Atypical manifestations of visceral leishmaniasis in ... Diro, Johan van Griensven, Rezika Mohammed, Robert Colebunders, Mesﬁ n Asefa, Asrat Hailu, Lutgarde Lynen

www.thelancet.com/infection Published online October 7, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70833-3 1

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Atypical manifestations of visceral leishmaniasis in patients with HIV in north Ethiopia: a gap in guidelines for the management of opportunistic infections in resource poor settingsErmias Diro, Johan van Griensven, Rezika Mohammed, Robert Colebunders, Mesfi n Asefa, Asrat Hailu, Lutgarde Lynen

In regions where it is endemic, visceral leishmaniasis is an important opportunistic infectious disease in people living with HIV. Typically, clinical presentation of visceral leishmaniasis includes chronic fever, hepatosplenomegaly, and weight loss. In Leishmania infantum endemic regions in Europe, atypical visceral leishmaniasis presentations have been well documented, with almost every possible organ involved. However, such reports are rare in Leishmania donovani endemic regions such as east Africa. In this Personal View, we describe the various atypical disease presentations in patients screened as part of an HIV and visceral leishmaniasis clinical trial in north Ethiopia, where up to 40% of patients with visceral leishmaniasis are co-infected with HIV. Atypical presentations such as these are not covered in clinical guidelines used in these settings. Apart from the lack of diagnostic facilities, this gap contributes to the underdiagnosis of atypical visceral leishmaniasis, with associated morbidity and mortality. Involvement of clinicians experienced with the management of HIV and visceral leishmaniasis co-infection in the development of HIV clinical guidelines in aff ected regions is warranted.

IntroductionIn areas where it is endemic, visceral leishmaniasis has become an important opportunistic infectious disease in the era of HIV.1 Co-infection has been reported in 35 countries.2 The north part of Ethiopia is one of the regions with a high incidence of co-infection, with the prevalence of HIV infection ranging from 15% to 30% in patients with visceral leishmaniasis.3 In east Africa in Sudan, Ethiopia, Somalia, Kenya, and Uganda the cause of visceral leishmaniasis is Leishmania donovani and the transmission is anthroponotic; the cutaneous form is mainly caused by Leishmania aethopica with hyraxes as the animal reservoir.4,5

Clinical manifestations of visceral leishmaniasis are chronic fever, weight loss, organomegaly, and pancytopenia. These major clinical manifestations are similar in HIV-positive and HIV-negative patients.6–8 However, one of the challenges in patients with co-infection is the variety of atypical clinical presentations, with leishmania parasites isolated from unusual sites such as gastrointestinal and oral mucosa, skin, pleura, pericardium, lymph nodes, Kaposi’s sarcoma lesions, and respiratory tract.9–24 These case reports were mainly from Leishmania infantum transmission regions in Europe, and were invariably associated with very low CD4 cell counts at diagnosis.8 Combined with the many opportunistic infections that can occur in patients with HIV, these atypical presentations add to the challenge of making a timely diagnosis.9

By contrast with numerous accounts from Europe, reports on atypical clinical manifestations of HIV infection and visceral leishmaniasis in L donovani endemic regions (east Africa and the Indian subcontinent) are extremely scarce (table 1). Although the occurrence of atypical presentations might be associated with the diff erent species of leishmania, we believe that underdiagnosis is

the most likely explanation, and mainly related to a low index of clinical suspicion and a lack of diagnostic facilities.

In this Personal View, we describe various atypical disease presentations noted in the screening of patients for enrolment into a clinical trial of therapy for HIV and visceral leishmaniasis in north Ethiopia. We discuss the reports on cases of L donovani and L infantum infection in endemic regions and to what extent atypical presentations are covered in clinical treatment guidelines in east African countries where both HIV and visceral leish-maniasis are endemic.

