailand


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Possible coinfections with Orientia tsutsugamushi, the causative agent of scrub typhus, were prospectively evaluated in rice farmers hospitalized with leptospirosis in Northeast Thailand. Of 22 adults with leptospirosis diagnosed by the microscopic agglutination test, 9 also had serologic evidence of scrub typhus. Of 9 individuals with possible coinfections, 5 had signs or symptoms typical of scrub typhus and atypical of leptospirosis. Patients who appeared to have mixed infections had significantly higher median platelet counts and significantly lower median serum bilirubin and creatinine concentrations (P < 0.05, Mann-Whitney U test) than did individuals with leptospirosis alone. One patient with serologic evidence of scrub typhus and leptospirosis was treated only with penicillin, to which scrub typhus is not sensitive. Respiratory distress worsened during therapy, and the patient died of respiratory failure. Physicians should consider the possibility of scrub typhus infection in leptospirosis patients who respond poorly to treatment or who have atypical disease manifestations.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Leptospirosis and scrub typhus are common infections in Thailand and have been associated with rice farming.1,2 Rice farmers could become infected with leptospirosis and Orientia tsutsugamushi, the causative agent of scrub typhus. Mixed infections have not been reported, however, perhaps because diagnostic tests for these 2 diseases are not readily available in rural Thailand.

A 46-year-old male Thai rice farmer presented to the hospital in Nakhon Ratchasima, northeastern Thailand, with typical features of Weil’s disease, the severe form of leptospirosis. A cigarette burn–like lesion characteristic of a scrub typhus eschar was noted on physical examination. Serodiagnostic tests supported the clinical suspicion that the patient had acute leptospirosis and probably also was infected with O. tsutsugamushi. This finding led us to evaluate prospectively possible scrub typhus coinfections in patients hospitalized with leptospirosis.


MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients. Informed consent from patients was obtained, and human experimentation guidelines of the U.S. Army Medical Research and Materiel Command and Nakhorn Ratchasima Maharaj Hospital were followed in the conduct of clinical research. The study was conducted during the rainy season months of October and November 1997, at Maharat Hospital, Nakhorn Ratchasima, a tertiary care referral hospital in Northeast Thailand. Hospitalized patients >=18 years old in whom leptospirosis was thought likely by history, physical examination, and admission laboratory test results were evaluated. Leptospirosis was suspected if there was a history of contact with water and severe myalgia or muscle tenderness. Jaundice, conjunctival suffusion, or increased serum creatinine concentration also raised the suspicion of leptospirosis.3

Serology. Serodiagnostic testing for leptospirosis was performed at the Royal Tropical Institute, World Health Organization collaborating Center for Reference and Research on Leptospirosis, Amsterdam, the Netherlands. Acute and convalescent sera from suspected cases were tested by the microscopic agglutination test, the gold standard serodiagnostic assay for leptospirosis.4 A panel of 20 strains representative for Thailand was used as antigen.5 The serogroups (serovars) included were Australis (bangkok, bratislava), Autumnalis (rachmati, new), Ballum (ballum), Bataviae (bataviae), Cani-cola (canicola), Celledoni (celledoni), Cynopteri (cynopteri), Djasiman (djasiman), Fainei (hurstbridge), Grippotyphosa (grippotyphosa), Icterohaemorrhagiae (copenhageni, ictero-haemorrhagiae), Javanica (poi), Louisiana (saigon), Pomona (pomona), Pyrogenes (pyrogenes), Sejroe (hardjo, sejroe), and Semaranga (patoc). Leptospirosis was diagnosed if there was a 4-fold rise in titer against any 1 serovar or any single titer was >=1:320.6 O. tsutsugamushi infection was diagnosed using a dot blot immunoassay of proven sensitivity and specificity.7 The cutoff titer for this test is set high such that a positive test result indicates active disease rather than residual antibody from past infection. A positive dot blot immunoassay correlates with IgG titers of >=1:1,600 or IgM titers of >=1:400, or both.


