Bryceson, A

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Anthony Bryceson

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Medical Microbiology and Immunology

Current issues in the treatment of visceral leishmaniasis

LSHTM Research Online

Malik, AN; John, L; Bryceson, AD; Lockwood, DN (2006) Chang-ing pattern of visceral leishmaniasis, United Kingdom, 1985-2004.Emerging infectious diseases, 12 (8). pp. 1257-9. ISSN 1080-6040Downloaded from: http://researchonline.lshtm.ac.uk/7150/Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: Creative Commons Attribution Non-commercial No Derivativeshttp://creativecommons.org/licenses/by-nc-nd/2.5/Changing Patternof VisceralLeishmaniasis,United Kingdom,1985–2004Aeesha N.J. Malik,* Lawrence John,* Anthony D.M. Bryceson,* and Diana N.J. Lockwood*A 20-year (1985–2004) retrospective review of 39patients with imported visceral leishmaniasis found thattourism to Mediterranean countries and HIV infection wereassociated with visceral leishmaniasis. Diagnosis wasoften delayed. Treatment with liposomal amphotericin Bhas improved prognosis. Visceral leishmaniasis should bemade a reportable disease.Each year, 500,000 new cases of visceral leishmaniasis(VL) are reported worldwide. The number of cases andendemic foci for VL have increased during the past 2decades (1–4). These increases may be the result ofimproved detection and surveillance methods, or they maybe actual increases in numbers, possibly driven by increas-ing rates of HIV infection (5,6). VL is a well-recognizedbut uncommon imported disease in the United Kingdom,but it is not reportable, so information on its importation isincomplete. Data for this report (e.g., date of confirmationof infection, country where acquired, HIVstatus) were col-lated and supplied by the Travel Health SurveillanceSection of the Health Protection Agency, CommunicableDisease and Surveillance Centre, United Kingdom.The StudyUK patients with VL are often referred to the Hospitalfor Tropical Diseases, London, for confirmation of diagno-sis or treatment. We reviewed all cases of VL seen at thishospital from 1985 through 2004. Thirty-nine patientswere identified from our hospital database and laboratoryrecords, representing 83% of cases reported in the UnitedKingdom (Figure 1).The mean age of these patients was 36 years (range2–66 years); 4 patients were <15 years of age. Themale:female ratio was 2:1. Patients acquired visceral leish-maniasis while in the following areas: 30 (76.9%) inMediterranean countries (13 in Spain, 9 in Italy, 4 inGreece, 3 in Malta, 1 in Cyprus), 5 (12.8%) from Africa, 3(7.7%) from Asia, and 1 (2.6%) from South America.During the entire 20-year period, 55.5% of patients hadbeen tourists to these VL-endemic regions, and 44.5%were immigrants or refugees, but after 2000, all patientswere tourists. One third of the patients were HIV-antibodypositive. Two patients had significant immunosuppressionfrom other causes: 1 from chronic lymphatic leukemia and1 from immunosuppressive drugs received after kidneytransplantation.Time from onset of symptoms to diagnosis was 1–11months (mean 3 months). Diagnoses of VL were con-firmed by >1 method: microscopic identification ofamastigotes in tissue aspirates; histologic examination ofbiopsy material from bone marrow, liver, or spleen; sero-logic analysis; and PCR for leishmania DNA (7).Leishmania amastigotes were found in 32 bone marrowaspirates, 3 liver biopsy specimens, 2 splenic aspirates, and1 skin biopsy specimen. PCR to detect leishmania DNAhas been performed in this study since 1995 and was pos-itive in 7 of 11 cases. It was the method of confirmatorydiagnosis for 1 patient (performed on a bone marrow aspi-rate that had no visible amastigotes). Serum analysis forleishmania antibodies was performed on samples from 33patients; results were positive for all HIV-negative patientsand for 2 of 13 HIV-positive patients (Table 1).Before 1995, treatment of leishmaniasis involved sev-eral drugs, including sodium stibogluconate, paro-momycin, meglumine antimoniate, and pentamidine. Thelatter 2 were used for patients who received initial treat-ment outside the United Kingdom; within the UnitedKingdom, most (59%) patients were treated with sodiumstibogluconate. After 1995, liposomal amphotericinbecame the drug of choice and was used in 14 (83%) of 17patients. HIV status did not affect drug choice. Figure 2 shows the frequency of relapses with eachdrug treatment in our cohort. Of the 13 patients who had arelapse, 8 (53%) had HIV coinfection. Of the 13 who hadEmerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 8, August 2006 1257*Hospital for Tropical Diseases, London, United KingdomFigure 1. Number of visceral leishmaniasis (VL) cases, UnitedKingdom, 1985–2004 (data from Health Protection Agency).HIV coinfection, 8 (62%) had a relapse, compared with 7(27%) of the 26 HIV-negative patients who had a relapse.Two patients had other risk factors for relapse: 1 had had akidney transplant, and the other had chronic active hepati-tis B. Three patients who had relapses had no apparent riskfactors. Relapse occurred in 5 (33%) of 15 patients whoreceived sodium stibogluconate, compared with 1 (7%) of14 who received liposomal amphotericin as their initialdrug. At first, relapsed patients were treated with a combi-nation of sodium stibogluconate and allopurinol, whichwas unsuccessful in contrast with its reported success inKenya, or with amphotericin deoxycholate (8). HIV-infect-ed patients who had relapses received further treatmentwith liposomal amphotericin, usually successful, but 2became unresponsive to treatment. Miltefosine was used in2 patients with HIV coinfection who had relapses, butrelapses recurred, 1 while the patient was still receiving thedrug (9). Since 2000, pentamidine prophylaxis has beenused in 3 immunocompromised patients.Table 2 summarizes outcomes. The number of patientsin the final cure category excludes patients who had had arelapse. The 2 patients who refused treatment had HIVcoinfection; 1 died. After 1995, the final cure rateimproved and fewer patients required retreatment. The 3patients who died had advanced HIV disease; 1 had anadditional