The atypical cases discussed here are taken from patients screened for inclusion in an ongoing clinical trial (NCT01360762) on the use of secondary prophylaxis with pentamidine for visceral leishmaniasis relapses in patients with HIV at the leishmaniasis research and treatment centre of the University of Gondar (Gondar, Ethiopia). The clinical trial has been approved by the relevant ethical committees involved (University of Gondar and National Research Ethics Committee, Ethiopia; and Institute of Tropical Medicine and University Hospital Antwerp, Belgium) and written consent was given by patients. Eight (15%) of 54 patients with visceral leishmaniasis co-infected with HIV screened during 14 months had atypical clinical presentations of leishmaniasis: three had skin lesions (one patient with scattered nodular lesions and two with post-kala-azar dermal leishmaniasis-like lesions [PKDL]), two had oral lesions, two had lymph node involvement (one with intra-abdominal lymph node involvement), and one patient had rectal lesions.

Although liposomal amphotericin B is the recom-mended treatment for these patients according to WHO and national guidelines, the scarcity of this medicine leads to the use of alternative drugs.2,79 Three of the four

Lancet Infect Dis 2014

Published OnlineOctober 7, 2014http://dx.doi.org/10.1016/S1473-3099(14)70833-3

Department of Internal Medicine (E Diro MD, R Mohammed MD) and Department of Pathology (M Asefa MD), University of Gondar, Gondar, Ethiopia; Department of Clinical Sciences, Institute of Tropical Medicine, University Hospital Antwerp, Belgium (J van Griensven MD, R Colebunders PhD, L Lynen PhD); and Department of Microbiology, Parasitology and Immunology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia (A Hailu PhD)

Correspondence to:Dr Ermias Diro, Department of Internal Medicine, University of Gondar, PO Box 196, Gondar, [email protected]

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patients described in this Personal View were treated with sodium stibogluconate, and one of whom needed prolonged treatment. The most critically ill of these patients, with extensive oral lesions, died of sepsis while on liposomal amphotericin B.

Intra-abdominal lymphadenopathyPatients with leishmaniasis presenting with isolated and persistent peripheral lymphadenopathy, or complicating other diseases that cause lymphadenopathy, were

Leishmania donovani Leishmania infantum

East Africa Indian subcontinent

Skin (other than PKDL) This report and25 One report26 15 reports10,13,27–39

Associated with other lesions: Kaposi’s sarcoma, herpes zoster, dermatofi broma, squamous-cell cancer, and rheumatoid nodules

·· ·· 11 reports12,17,40–48

Upper aerodigestive and oral tract This report and49 One report50 Six reports15,16,23,51–53

Intestinal mucosa (stomach and duodenum, and colon) and malabsorption syndrome This report ·· 18 reports17,19, 34,54–68

Intra-abdominal lymphadenopathy This report ·· ··

Renal involvement (nephritic syndrome and amyloidosis) ·· ·· Four reports69–72

Lung, heart, pleura, pericardium, and peritoneum ·· ·· Four reports24,73–75

Liver ·· ·· Three reports20,76,77

Adrenal gland ·· ·· One report78

PKDL=post kala-azar dermal leishmaniasis. This summary table is not an exhaustive list of all atypical case reports from the L infantum endemic region.

Table 1: Atypical cases reported from leishmania endemic regions

Panel 1: Intra-abdominal lymphadenopathy in a 35-year-old man from a Leishmania donovani transmission region

This man presented with 4 months of high-grade persistent fever, weight loss, and symptoms of anaemia. He had hepatosplenomegaly and bilateral cervical lymphadenopathy. An abdominal mass, later proven to be lymph nodes, was palpable in the perumbilical and left lower quadrant of the abdomen. His haematology profi le showed pancytopenia. He was already diagnosed with HIV and had been on combination antiretroviral therapy (cART) and co-trimoxazole for 5 months. His CD4 count had declined from 84 cells per μL at the start of cART to 30 cells per μL at presentation. Diff erential diagnoses of HIV treatment failure, lymphoma, and disseminated tuberculosis were considered, of which the last was also supported by a fi brotic lesion seen on chest radiography. A Giemsa-stained abdominal lymph node aspirate (ultrasound-guided fi ne-needle aspiration) showed many histiocytes fi lled with Leishman-Donovan bodies with a parasite load of grade 5. Microscopy of cervical lymph node and splenic aspirates showed no leishmania parasites. The patient was successfully treated with sodium stibogluconate and the enlargement of the lymph nodes was absent on control ultrasound, whereas the splenomegaly persisted, but spleenic aspirates tested negative for leishmania parasites. His CD4 count rose to 104 cells per μL.