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 22 adults infected with leptospirosis, 19 were men (Table 1Go). All patients were agricultural workers, and 20 of 22 (91%) worked in rice fields. Every patient reported contact with flooded streets or rice fields during the month before admission to the hospital. Compared with patients with leptospirosis only, patients with serologic evidence of scrub typhus in addition had significantly (Mann-Whitney U test) higher median platelet counts (96,000 and 183,000, P = 0.049), significantly lower median serum bilirubin concentrations (12.4 and 3.3 mg/dl, P = 0.002), and significantly lower median serum creatinine concentrations (5.4 and 1.3 mg/dl, P = 0.018).


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TABLE 1
Admission characteristics of patients with serologic evidence of leptospirosis alone or serologic evidence of leptospirosis and scrub typhus. The standard deviation is shown in brackets for mean values and the range for median values
 
Scrub typhus coinfection was suspected serologically in 9 patients, but coinfection could not be documented definitively because O. tsutsugamushi was not isolated from patient samples. Of these 9 patients, 4 had a 4-fold rise in leptospirosis antibody titer and 5 had a reciprocal titer >320 in a single sample. In the 13 individuals with leptospirosis only, 7 patients had a 4-fold rise in leptospirosis antibody titer, and 6 had a reciprocal titer >320 in a single sample. Of the 9 dually infected patients, 5 had signs or symptoms typical of scrub typhus and atypical of leptospirosis. Three patients had es-chars, which are pathognomonic when seen by a physician experienced in scrub typhus diagnosis. One patient had a rash typical of scrub typhus, and 1 of these individuals gave a history of hearing loss coincident with the onset of fever. This is an uncommon but specific symptom of scrub typhus (G. Watt, unpublished data) and has not been reported with leptospirosis.

One patient with an apparent double infection was begun on penicillin for presumed leptospirosis but deteriorated during treatment and developed respiratory distress. Scrub typhus was suspected, and a change in antibiotics from penicillin to intravenous chloramphenicol was followed by clinical recovery. Another similar patient with serologic evidence of scrub typhus succumbed to respiratory failure. This patient received high-dose intravenous penicillin G (3.2 million U every 4 hours) but was not given antibiotics active against O. tsutsugamushi because clinical and laboratory findings did not suggest scrub typhus.


DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
To our knowledge, this is the first published report suggesting that coinfection with leptospirosis and scrub typhus is not rare; 41% of agricultural workers with acute leptospirosis had serologic evidence of O. tsutsugamushi infection. Of the patients, 91% were rice farmers, an occupational group known to be at high risk for scrub typhus and leptospirosis in Thailand.1,8 Causative agents were not obtained, and the possibility that patients had 2 distinct, yet temporally close infections cannot be excluded with certainty. The serologic evidence of dual infection was supported by physical findings and results from routine hematology and biochemistry. Of the 9 patients with serologic evidence of dual infections, 5 had signs atypical of leptospirosis alone and suggestive of active, acute scrub typhus.

Scrub typhus and leptospirosis are common, serious infections that can be fatal if not treated. One of the patients in this series presented with leptospirosis and was treated appropriately with high-dose intravenous penicillin. Her condition deteriorated rapidly, however, and she died with adult respiratory distress syndrome, the most common cause of death from O. tsutsugamushi infection.9 Perhaps a fatal outcome could have been avoided had antibiotics active against scrub typhus been administered.

A mixed infection should be considered in patients with either leptospirosis or scrub typhus who are responding poorly to treatment. Even if diagnosed, however, a severe, combined infection with leptospirosis and scrub typhus is difficult to treat. Intravenous penicillin is the treatment of choice for severe leptospirosis,10 but O. tsutsugamushi is not susceptible to this antibiotic.11 Patients in rural Asia with severe scrub typhus generally are treated with intravenous chloramphenicol, which would not be expected to be effective against leptospirosis. Clinicians probably would opt to treat severe, dual infections with penicillin combined with either chloramphenicol or doxycycline even though this violates the interdiction against combining a bactericidal with a bacteriostatic antibiotic. Mild cases of either disease generally respond well to oral doxycycline.11,12

It is difficult to make physicians aware of leptospirosis/ scrub typhus coinfections. The clinical manifestations of these 2 diseases can be nonspecific, and fever, headache, myalgia, and conjunctival suffusion occur in both. Rapid diagnostic tests exist but are not generally available in geographic areas where the diseases are common. Mixed infections should be kept in mind in trials of new diagnostic tests and in febrile travelers returning from endemic areas. Leptospirosis is found worldwide, whereas scrub typhus occurs only in Asia, the South Pacific, and northern Australia. Leptospirosis and scrub typhus occur in travelers returning from endemic areas, and both have been associated with ecotourism.11,13

Received March 6, 2002. Accepted for publication September 25, 2002.

