• 1

    Sulzer AJ, Sulzer KR, Cantella RA, Colichon H, Latorre CR, Welch M, 1978. Study of coinciding foci of malaria and leptospirosis in the Peruvian Amazon area. Trans R Soc Trop Med Hyg 72 :76–83.

    • Search Google Scholar
    • Export Citation
  • 2

    Ravindran B, Sahoo PK, Dash AP, 1998. Lymphatic filariasis and malaria: concomitant parasitism in Orissa, India. Trans R Soc Trop Med Hyg 92 :21–23.

    • Search Google Scholar
    • Export Citation
  • 3

    Graham SM, Walsh AL, Molyneux EM, Phiri AJ, Molyneux ME, 2000. Clinical presentation of non-typhoidal Salmonella bacteraemia in Malawian children. Trans R Soc Trop Med Hyg 94 :310–314.

    • Search Google Scholar
    • Export Citation
  • 4

    Levett PN, Branch SL, Edwards CN, 2000. Detection of dengue infection in patients investigated for leptospirosis in Barbados. Am J Trop Med Hyg 62 :112–114.

    • Search Google Scholar
    • Export Citation
  • 5

    Flannery B, Pereira MM, Velloso L de F, Carvalho C de C, de Codes LG, Orrico G de S, Dourado CM, Riley LW, Reis MG, Ko AI, 2001. Referral pattern of leptospirosis cases during a large urban epidemic of dengue. Am J Trop Med Hyg 65: 657–663.

    • Search Google Scholar
    • Export Citation
  • 6

    Kudesia G, Christie P, Walker E, Pinkerton I, Lloyd G, 1988. Dual infection with Leptospira and hantavirus (letter). Lancet 1 :1397.

  • 7

    Markotic A, Kuzman I, Babic K, Gagro A, Nichol S, Ksiazek TG, Rabatic S, Dekaris D, 2002. Double trouble: hemorrhagic fever with renal syndrome and leptospirosis. Scand J Infect Dis 34 :221–224.

    • Search Google Scholar
    • Export Citation
  • 8

    Levi GC, 1998. Management of opportunistic infections in HIV(+) patients: contrasts between Europe and South America. Braz J Infect Dis 2 :118–127.

    • Search Google Scholar
    • Export Citation
  • 9

    Flatau E, Reichman N, Elias M, Raz R, 2000. Malaria and Borrelia co-infection. J Travel Med 7 :98–99.

  • 10

    Magill AJ, 1998. Fever in the returned traveler. Infect Dis Clin North Am 12 :445–469.

  • 11

    Smits HL, Hartskeerl RA, Terpstra WJ, 2000. International multi-centre evaluation of a dipstick assay for human leptospirosis. Trop Med Int Health 5 :124–128.

    • Search Google Scholar
    • Export Citation
  • 12

    Effler PV, Bogard AK, Domen HY, Katz AR, Higa HY, Sasaki DM, 2002. Evaluation of eight rapid screening tests for acute leptospirosis in Hawaii. J Clin Microbiol 40 :1464–1469.

    • Search Google Scholar
    • Export Citation
  • 13

    Levett PN, 2001. Leptospirosis. Clin Microbiol Rev 14 :296–326.

  • 14

    Faine S, 1988. Leptospirosis. Turano A, ed. Laboratory Diagnosis of Infectious Diseases: Principles and Practice. New York: Springer-Verlag.

  • 15

    Vinetz JM, 2001. Leptospirosis. Curr Opin Infect Dis 14 :527–538.

  • 16

    Panaphut T, Domrongkitchaiporn S, Thinkamrop B, 2002. Prognostic factors of death in leptospirosis: a prospective cohort study in Khon Kaen, Thailand. Int J Infect Dis 6 :52–59.

    • Search Google Scholar
    • Export Citation
  • 17

    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, 1998. Am J Trop Med Hyg 63 :204–208.

    • Search Google Scholar
    • Export Citation
  • 18

    Niwattayakul K, Homvijitkul J, Khow O, Sitprija V, 2002. Leptospirosis in northeastern Thailand: hypotension and complications. Southeast Asian J Trop Med Public Health 33 :155–160.