In addition to the intra-abdominal lymph node manifestation in this patient, a positive rK39 serology test at the start of therapy was negative by the end of therapy; contrary to the expectation that antibodies persist in the circulation. In such a situation, the initial rK39 positivity might be a false positive associated with the immune dysregulation in both diseases.

Leishmania parasites were shown only in the abdominal lymph nodes, even though he had generalised peripheral lymphadenopathy and splenomegaly. Leishman-Donovan bodies can get sequestered and remain in localised sites such as these even after treatment although the mechanism involved is unclear.14 This observation shows the need to take samples from diff erent sites. Several opportunistic infections in patients with HIV can present with diff erent forms of lymphadenopathy, and visceral leishmaniasis should be considered as one of the diff erential diagnoses for patients from endemic regions or travellers to these regions.

Panel 2: Oral mucosal involvement in a 29-year-old woman from a Leishmania donovani transmission region

A woman who was HIV positive stayed without combination antiretroviral therapy for 7 years after diagnosis of HIV, and presented with watery diarrhoea, fever, vomiting, and oral lesions of 1 month duration. The oral lesions had increased in size causing dysphagia and bleeding. On examination, the patient looked chronically ill, emaciated, and was unable to support herself. She was febrile and anaemic. Inspection of the mouth revealed a ragged, fungating, and disfi guring mass on the palate. The mass was dark purple, and easily bled with movement of the teeth. She was severely pancytopenic (white blood cell count 1300 cells per μL, haemoglobin 75 g/L, platelet count 10 000 per μL) and with a very low CD4 count (71 cells per μL). Aspirates from the bone marrow had Leishman-Donovan bodies with a parasite load of grade 4; aspirates from the palatal lesions had Leishman-Donovan bodies with a parasite load of grade 3.

Treatment was started with liposomal amphotericin B for the leishmania infection and broad spectrum antibiotics (ceftriaxone and metronidazole) for possible sepsis secondary to a superinfected oral lesion. At the start of treatment, the oral mass was sloughing off and the bleeding worsened, hindering the ingestion of food and necessitating feeding of the patient through a nasogastric tube. Eventually, the patient died of septic shock.

Visceral leismaniasis caused by dissemination of L donovani to the oral mucosa or visceralisation of mucocutaneous leishmaniasis caused by Leishmania aethiopica (a common cause of the cutaneous form of leishmaniasis in Ethiopia) is a possibility in this patient. Parasite species identifi cation was not done.


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repeatedly reported from both L donovani and L infantum endemic regions.14,80–84 Peripheral lymphadenopathy is one of the frequent manifestations of visceral leish-maniasis seen in Sudan.85 However, lymph node involvement is less frequent in patients with visceral leishmaniasis in north-west Ethiopia, occurring in 15% of patients.6 A 35-year-old male patient with leishmaniais involving-intra-abdominal lymph nodes and HIV co-infection is described in panel 1.

Oral mucosal diseaseA mucocutaneous form of leishmaniasis that involves the margins of the lips and nostrils can be caused by a number of the Leishmania spp. Deep mucosal involvement of oral and upper aero-oesophageal areas in leishmaniasis in L infantum transmission regions in patients with HIV are very common (table 1).15,16 Infi ltrative palatal lesions such as non-Hodgkin lymphoma, Kaposi’s sarcoma, cytomegalovirus infections, and deep fungal infections in

people who are HIV-positive should be considered in the diff erential diagnosis. Leishmania spp infection superimposed on other pathologies has also been reported and can further complicate the diagnosis.17,45,86 A patient with oral mucosal disease from an L donovani transmission region is described in panel 2.

