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Am. J. Trop. Med. Hyg., 81(4), 2009, pp. 555558 doi:10.4269/ajtmh.2009.

09-0268 Copyright 2009 by The American Society of Tropical Medicine and Hygiene

Case Report: Co-Infection of Leishmania (Viannia) braziliensis and HIV: Report of a Case of Mucosal Leishmaniasis in Cochabamba, Bolivia
Faustino Torrico, Rudy Parrado, Rosario Castro, Carla Jimena Marquez, Mary Cruz Torrico, Marco Solano, Richard Reithinger, and Ana Lineth Garca*
Facultad de Medicina, Universidad Mayor de San Simn, Cochabamba, Bolivia; Laboratorio de Referencia Departamental, Servicio Departamental de Salud, Cochabamba, Bolivia; Infectologa, Hospitalario Viedma, Cochabamba, Bolivia; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; School of Medicine and Health Science, George Washington University, Washington, DC

Abstract. We describe the first case of Leishmania/HIV co-infection reported in Bolivia. Initially hospitalized with a diagnosis of pneumonia and bronchitis, the patient had numerous cutaneous and mucosal lesions caused by Leishmania (Viannia) braziliensis. The patient was also diagnosed as severely immunocompromised because of HIV infection.

INTRODUCTION The leishmaniases are a group of protozoan diseases transmitted to mammals including humans by phlebotomine sand flies. They are characterized by a spectrum of clinical manifestations: disseminated visceral infection (visceral leishmaniasis [VL]) to various manifestations of cutaneous leishmaniasis (CL), including ulcerative skin lesions developing at the site of the sand fly bite (i.e., localized cutaneous leishmaniasis [LCL]); multiple non-ulcerative nodules (i.e., diffuse cutaneous leishmaniasis [DCL]); and destructive mucosal inflammation (i.e., mucosal leishmaniasis [ML]).1,2 The latter is also referred to as mucocutaneous leishmaniasis (MCL) as commonly coinciding with LCL or DCL. Globally, ~350 million people are thought to be at risk of infection and disease. It is estimated that an annual 1.52 million new leishmaniasis cases occur, and 70,000 deaths are attributable to the disease.3 In Bolivia, the leishmaniases are endemic in seven of nine of the countrys departments; the two departments without notified cases are Oruro and Potos, largely because their high average altitude limits the geographic habitat of sand fly vectors. The country probably has the highest incidence of LCL and ML in Latin America, with 31,095 cases of LCL and 4,619 cases of ML in the last 24 years (19832006).4 Of all countries in Latin America, Bolivia also reports the greatest LCL:ML case ratio, with national case notification data for 2006 showing a ratio of six LCL cases for every ML case.4 In contrast, during the 19832006 time period, only 10 and 4 cases of VL and DCL were reported, respectively. All VL cases were reported from the Yungas region (i.e., La Paz department); DCL cases were reported from Beni and La Paz departments. The increase in LCL and ML cases in Bolivia is mirrored by the increasing number of LCL and ML patients with a travel history to Bolivia attending travel medicine clinics in non-endemic countries (e.g., of 79 LCL and 6 ML patients seen between 1995 and 2003 at the Hospital of Tropical Diseases, London, UK, 7 and 3 were from Bolivia, respectively).5 From 1984 to 2006, the total number of HIV/AIDS cases reported in Bolivia rose to 2,190.6 HIV/AIDS diagnosis is often delayed, with ~50% of cases having AIDS at the time

of diagnosis. The HIV/AIDS epidemic in Bolivia is concentrated, with prevalence rates > 5% among the at-risk population, primarily men who have sex with men. Under-reporting is estimated to be > 70% country-wide, and The Joint United Nations Program on HIV/AIDS (UNAIDS) estimated that, in 2006, 8,100 people were living with HIV/AIDS in Bolivia.7 Over the past 20 years, leishmaniases have increasingly been recognized as an opportunistic infection in HIV-infected patients, with LeishmaniaHIV co-infection common in areas where both diseases are endemic.8 In contrast to VL, only scarce data are available on LCL in HIV-infected patients in the Americas, with isolated case reports available from Argentina, Brazil, Colombia, French Guyana, Peru, and Venezuela.8 Literature on ML in HIV-infected patients is even rarer, with only a dozen or so of cases reported in Argentina,9 Brazil,1014 French Guyana,15,16 and Peru.17 We describe an ML patient attending the Hospital of Viedma Hospital in Cochabamba, Bolivia, who on further examination, was found to be infected with HIV; the patient was started on amphotericin B therapy, responded well, but was lost to follow-up. CASE REPORT In June 2006, a 32-year-old male road and market worker from Cochabamba, Bolivia, presented himself to the hospital with a 1-week history of respiratory difficulties, characterized by a cough, productive of mainly clear but occasionally bloody sputum, sore throat, dysphagia, and dysphonia. Chest examination showed decreased breath sounds on both sides and sporadic and disseminated crepitations in the left lung. No fever or weight loss (body weight, 43 kg) was reported. The patient was hospitalized with a diagnosis of pneumonia and bronchitis. Physical examination showed that the patient had numerous maculo-papulo-nodular lesions on the face, eyebrows, and left ear lobe, as well as ulcerative and crusted lesions on the nose (Figure 1A). There were ulcerative lesions on the lower and upper lip as well as the tongue; the uvula had been completely eroded, and a pussy oropharyngeal discharge was noted (Figure 1B). Another lesion was noted on the hand, with well-delineated borders. Further maculo-papulo-nodular lesions were noted on the patients left and right legs and feet (Figure 1C, D), filled with yellow exudate, which the patient attributed to carrying heavy work equipment, as well as to a road accident in which a car had driven over both his feet.