complication of liver failure secondary to hepa-titis C cirrhosis.ConclusionsThe data from this cohort show that VLis imported intothe United Kingdom at a constant rate, particularly in adultmale tourists to the Mediterranean, and that during the past20 years, HIV and VL had interacted strikingly. TheMediterranean VL-endemic zone accounts for only a smallproportion of VL cases globally, but it is a popular holidaydestination for the British, and tourism is driving the epi-demiology of the imported infection. In the past 5 years,we have seen no immigrants or refugees with VL. The datashow that high rates of tourism to an area of low endemic-ity for a parasitic disease can result in a substantial numberof imported cases.One third of our patients were immunocompromised.The highest rates of reported HIV coinfection worldwideare from Europe, where 85% of the cases are from thesouthwest; 71% of these are in intravenous drug users (2).HIV/VLcoinfection is a serious disease that has high deathrates, reflected by the 3 deaths in our cohort. Thesepatients had late-stage HIV disease and additional coexist-ing conditions. HIV/VL-coinfected patients have higherrelapse rates and decreased life expectancy. Highly activeantiretroviral therapy for HIV is decreasing the numbers ofthese coinfections and improving survival rates (10,11).The mean time from symptom onset to diagnosis was 3months. This delay resulted mainly from physicians’ fail-ure to consider the diagnosis, although a few cases weredifficult to diagnose. For 2 patients, initial microscopicexamination of bone marrow biopsy results did not showamastigotes; reinspection showed scarce amastigotes. Foranother patient, serologic results by direct agglutinationwere negative when performed early in the course of dis-ease but positive when repeated. The low sensitivity ofserologic tests for HIV-infected patients in this cohort con-firms that serologic tests cannot be relied on as a means ofexcluding VL in HIV-infected patients.Our cohort shows a rise and fall in the proportion ofcases of HIV/VL coinfection, starting in the early 1990s,rising to a peak of 50% during 1993–1996, and thendecreasing, possibly because of greater use of highlyactive antiretroviral therapy. Official UK data on VL areincomplete and do not accurately reflect trends. VLremains an imported disease in the United Kingdom and isoften associated with HIV infection. We suggest that a for-DISPATCHES1258 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 8, August 2006Figure 2. Initial drug treatment for patients with visceral leishmani-asis and number of relapses.  Na stibo, stibogluconate; Meg, meg-lumine antimoniate; Paro, paromomycin; Pent, pentamidine; Amb,ambisome; Amp, amphotericin.mal notification system for visceral leishmaniasis in theUnited Kingdom, as elsewhere in Europe, would be bene-ficial for monitoring trends and health planning (12). Ourdata also show the importance of looking at rare importeddiseases over a long period so that emerging risk factorscan be identified. These data also highlight the usefulnessof having 1 center that deals with unusual infections,where expertise in diagnosis and management can be builtup and maintained.Acknowledgments We thank Maggie Armstrong for help with the hospital data-base and our colleagues in the Department of Parasitology, par-ticularly Kalim Lalloo, for their sustained interest and theprovision of parasitologic data. Rob Miller gave valuable help incollecting information from HIV-coinfected patients. Dr Malik was senior house officer at the Hospital forTropical Diseases when she became interested in VL. She is nowpursuing a career in ophthalmology.References1. Desjeux P. The increase in risk factors for leishmaniasis worldwide.Trans R Soc Trop Med Hyg. 2001;95:239–43.2. Gabutti G, Balestra G, Fkego G, Crovari P. Visceral leishmaniasis inLiguria, Italy. Lancet. 1998;351:1136.3.  Punda-Polic V, Sardelic S, Bradaric N. Visceral leishmaniasis insouthern Croatia. Lancet. 1998;351:188.4. World Health Organization. Leishmaniasis and leishmania/HIV co-infection. WHO report on global surveillance of epidemic-proneinfectious diseases 2000. Report no. WHO/CDS/CSR/ISR/2000.1.Geneva: The Organization; 2000.5. Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P, etal. Visceral leishmaniasis: current status of control, diagnosis, andtreatment, and a proposed research and development agenda. LancetInfect Dis. 2002;2:494–501.6.  Alvar J, Canavate C, Guiterrez-Solar B, Jimenez M, Laguna F,Lopez-Velez R, et al. Leishmania and human immunodeficiencyvirus co-infection: the first 10 years. Clin Microbiol Rev.1997;10:298–319.7. Noyes HA, Reyburn H, Bailey W, Smith D. A nested PCR basedschizodeme method for identifying Leishmania kinetoplast minicircleclasses directly from clinical samples and its application to the studyof the epidemiology of Leishmania tropica in Pakistan. J ClinMicrobiol. 1998;36:2877–81.8. Chunge CN, Gachini G, Muigai R, Wasunna K, Rashid JR, ChulayJD, et al. Visceral leishmaniasis in response to antimonial drugs. III.Successful treatment using a combination of sodium stibogluconateplus allopurinol. Trans R Soc Trop Med Hyg. 1985;79:715–8.9. Sindermann H, Engel KR, Fischer C, Bommer W. Oral miltefosinefor leishmaniasis in immunocompromised patients: compassionateuse in 39 patients with HIV co-infection. Clin Infect Dis.2004;39:1520–3.10. Pagliano P, Rossi M, Rescigno C, Altieri S, Coppola MG, GramicciaM, et al. Mediterranean visceral leishmaniasis in HIVnegative adults:a retrospective analysis of 64 consecutive cases (1995–2001). JAntimicrob Chemother. 2003;52:264–8.11. Russo R, Laguna F, Lopez-Velez R, Medrano FJ, Rosenthal E,Cacopardo B, et al. Visceral leishmaniasis in those infected with HIV:clinical aspects and other opportunistic infections. Ann Trop MedParasitol. 2003;97:99–105.12. Harms G, Schonian G, Feldmeier H. Leishmaniasis in Germany.Emerg Infect Dis. 2003;9:872–5.Address for correspondence: Diana N.J. Lockwood, Hospital for TropicalDiseases, London, UK WC1E 6AU; email: diana.lockwood@lshtm.ac.ukVisceral Leishmaniasis, United KingdomEmerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 8, August 2006 1259