    • Search Google Scholar
    • Export Citation

 

 

 

 

CO-INFECTION WITH MALARIA AND LEPTOSPIROSIS

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  • 1 Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; Brooke Army Medical Center, Fort Sam Houston, San Antonio, Texas: Veterinary Command Food Analysis and Diagnostic Laboratory, Fort Sam Houston, San Antonio, Texas; Kwai River Christian Hospital, Sangkhlaburi, Kanchanaburi, Thailand; Walter Reed Army Institute of Research, Silver Spring, Maryland

Malaria and leptospirosis are both common in the tropics. Simultaneous infections are possible, although not previously reported. We report two cases of malaria from an area of Thailand on the Thailand-Myanmar border with compelling serologic evidence of simultaneous acute leptospirosis. One was a case of infection with Plasmodium falciparum with acute and convalescent microscopic agglutination test (MAT) titers for Leptospira serovar icterohaemorrhagiae of 1:200 and 1:1,600, respectively. The other was a case of infection with P. vivax that seroconverted to a titer of 1:3,200 for Leptospira serovar bataviae. Additionally, there were five probable cases of leptospirosis with patent malaria parasitemia (three P. falciparum and two P. vivax) detected. Management of dual infections is complicated by their similar clinical presentations, and because the confirmatory diagnosis of malaria is readily available as opposed to that of leptospirosis. Treatment focusing on malaria mono-infections instead of dual infections could result in a delay of specific therapy for leptospirosis and possible consequences of serious complications.

INTRODUCTION

Malaria and leptospirosis are cosmopolitan infections with overlapping geographic distributions, especially in the tropics. Their co-foci have been suggested by a seroepidemiologic study in the Peruvian Amazon.1 Simultaneous infections are likely, although, to our knowledge, have not previously reported. Co-infections of malaria with filariasis,2 non-typhoidal Salmonella bacteremia,3 dengue,4,5 hantavirus,6,7 human immunodeficiency virus,8 and Borrelia9 have been reported. The similar clinical presentations of acute malaria, leptospirosis, and other undifferentiated fevers make discrimination on clinical grounds difficult.10 We report seven cases with clinical and laboratory evidence of co-infection with malaria and leptospirosis in western Thailand.

MATERIALS AND METHODS

Between June 1999 and March 2002, 613 patients were enrolled in a study to determine the specific etiology of febrile illnesses in residents of Sangkhlaburi District in Kanchanaburi Province, on the Thailand-Myanmar border. Patients ≥ 20 years old presenting with acute fever (within 72 hours) to the Kwai River Christian Hospital in Sangkhlaburi, Thailand were eligible for the study. Evaluation included a medical history, physical examination, and routine clinical laboratory tests. Blood specimens were obtained on presentation and at convalescence 3–4 weeks later. This study was reviewed and approved by the Thai Ministry of Public Health and the Walter Reed Army Institute of Research. All subjects provided written informed consent for participation and sample donation.

Sera were screened for leptospirosis by a dot–enzyme-linked immunosorbent assay (ELISA) (INDX Multi-test DipS-Ticks®; PanBio-INDX, Baltimore, MD) for the detection of Leptospira-specific total immunoglobulin G (a dot intensity score of 0–1 = negative, 1+ = borderline, and 2–4 = positive) and by an ELISA (PanBio, Ltd., Brisbane, Queensland, Australia) for IgM (positive cut-off value of 11 PanBio units is recommended by the manufacturer but based on our experience using the assay in this population, a more stringent cut-off value of 18 PanBio units was applied to improve specificity). These assays are sensitive and have the advantages of their ease of use.11,12 Results were not available to affect care by the clinician. Paired sera from 96 patients (including 18 with malaria), which were suspicious of leptospirosis based on these screening tests or clinical findings, were sent for a confirmatory microscopic agglutination test (MAT) at the Veterinary Command Food Analysis and Diagnostic Laboratory. A standard MAT was performed using a battery of 24 serovars from 20 serogroups common for Asia.

Clinical case description for leptospirosis is characterized by fever, headache, chills, myalgia, conjunctival suffusion, and, less frequently, meningitis, rash, jaundice, or renal insufficiency. Laboratory criteria for a confirmed diagnosis are 1) the isolation of Leptospira from a clinical specimen, or 2) a four-fold or greater increase in Leptospira microagglutination titer between acute-phase and convalescent-phase serum specimens obtained two or more weeks apart and studied at the same laboratory, or 3) demonstration of Leptospira in a clinical specimen by immunofluorescence. Case classifications are 1) probable: a clinically compatible case with supportive serologic findings (i.e., a Leptospira microagglutination titer ≥ 200 in one or more serum specimens) and 2) confirmed: a clinically compatible case that is laboratory confirmed.13 We have applied an agglutination titer ≥ 800 instead of ≥ 200 (as probable acute leptospirosis) to our case series. An increased cut-off value has been suggested for populations with possibly high background exposure to leptospires.14