Lower gastrointestinal involvementAlthough several reports18,19,21,22,62,87,88 from L infantum endemic regions have discussed patients with visceral leishmaniasis and gastrointestinal system involvement this fi nding has not been reported from the L donovani endemic regions in east Africa to date (table 1; panel 3).

Skin and visceral lesionsPapular, nodular, papulonodular, macular and other types of skin lesions might occur in patients with visceral leishmaniasis before, during, or after treatment of an episode (panel 4). Skin lesions in patients with leishmaniasis and HIV co-infection can occur as a reactivation of a latent infection or as dissemination of a recent infection,39 and might produce PKDL-like lesions. As a result, in patients with HIV infection, whether the

Panel 3: Rectal involvement in a 30-year-old man in a Leishmania donovani endemic region

This HIV-positive man presented with anal bleeding that had gradually worsened over the past year and was recently mixed with pus and produced a foul smell. He was febrile, with substantial weight loss and symptoms of anaemia. On examination, he looked chronically ill with body mass index 15·9 kg/m² and splenomegaly. On rectal examination, he had irregular tender mass and external haemorrhoids. His haemogram showed pancytopenia and his CD4 count was 98 cells per μL. The rK39 serology result was positive and the splenic aspiration showed Leishman-Donovan bodies with a parasite load of grade 6.

The patient had multiple para-aortic lymphadenopathies and hepatosplenomegaly on ultrasound. Sigmoidoscopy revealed thickened rectal mucosa and a rectal ulcer. Diff erential diagnosis included a colorectal infection with cytomegalovirus, herpes simplex, and metastatic anal cancer. The histology examination of the rectal tissue showed ulcerated rectal mucosa with the lamina propria diff usely infi ltrated with lymphocytes and macrophages. The cytoplasm of the macrophages was fi lled with Leishman-Donovan bodies (fi gure 1). We noted no signs of malignancy and the patient responded to treatment with sodium stibogluconate but eventually developed faecal incontinence.

Symptoms of lesions in the lower gastrointestinal system might have various causes. When patients present with anal pain or a rectal mass and bleeding, besides more common conditions such as haemorrhoids, anal fi ssures, genital mucocutaneous herpes, and rectal cancer, leishmaniasis should be considered in patients who are HIV-positive from visceral leishmaniasis endemic regions. This case should alert clinicians in visceral leishmaniasis endemic regions that the disease should be included in the diff erential diagnosis of rectal lesions in patients with HIV.

Figure 1: Haematoxylin-eosin stain of a rectal biopsy sampleRectal mucosa (A; 4 × magnifi cation) and histiocytes congested with Leishman-Donovan bodies (B; 100 × magnifi cation).

B

A


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skin lesions are PKDL or an atypical presentation of visceral leishmaniasis is not always clear.89 Although PKDL might be a sign of immune reconstitution infl ammatory syndrome, simultaneous demonstration of leishmania parasites in reticuloendothelial tissue and skin might instead indicate dissemination of parasites and severe immuno suppression. Various related skin lesions or other skin disorders were described in reports from the L infantum transmission regions.10,17,21,27–29,31,40,42

Overview of published reports on atypical visceral leishmaniasisWe did a literature review to compare reports of atypical disease presentation in visceral leismaniasis endemic regions. Most of the published reports relate to the L infantum transmission regions in southern Europe at the peak of the HIV epidemic in the late 1990s and early 2000s (table 1). Skin and gastrointestinal mucosa were the most common sites involved. However, the case reports show that potentially all organs and systems can be aff ected by visceral leishmaniasis. Some of these case reports have shown leishmania infection complicating other diseases involving lesions of the kidney, liver, adrenal glands, lung, and serous membranes. Only recently, was visceral leishmaniasis with disseminated cutaneous lesions, as an atypical presentation caused by L donovani in patients with HIV co-infection, reported from Ethiopia.25 Reports from the Indian subcontinent are equally few in number.