A nested PCR based schizodeme method for identifying Leishmania kinetoplast minicircle classes directly from clinical samples and its application to the study of the epidemiology of Leishmania tropica in Pakistan.

Leishmania and human immunodeficiency virus co-infection: the first 10 years. Clin Microbiol Rev.

Leishmaniasis in Germany. Emerg Infect Dis. 2003;9:872–5. Address for correspondence: Diana N.J. Lockwood, Hospital for Tropical Diseases, London,

Mediterranean visceral leishmaniasis in HIVnegative adults: a retrospective analysis of 64 consecutive cases (1995–2001). J Antimicrob Chemother.

Oral miltefosine for leishmaniasis in immunocompromised patients: compassionate use in 39 patients with HIV co-infection. Clin Infect Dis.

Organization. Leishmaniasis and leishmania/HIV coinfection. WHO report on global surveillance of epidemic-prone infectious diseases 2000. Report no. WHO/CDS/CSR/ISR/2000.1. Geneva: The Organization;

The increase in risk factors for leishmaniasis worldwide. Trans R Soc Trop Med Hyg.

Visceral leishmaniasis in

Visceral leishmaniasis in response to antimonial drugs. III. Successful treatment using a combination of sodium stibogluconate plus allopurinol. Trans R Soc Trop Med Hyg.

Visceral leishmaniasis in southern Croatia.

Visceral leishmaniasis in those infected with HIV: clinical aspects and other opportunistic infections. Ann Trop Med Parasitol.

Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis.

Current issues in the treatment of visceral leishmaniasis.

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Current issues in the treatment of visceral leishmaniasis.

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