* Address correspondence to Ana Lineth Garcia, Av. Aniceto No. 371, Facultad de Medicina IIBISMED-CUMETROP, Universidad de Cochabamba, Cochabamba, Bolivia. E-mail: lineth.garcia@gmail.com

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Figure 1. Cutaneous and mucosal leishmaniasis caused by L. (V.) braziliensis in a HIV-infected patient in Cochabamba, Bolivia. A, Numerous maculo-papulo-nodular lesions were observed on the face, eyebrows, and left ear lobe, as well as ulcerative and crusted lesions on the nose. Of note, the patient also had an inflamed upper and lower lip. B, Ulcerative lesions were observed on the lower and upper lip as well as tongue; the uvula had been completely eroded, and a pussy oropharyngeal discharge was noted. C, Cutaneous lesion on the right leg. D, Cutaneous lesion on the left foot; lesion scraping histopathology and Giemsa-stained slides were all positive for Leishmania amastigotes. Parasites were successfully isolated and characterized as Leishmania (V.) braziliensis. This figure appears in color at www.ajtmh.org.

The patient also reported having gone to work for 3 months in Chimor (a town located in the low-lying Chapare region) a month before hospitalization, where he had entered the forest for coca cultivation. A chest x-ray showed right parahilar infiltration. Blood tests showed a hemoglobin of 10 g/dL (13.517.2 g/dL); a white blood cell count of 4 109/L (411 109/L) (neutrophils 77% [4075%]; lymphocytes 15% [2045%]; monocytes 7% [210%]; and eosinophils 1% [16%]); and an erythrocyte sedimentation rate (ESR) of 64 mm/h. Direct examination of stool samples for parasites showed Entamoeba histolytica cysts, Hymenolepis nana (tapeworm), and Trichuris trichura eggs. Sputum cultures for bacteria and acid fast bacilli were negative, as was the serology for hepatitis B, toxoplasmosis, and Chagas disease. The rapid test, ELISA, and Western blot for HIV were positive, with CD4 and CD8 cell counts of 67/L and 384/L, respectively. Histologic examination of scrapings from lesions on the face, palate, and left foot showed inflammatory infiltrates characterized by leukocytes, neutrophils, and lymphocytes, with large numbers of macrophages infected with a variable number of Leishmania spp. amastigotes. Leishmania etiology was confirmed through GIEMSA-stained slides of scrapings from lesions on the hand and left foot showing numerous intracellular and extracellular amastigotes, as well as through positive parasite culture of lesion aspirates in NNN media according to the guidelines of the National Reference Laboratory for Leishmaniasis. Leishmania DNA was extracted from the parasite culture with DNAZol (Invitrogen, Merelbeke, Belgium) according to the manufacturers instructions and amplified using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) protocol using primers target-

ing the hsp70 gene and HaeIII endonuclease for cleavage of amplification products.18 PCR-RFLP identified L. (Viannia) braziliensis in all samples tested. Although the patient refused anti-retroviral therapy, he was given primary prophylaxis (with cotrimoxazole) against Pneumocystis carinii pneumonia. Metronidazol (750 mg orally, three times daily for 10 days) and albendazole (400 mg orally, single dose) were given for the intestinal parasites; iron supplements were given for the underlying anemia. Intravenous amphotericin B therapy (50 mg every 48 hours) was started. Although the cumulative dose of amphotericin B had reached 2,000 mg within 80 days, the evolution of the ulcerative lesions was stationary, with active lesions persisting in the face, lower and upper limbs, and the palate; only the lesion on the lower lip and tongue showed signs of reepithelialization. Systematic weekly analysis of liver and kidney function was carried during the treatment and showed no remarkable alteration. Approximately 3 months after hospitalization, the patient discharged himself, so that further follow-up could not be made. DISCUSSION The leishmaniases are characterized by a spectrum of clinical pathologies. More than 15 Leishmania spp. are known to cause VL or CL in humans. Diagnosis and treatment of the leishmaniases is difficult because of a number of differential diagnoses (e.g., leprosy, skin cancers, tuberculosis, cutaneous mycoses) and the limited number of available therapeutic approaches, respectively.2 ML is a progressive disease that can be disfiguring and life threatening.2 In most endemic areas,