RESULTS

Forty paired specimens were considered MAT positive for leptospirosis, seven with malaria. The other 11 malaria cases were MAT negative. These 18 patients were divided into those with confirmed leptospirosis and malaria co-infection (two cases), those with probable leptospirosis and malaria co-infection (five cases), and those with malaria-only infection (11 cases) (Table 1). Both patients in the confirmed co-infection group clearly met the criterion for acute leptospirosis. The five probable cases had either acute or convalescent or both MAT titers ≥ 1:800. The malaria-only group did not meet our stricter definition of a positive MAT result.

All seven co-infection cases were men with a median age of 33 years (range = 20–38). The median age was 34 years (range = 20–58) among the 11 with malaria mono-infection, four of whom were women. Most patients lived in poor socioeconomic conditions, and/or had occupations such as rice farming and rubber tapping, known to be high-risk conditions for zoonotic and vector-borne diseases.

Fever, chill, headache, and myalgia were the most common symptoms among all of our patients, but jaundice was not present. Hepatomegaly (5 cm below costal margin) was detected in a case of probable co-infection (patient 4). Dysuria was present in both the co-infection cases (2 of 7) and the malaria-only cases (2 of 11). No clinical finding allowed classification of the co-infection group from the malaria mono-infection group. As shown in Table 1, the presence of co-infection did not have an impact on the level of parasitemia.

Patients with the co-infection had significantly higher white blood cell counts than the malaria-only patients (median = 7,300/μL versus 4,600/μL; P = 0.0132, by Wilcoxon rank-sum test). On average, our patients had subnormal levels of platelets, with the malaria-only group showing a more depressed level (66,000/μL) than the co-infection group (120,400/μL; P = 0.0326, by t-test). Elevated levels of γ-glutamyltransferase (> 150 units/L; normal = 8–78 units/L) and/or alanine aminotransferase (> 100 units/L; normal = 13–61 units/L in men and 3–42 units/L in women) were more frequently observed in the co-infection group (3 of 7 versus 1 of 11). Both co-infection cases (patient 1 and 2) required four days of hospitalization. Their relatively low-density parasitemia suggested that leptospirosis was predominantly responsible for their clinical presentation. With the exception of two additional cases, both malaria-only cases with relatively high parasitemia (patients 10 and 11), all other patients in our series were treated on an outpatient basis. Overall, our observations suggested a more severe clinical presentation associated with co-infection than with malaria mono-infections. All hematologic and biochemical alterations returned to their normal or nearly normal levels at follow-up.

DISCUSSION

Our observation provides compelling evidence for leptospirosis-malaria co-infection in this Thailand-Myanmar border community and raises dual issues concerning its diagnosis. First, leptospirosis is difficult to diagnose on the spot and diagnostic tools are usually unavailable in remote settings. Second, it is common practice in a malaria-endemic area that if an acutely febrile patient is found to be malaria-positive, malaria is naturally assumed as the sole cause of the fever. Failure to recognize acute leptospirosis co-infection means a delay in the initiation of its proper therapy and possibly ensuing severe complications such as Weil’s syndrome (jaundice and renal failure), pulmonary hemorrhage, and uveitis.15 No severe complications were observed among our cases. Case fatality rates of as high as 1–14% have been reported in hospital series.15,16 However, most cases of leptospirosis do not receive medical attention, are undiagnosed or untreated, and mostly result in self-recovery.

The high IgM levels during the acute phase in the confirmed co-infection cases (patients 1 and 2) with the parallel negative MAT results illustrate the known limitation of the MAT in the early detection of agglutinating antibodies.13 New, accurate, and rapid techniques may help in improving diagnostic practice of leptospirosis in areas where they are most needed.11

No isolation of leptospires was attempted in this study because the primary objective was febrile disease surveillance and leptospirosis had not been realized a priori as a prevalent zoonotic disease in this border region. Leptospirosis in Thailand is known to be largely endemic in the northeastern part of the country.16–18 Attempts to culture leptospires will be planned for the future phase of this study.

Confirmation of co-infections with leptospirosis and malaria warrants careful diagnostic evaluation and presents a therapeutic dilemma among febrile patients in Sangkhlaburi. In the case of P. falciparum, artesunate-doxycycline therapy, one of the regimens of choice for this region of Thailand known for its high prevalence of multidrug-resistant malaria, will cover both diseases. For P. vivax, and in places where doxycycline is not routinely used for the treatment of P. falciparum malaria, prescription of doxycycline for a case with any index of suspicion should be considered.