Guidelines on use of a syndromic approach for the management of opportunistic infectionsMany guidelines propose a syndromic approach to the diagnosis and treatment of opportunistic infections in people who are HIV-positive in low-resource settings. We looked at the guidelines’ coverage of visceral leishmaniasis in the syndromes of skin lesions, gastrointestinal and mucosal problems, and lymphadenopathy in patients with HIV infection. We used a Google Scholar search for guidelines on the treatment of opportunistic infections, with the search terms “opportunistic infections” and “HIV” and “syndromic approach” and “leish*” and “Africa”.

Although classic visceral leishmaniasis is dealt with in most of the guidelines on opportunistic infections with respect to chronic fever, the atypical lesions of visceral leishmaniasis are often excluded from guidelines on the diff erential diagnosis of patients with oral lesions, lymphadenopathy, skin lesions, and gastrointestinal ulcers (table 2).90–93

We accessed the national guidelines on management of opportunistic infections in Ethiopia published in 2008, Sudan (2008), and Kenya (2008).79,94,95 None of them used a syndromic approach. Only the guidelines from Ethiopia mention that presentation of visceral leishmaniasis

Panel 4: Atypical cutaneous manifestations in a 41-year-old man from the Leishmania donovani transmission region

This man presented with one variety of atypical cutaneous manifestation concomitant with visceral leishmaniasis. He was HIV-positive and had been on combined antiretroviral therapy (cART) and co-trimoxazole preventive therapy for the previous 4 years and presented with numerous nodular skin lesions of 1 year duration. The lesions were painless and involved the face and upper extremities predominantly at the tip of the nose and on the elbows (fi gure 2A). He had been treated for visceral leishmaniasis twice, 7 years previously. During his recent presentation the common symptoms of patients with visceral leishmaniasis such as fever, anorexia, weight loss, and bleeding were absent. He had splenomegaly, 6 cm below the costal margin and was pancytopenic (white blood cell count 1300 cells per μL, haemoglobin 110 g/L and platelet count 60 000 per μL). His CD4 count after 4 years on cART was 72 cells per μL coming from a nadir of 19 cells per μL. Leishman-Donovan bodies were detected in Giemsa-stained smears from the spleen and the skin lesions on the face and the arms with a parasite load of grade 6. He was treated with sodium stibogluconate for 45 days with a brief interruption to treatment because of transient renal dysfunction. The spleen became non-palpable and the skin lesions subsided (fi gure 2B). Because of failed parasite clearance, treatment was prolonged from day 30 to day 45 when bone-marrow aspirates showed no parasites. His CD4 count increased to 116 cells per μL after treatment. The very low CD4 count and high parasite load shown both in the skin lesions and the spleen indicate profound immunosuppression and overwhelming disseminated disease.

B

A

Figure 2: Nodular skin lesions on the face and arms of a patient co-infected with HIV and visceral leishmaniasisBefore treatment (A) and at the end of treatment for visceral leishmaniasis (B).


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might be atypical in patients who are HIV-positive, without going into further details. No national guidelines on opportunistic infections were electronically available for Uganda and Somalia. Since 2006, WHO has judged atypical disseminated leishmaniasis as a stage 4 (AIDS) defi ning condition.96 The 2010 WHO technical report on the control of leishmaniasis also provides guidance for diagnosis and treatment of co-infection with HIV.2

Conclusions and recommendationsOnly a few cases of atypical visceral leishmaniasis had been reported from east Africa.25,49 Factors contributing to this scarcity of published reports on atypical disease presentation probably relate to a lack of clinical suspicion and limitations of the diagnostic facilities available in endemic regions.