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110% of LCL infections result in ML 15 years after LCL has healed; however, reports do exist for which ML presented at the same time as LCL or for which 25% of LCL resulted in ML. Risk factors for ML include L. (V.) braziliensis infection, male sex, genetic predisposition, and immunosuppression. ML never heals spontaneously, is very difficult to treat, with secondary bacterial infections common, and is potentially fatal.2 Co-infection with HIV results in even more atypical clinical pathology (e.g., Leishmania spp. that are thought to be dermatropic may cause VL and vice versa), with LCL symptoms tending to be more severe and LCL lesions taking longer to resolve (especially in those HIV patients with low CD4+ T-cell counts).8 Although the first-line treatment of the leishmaniases, including LCL and ML, is pentavalent antimonials at a dose of 20 mg/kg administered daily for 2028 days,2 no established therapeutic protocol exists for Leishmania-HIV co-infections.8 The treatment of co-infected patients is confounded by the dearth of formalized clinical data. Thus, compared with immunocompetent patients, treatment response of Leishmania HIV infections to antimonials tends to be poor (e.g., whereas efficacy of antimonials is > 85% in immunocompetent CL patients, it is 3382% in HIV-infected individuals),2,8 with high rates of relapse (1457% of patients)8 and mortality reported. Amphotericin B has been used for the treatment of co-infected patients; although initial cure rates are moderate to good at 5882%,8 patients often relapse and suffer from renal toxicity (in up to 35% of cases).8 Lipid amphotericin B formulations (e.g., AmBisome, Gilead Sciences, Inc., Foster City, CA) have a better safety profile than amphotericin B and have proven to be effective for the treatment of Leishmania (VL)HIV co-infections, with cure rates reportedly between 33% and 100% depending on the lipid amphotericin B formulation; nonetheless, relapse rates are high (38100% of patients).8 Recently, miltefosine has been used in treating co-infected patients. Although the initial treatment response is good, with cure rates between 64% and 89% and low mortality, relapse rates are comparable to other treatment approaches (3188%).8 Here we report the first case of Leishmania/HIV co-infection in Bolivia. The patient was anemic, with a raised ESR and signs of a chest infection, as well as intestinal parasites. In addition, he was severely immunocompromized by HIV infection. Of note is the rapid evolution within 3 months from LCL in both feet to a disseminated pathology, with multiple ulcerative lesions in the face and upper and lower limbs, a pathology already observed in other co-infection cases reported in Latin America.1017 Additionally, the patient presented with ML, characterized by several lesions on the lips, palate, pharynx, larynx, and bronchia, which probably caused the severe dysphonia, dysphagia, and hyper-secretion. The patient reported to have gone to work in an area (i.e., Chapare) known to be endemic for LCL and ML.19 Treatment with amphotericin B did not result in clinical cure of lesions, and it is likely that the poor treatment response was compounded by the severe immunosuppression of the patient. Given that Bolivia has the highest incidence of LCL and ML in the Americas,4 as well as having an increasing number of reported HIV cases,6 further studies should be made to estimate the burden of Leishmania/HIV co-infection in the country. Certainly, in-country case management guidelines should be updated to include a section on diagnosis and treatment of Leishmania/HIV co-infections.

Received May 19, 2009. Accepted for publication June 20, 2009. Acknowledgments: The authors thank all hospital staff involved in the diagnosis and follow-up of the patient and Meena Ghandi for comments on the manuscript. The American Committee on Clinical Tropical Medicine and Travellers Health (ACCTMTH) assisted with publication expenses. Financial support: Funding support was provided under Grant A50990A of the UNICEF/UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases (TDR). Disclosure: The authors have no conflicts of interest. The opinions expressed in this paper are those of the authors and may not reflect the position of their employing organization nor of their works sources of funding. Authors addresses: Faustino Torrico, Rudy Parrado, Ernesto Rojas, Ral Delgado, and Ana Lineth Garca, Av. Aniceto Arce No. 371, Facultad de Medicina IIBISMED-CUMETROP, Universidad Mayor de San Simn, Cochabamba, Bolivia. Rosario Castro, Laboratorio de Referencia Departamental de Salud, Cochabamba, Bolivia. Carla Jimena Marquez, Infectologa, Hospitalario Viedma, Cochabamba, Bolivia. Richard Reithinger, Disease Control and Vector Biology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK and School of Medicine and Health Science, George Washington University, Washington, D.C.

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