Acknowledgments: The authors thank the staff of the Department of Internal Medicine, Maharaj Hospital, for referring patients and providing essential help in conducting this study. Rudy Hartskeerl, Henk L. Smits, and the staff at the Royal Tropical Institute, the Netherlands, kindly provided microscopic agglutination test facilities. Disclaimer: The opinions or assertions in this report are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army.

Reprint requests: George Watt, HIV Interaction Section, Department of Retrovirology, AFRIMS, APO AP 96546, E-mail: wattgh{at}thai.amedd.army.mil

Authors’ addresses: George Watt and Krisada Jongsakul, Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, APO AP 96546, USA. Chuanpit Suttinont, Department of Internal Medicine, Maharaj Nakhon Ratchasima Hospital, 49 Chang-Phuek Road, Amphur Muang, Nakhon Ratchasima 30000, Thailand.


REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Tangkanakul W, Tharmaphornpil P, Plikaytis BD, Bragg S, Poonsuksombat D, Choomkasien P, Kingnate D, Ashford DA, 2000. Risk factors associated with leptospirosis in northeastern Thailand. Am J Trop Med Hyg 63: 204–208.[Abstract]
  2. Tanskul P, Linthicum KJ, 1999. Redescription of Leptotrombidium (Leptotrombidium) imphalum (Acari: Trombiculidae), with observations on bionomics and medical importance in northern Thailand. J Med Entomol 36: 88–91.[ISI][Medline]
  3. Watt G, 1997. Leptospirosis. Curr Opin Infect Dis 10: 149–152.
  4. Levett PN, 2001. Leptospirosis. Clin Microbiol Rev 14: 296–326.[Abstract/Free Full Text]
  5. van Crevel R, Speelman P, Gravekamp C, Terpstra WJ, 1994. Leptospirosis in travelers. Clin Infect Dis 19: 132–134.[Medline]
  6. Smits HL, Ananyina YV, Chereshsky A, Dancel L, Lai-A-Fat RF, Chee HD, Levett PN, Masuzawa T, Yanagihara Y, Muthusethupathi MA, Sanders EJ, Sasaki DM, Domen H, Yersin C, Aye T, Bragg SL, Gussenhoven GC, Goris MG, Terpstra WJ, Hartskeerl RA, 1999. International mulitcenter evaluation of the clinical utility of a dipstick assay for detection of Leptspira-specific immunoglobulin M antibodies in human serum specimens. J Clin Microbiol 37: 2904–2909.[Abstract/Free Full Text]
  7. Watt G, Strickman D, Kantipong P, Jongsakul K, Paxton H, 1998. Performance of a dot blot immunoassay for the rapid diagnosis of scrub typhus in a longitudinal case series. J Infect Dis 77: 800–802.
  8. Trishnananda M, Vasuvat C, Harinasuta C, 1964. Investigation of scrub typhus in Thailand. J Trop Med Hyg 67: 215–219.[Medline]
  9. Tsay RW, Chang FY, 1998. Serious complications in scrub typhus. J Microbiol Immunol Infection 31: 240–244.[Medline]
  10. Watt G, Padre LP, Tuazon ML, Calubaquib C, Santiago E, Ranoa CP, Laughlin LW, 1988. Placebo-controlled trial of intravenous penicillin for severe and late leptospirosis. Lancet 1: 433–435.[ISI][Medline]
  11. Silpapojakul K, 1997. Scrub typhus in the Western Pacific region. Ann Acad Med Singapore 26: 794–800.[Medline]
  12. McClain JB, Ballou WR, Harrison SM, Steinweg DL, 1988. Doxycycline therapy for leptospirosis. Ann Intern Med 100: 696–698.
  13. Stone SC, McNutt E, 2000. Update: Outbreak of acute febrile illness among athletes participating in Eco-Challenge-Sabah 2000-Borneo, Malaysia, 2000. Ann Emerg Med 38: 83–84.



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