Importantly, these atypical presentations are not included in the opportunistic infection guidelines that use a syndromic approach to diagnosis and treatment, especially the national guidelines in leishmania endemic regions. The starting point for screening patients and investigations for visceral leishmaniasis is WHO case defi nition of a patient with suspected visceral leishmaniasis (prolonged fever, weight loss, and splenomegaly), which addresses the typical presentation.2 This approach carries the risk that atypical visceral leishmaniasis remains undiagnosed in clinical settings, or is diagnosed with substantial delay. Visceral leishmaniasis is a fatal disease that needs early recognition and treatment. Most of the unusual clinical manifestations occur in patients with HIV with very low CD4 counts, who might also be aff ected with other opportunistic infections. To increase survival for these susceptible patients, clinicians should consider fatal but treatable conditions in their diff erential diagnosis. For patients in Leishmania spp endemic regions, this should include visceral leishmaniasis.

In addition to diagnostic delays, the prognostic importance of atypical presentation of visceral leish-maniasis needs to be addressed. In these reports, the CD4 counts of patients were very low even in those who were already on combination antiretroviral therapy. Dis-semination of visceral leishmaniasis to organs that are not

normally involved suggests advanced immuno sup-pression. This fi nding was also described in reports from L infantum endemic regions.8 Damage to the involved organs by leishmania infection can lead to further complications. The oral lesions causing dysphagia in one patient were complicated by secondary bacterial sepsis, which led to the death of the patient. Rectal involvement led to anal sphincter insuffi ciency in another patient. Overall, atypical visceral leishmaniasis causes substantial morbidity and mortality.

We recommend that guidelines for the management of opportunistic infections in the Leishmania spp endemic regions in east Africa include these atypical visceral leishmaniasis lesions in the diff erential diagnosis of oral lesions, lymphadenopathy, gastro-intestinal ulcers, and skin lesions. To achieve this aim, the involvement of physicians who frequently treat HIV-leishmania co-infected patients in the development of treatment guidelines is essential.ContributorsED was involved in management of patients and writing this Personal View. RM was involved in patient management and writing of the case studies. JvG, RC, AH, and LL were involved in management of the patients for case studies and in writing this Personal View. MA was responsible for histopathological diagnosis and was involved in write up of case studies.

Declaration of interestsWe declare no competing interests.

AcknowledgmentsED is supported by a PhD grant from the Belgian Directorate General for Development. The clinical trial (NCT01360762) is supported by the Institute of Tropical Medicine, Antwerp (with funding from the Department of Economy, Science and Innovation of the Flemish Government), the UBS Foundation, the Drugs for Neglected Diseases Initiative (DNDi), and MSF-Holland. JvG is supported by the Inbev-Baillet Latour Fund. Sanofi -Aventis is providing the pentamidine used in the clinical trial. We are grateful to the patients who have given consent to be involved in the study.

References1 Marlier S, Menard G, Gisserot O, Kologo K, De Jaureguiberry JP.

Leishmaniasis and human immunodefi ciency virus: an emerging co-infection?. Med Trop (Mars) 1999; 59: 193–200 (in French).

2 WHO. Control of the leishmaniases 2010. http://apps.who.int/iris/bitstream/10665/44412/1/WHO_TRS_949_eng.pdf (accessed Feb 5, 2013)

3 Alvar J, Aparicio P, Aseff a A, et al. The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev 2008; 21: 334–59.

Typical symptoms Atypical symptoms

Gastrointestinal mucosal lesions

Lymphadenopathy Skin

Clinical HIV/AIDS care guidelines for resource-poor settings; MSF (2006)90 Addressed Not addressed Addressed Addressed

IMAI acute care: interim guidelines for fi rst level facility health workers at health centre and district outpatient clinic; WHO (2009)91

Not addressed Not addressed Not addressed Not addressed

IMAI/IMCI chronic care with antiretroviral therapy and prevention: interim guidelines for fi rst level facility health workers at health centres and district outpatient clinic; WHO (2007)92

Only in WHO clinical staging

Not addressed Not addressed Not addressed

MSF=Médecins Sans Frontières. IMAI=integrated management of adolescent and adult illness. IMCI=integrated management of childhood illness.