Table 1

Laboratory findings and treatment regimens for the patients with malaria-leptospirosis co-infection (confirmed and probable) and those with malaria mono-infection

Patient group and subject numberMalaria smear*Microscopic agglutination test reciprocal titer acute/convalescence†Leptospira-specific IgM (PanBio unit)‡ acute/convalescenceLeptospira-specific total Ig (dipstick intensity score)§ acute/convalescenceTreatment
* Asexual malaria parasites/microliter on presentation; Pf = Plasmodium falciparum; Pv = P. vivax; Pm = P. malariae.
† Terms in parentheses are serovars of Leptospira.
‡ By PanBio enzyme-linked immunosorbent assay kit, recommended cut-off ≥ 11 PanBio units, cut-off used for this study ≥ 18 PanBio units.
§ By INDX Multi-test Dip-S-Tick® (0–1-negative; 1+-borderline positive; ≥2-positive).
¶ Doxycycline was added because leptospirosis was clinically suspected.
# Initially misdiagnosed as a mixed infection of P. falciparum and P. vivax.
Co-infection
1Pf 37,380/μL200/1,600 (icterohaemorrhagiae)40.2/36.23/3Artesunate, doxycycline
2Pv 26/μL0/3,200 (bataviae)30.0/29.52/4Chloroquine, doxycycline¶
Probable coinfection
3Pv 20,368/μL800/400 (grippotyphosa)17.2/17.71/2Chloroquine
4Pv 1,860/μL800/800 (bratislava)40.6/32.91+/2Chloroquine
5Pf 146/μL800/1,600 (bataviae)21.6/20.33/3Artesunate, mefloquine
6Pf 361,180/mcL800/800 (pyrogenes)<11/<112/2Artesunate, doxycycline
7Pf 10,272/μL800/800 (grippotyphosa)21.2/15.33/4Artesunate, mefloquine
800/800 (hardjo)
Malaria only
8Pf 3,936/μLNegative22.0/12.21+/1Artesunate, doxycycline
9Pv 8,844/μL100/100 (each for bratislava, autumnalis, icterohaemorrhagiae)<11/<112/2Artesunate, mefloquine#
10Pf 44,240/μL100/100 (pyrogenes)<11/<113/3Artesunate, mefloquine
11Pf 25,404/μL200/200 (bataviae)8.4/22.32/1.5Artesunate, mefloquine
12Pv 6,608/μL0/100 (cynopteri)6.2/13.71/4Artesunate, mefloquine#
13Pf 14,004/μL200/0 (bratislava)<11/<111+/2Azithromycin, quinine
14Pv 281/μLNegative<11/<112/2Chloroquine
15Pf 1,276/μL200/200 (bratislava)<11/<112/3Artesunate, mefloquine
100/100 (autumnalis)
16Pf 36/μL200/200 (bratislava)<11/<112/2Artesunate, mefloquine
200/400 (autumnalis)
17Pf 36,448/μLNegative<11/<113/1+Artesunate, doxycycline
18Pm 1,489/μLNegative<11/<113/2Amoxicillin, chloroquine

Authors’ addresses: Chansuda Wongsrichanalai, R. Scott Miller, Wilson J. Liao, and Amy L. Pickard, Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok 10400, Thailand. Clinton K. Murray, Infectious Disease Service, Brooke Army Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, TX 78234-6200. Michael Gray, Veterinary Command Food Analysis and Diagnostic Laboratory, Fort Sam Houston, TX 75234-6232. Philip McDaniel, Kwai River Christian Hospital, Sangkhlaburi, Kanchanaburi 71240, Thailand. Alan J. Magill, Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500.

Acknowledgments: We are grateful to the Fever Study Team of the Armed Forces Research Institute of Medical Sciences and the staffs of the Kwai River Christian Hospital and the Vector Borne Diseases Control Unit No. 9 (Sangkhlaburi) for their support.

Financial support: This study was supported by the U.S. Department of Defense Global Emerging Infections Surveillance and Response System (DoD-GEIS).

Disclaimer: The opinions or assertions contained herein are those of the authors and should not be construed as reflecting the official positions of the U.S. Army or U.S. Department of Defense.

REFERENCES

  • 1

    Sulzer AJ, Sulzer KR, Cantella RA, Colichon H, Latorre CR, Welch M, 1978. Study of coinciding foci of malaria and leptospirosis in the Peruvian Amazon area. Trans R Soc Trop Med Hyg 72 :76–83.