Table 2: Coverage of visceral leishmaniasis presentations in guidelines for opportunistic infection diagnosis using a syndromic approach in resource-poor settings


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4 van Griensven J, Diro E. Visceral leishmaniasis. Infect Dis Clin North Am 2012; 26: 309–22.

5 Gelanew T, Kuhls K, Hurissa Z, et al. Inference of population structure of Leishmania donovani strains isolated from diff erent Ethiopian visceral leishmaniasis endemic areas. PLoS Negl Trop Dis 2010; 4: e889.

6 Hurissa Z, Gebre-Silassie S, Hailu W, et al. Clinical characteristics and treatment outcome of patients with visceral leishmaniasis and HIV co-infection in northwest Ethiopia. Trop Med Int Health 2010; 15: 848–55.

7 Laguna F, Adrados M, Alvar J, et al. Visceral leishmaniasis in patients infected with the human immunodefi ciency virus. Eur J Clin Microbiol Infect Dis 1997; 16: 898–903.

8 Pintado V, Martin-Rabadan P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodefi ciency virus (HIV)-infected and non-HIV-infected patients. A comparative study. Medicine (Baltimore) 2001; 80: 54–73.

9 Ejara ED, Lynen L, Boelaert M, van Griensven J. Challenges in HIV and visceral leishmania co-infection: future research directions. Trop Med Int Health 2010; 15: 1266–67.

10 Ara M, Maillo C, Peon G, et al. Visceral leishmaniasis with cutaneous lesions in a patient infected with human immunodefi ciency virus. Br J Dermatol 1998; 139: 114–17.

11 Bosch RJ, Rodrigo AB, Sanchez P, de Galvez MV, Herrera E. Presence of leishmania organisms in specifi c and non-specifi c skin lesions in HIV-infected individuals with visceral leishmaniasis. Int J Dermatol 2002; 41: 670–75.

12 Gonzalez-Beato MJ, Moyano B, Sanchez C, et al. Kaposi’s sarcoma-like lesions and other nodules as cutaneous involvement in AIDS-related visceral leishmaniasis. Br J Dermatol 2000; 143: 1316–18.

13 Postigo C, Llamas R, Zarco C, et al. Cutaneous lesions in patients with visceral leishmaniasis and HIV infection. J Infect 1997; 35: 265–68.

14 Dereure J, Duong TH, Lavabre-Bertrand T, et al. Visceral leishmaniasis. Persistence of parasites in lymph nodes after clinical cure. J Infect 2003; 47: 77–81.

15 Aliaga L, Cobo F, Mediavilla JD, et al. Localized mucosal leishmaniasis due to Leishmania (Leishmania) infantum: clinical and microbiologic fi ndings in 31 patients. Medicine (Baltimore) 2003; 82: 147–58.

16 Cortes P, Cardenosa N, Romani J, et al. Oral leishmaniasis in an HIV-positive patient caused by two diff erent zymodemes of Leishmania infantum. Trans R Soc Trop Med Hyg 1997; 91: 438–39.

17 Albrecht H, Stellbrink HJ, Gross G, Berg B, Helmchen U, Mensing H. Treatment of atypical leishmaniasis with interferon gamma resulting in progression of Kaposi’s sarcoma in an AIDS patient. Clin Investig 1994; 72: 1041–47.

18 Alguacil GF, Moreno J, Ortolano A, Hallal H. A malabsorption syndrome, gastrointestinal leishmaniasis and HIV infection. Gastroenterol Hepatol 1997; 20: 386 (in Spanish).

19 Alonso MJ, Munoz E, Picazo A, et al. Duodenal leishmaniasis diagnosed by biopsy in two HIV-positive patients. Pathol Res Pract 1997; 193: 43–47.