    • Search Google Scholar
    • Export Citation
  • 2

    Ravindran B, Sahoo PK, Dash AP, 1998. Lymphatic filariasis and malaria: concomitant parasitism in Orissa, India. Trans R Soc Trop Med Hyg 92 :21–23.

    • Search Google Scholar
    • Export Citation
  • 3

    Graham SM, Walsh AL, Molyneux EM, Phiri AJ, Molyneux ME, 2000. Clinical presentation of non-typhoidal Salmonella bacteraemia in Malawian children. Trans R Soc Trop Med Hyg 94 :310–314.

    • Search Google Scholar
    • Export Citation
  • 4

    Levett PN, Branch SL, Edwards CN, 2000. Detection of dengue infection in patients investigated for leptospirosis in Barbados. Am J Trop Med Hyg 62 :112–114.

    • Search Google Scholar
    • Export Citation
  • 5

    Flannery B, Pereira MM, Velloso L de F, Carvalho C de C, de Codes LG, Orrico G de S, Dourado CM, Riley LW, Reis MG, Ko AI, 2001. Referral pattern of leptospirosis cases during a large urban epidemic of dengue. Am J Trop Med Hyg 65: 657–663.

    • Search Google Scholar
    • Export Citation
  • 6

    Kudesia G, Christie P, Walker E, Pinkerton I, Lloyd G, 1988. Dual infection with Leptospira and hantavirus (letter). Lancet 1 :1397.

  • 7

    Markotic A, Kuzman I, Babic K, Gagro A, Nichol S, Ksiazek TG, Rabatic S, Dekaris D, 2002. Double trouble: hemorrhagic fever with renal syndrome and leptospirosis. Scand J Infect Dis 34 :221–224.

    • Search Google Scholar
    • Export Citation
  • 8

    Levi GC, 1998. Management of opportunistic infections in HIV(+) patients: contrasts between Europe and South America. Braz J Infect Dis 2 :118–127.

    • Search Google Scholar
    • Export Citation
  • 9

    Flatau E, Reichman N, Elias M, Raz R, 2000. Malaria and Borrelia co-infection. J Travel Med 7 :98–99.

  • 10

    Magill AJ, 1998. Fever in the returned traveler. Infect Dis Clin North Am 12 :445–469.

  • 11

    Smits HL, Hartskeerl RA, Terpstra WJ, 2000. International multi-centre evaluation of a dipstick assay for human leptospirosis. Trop Med Int Health 5 :124–128.

    • Search Google Scholar
    • Export Citation
  • 12

    Effler PV, Bogard AK, Domen HY, Katz AR, Higa HY, Sasaki DM, 2002. Evaluation of eight rapid screening tests for acute leptospirosis in Hawaii. J Clin Microbiol 40 :1464–1469.

    • Search Google Scholar
    • Export Citation
  • 13

    Levett PN, 2001. Leptospirosis. Clin Microbiol Rev 14 :296–326.

  • 14

    Faine S, 1988. Leptospirosis. Turano A, ed. Laboratory Diagnosis of Infectious Diseases: Principles and Practice. New York: Springer-Verlag.

  • 15

    Vinetz JM, 2001. Leptospirosis. Curr Opin Infect Dis 14 :527–538.

  • 16

    Panaphut T, Domrongkitchaiporn S, Thinkamrop B, 2002. Prognostic factors of death in leptospirosis: a prospective cohort study in Khon Kaen, Thailand. Int J Infect Dis 6 :52–59.

    • Search Google Scholar
    • Export Citation
  • 17

    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, 1998. Am J Trop Med Hyg 63 :204–208.

    • Search Google Scholar
    • Export Citation
  • 18

    Niwattayakul K, Homvijitkul J, Khow O, Sitprija V, 2002. Leptospirosis in northeastern Thailand: hypotension and complications. Southeast Asian J Trop Med Public Health 33 :155–160.

    • Search Google Scholar
    • Export Citation

Author Notes

Reprint requests: Chansuda Wongsrichanalai, Parasitic Diseases Program, U.S. Naval Medical Research Unit No. 2, Kompleks P2M/PLP-LITBANGKES, Jalan Percetakan Negara No. 29, Jakarta 10560, Indonesia, Telephone: 62-21-421-4458 extension 1230, Fax: 62-21-424-4507, E-mail: chansuda@namru2.med.navy.mil
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