20 Angarano G, Maggi P, Rollo MA, et al. Diff use necrotic hepatic lesions due to visceral leishmaniasis in AIDS. J Infect 1998; 36: 167–69.

21 Balkhair A, Ben AF. Gastric and cutaneous dissemination of visceral leishmaniasis in a patient with advanced HIV. Int J Infect Dis 2008; 12: 111–13.

22 Betz P, Elsing C, Purrmann J, Frenzel H. Leishmaniasis of the upper gastrointestinal tract in an HIV positive patient. Pathologe 1990; 11: 97–100 (in German).

23 Canovas DL, Carbonell J, Torres J, Altes J, Buades J. Laryngeal leishmaniasis as initial opportunistic disease in HIV infection. J Laryngol Otol 1994; 108: 1089–92.

24 Heudier P, Taillan B, Garnier G, Marty P, Fuzibet JG, Dujardin P. Pulmonary site of visceral leishmaniasis in HIV infection. Presse Med 1993; 22: 1060 (in French).

25 Gelanew T, Hurissa Z, Diro E, et al. Disseminated cutaneous leishmaniasis resembling post-kala-azar dermal leishmaniasis caused by Leishmania donovani in three patients co-infected with visceral leishmaniasis and human immunodefi ciency virus/acquired immunodefi ciency syndrome in Ethiopia. Am J Trop Med Hyg 2011; 84: 906–12.

26 Vyas DH, Shah PD. Atypical presentation of visceral leishmaniasis in a HIV-positive patient from a nonendemic area. J Lab Physicians 2011; 3: 119–21.

27 Boumis E, Chinello P, Della RC, Paglia MG, Proietti MF, Petrosillo N. Atypical disseminated leishmaniasis resembling post-kala-azar dermal leishmaniasis in an HIV-infected patient. Int J STD AIDS 2006; 17: 351–53.

28 Calza L, D’Antuono A, Marinacci G, et al. Disseminated cutaneous leishmaniasis after visceral disease in a patient with AIDS. J Am Acad Dermatol 2004; 50: 461–65.

29 Carnauba D Jr, Konishi CT, Petri V, Martinez IC, Shimizu L, Pereira-Chioccola VL. Atypical disseminated leishmaniasis similar to post-kala-azar dermal leishmaniasis in a Brazilian AIDS patient infected with Leishmania (Leishmania) infantum chagasi: a case report. Int J Infect Dis 2009; 13: e504–07.

30 Catorze G, Alberto J, Afonso A, Vieira R, Cortes S, Campino L. Leishmania infantum/HIV co-infection: cutaneous lesions following treatment of visceral leishmaniasis. Ann Dermatol Venereol 2006; 133: 39–42 (in French).

31 Colebunders R, Depraetere K, Verstraeten T, et al. Unusual cutaneous lesions in two patients with visceral leishmaniasis and HIV infection. J Am Acad Dermatol 1999; 41: 847–50.

32 Gobels K, Feldt T, Oette M, et al. Visceral leishmaniasis presenting as subcutaneous nodules in a HIV-positive patient. Eur J Clin Microbiol Infect Dis 2003; 22: 329–31.

33 Gomez ME, Hiraldo GA, Sanz TA, Jimenez OF. Cutaneous leishmaniasis associated with visceral leishmaniasis in a patient infected with human immunodefi ciency virus. Med Clin (Barc) 2009 ; 133: 648 (in Spanish).

34 Hamour AA, Skelly R, Jowitt SN, et al. Visceral leishmaniasis (Kala-azar) in two patients with HIV-1 infection: atypical features and response to therapy. J Infect 1998; 36: 217–20.

35 Manfredi R, Passarini B, D’Antuono A, Misciali C, Marinacci G, Calza L. Diff use skin spread of HIV-associated visceral leishmaniasis: cumbersome diagnostic and therapeutic issues. G Ital Dermatol Venereol 2008; 143: 339–46.

36 Manfredi R, Marinacci G, Calza L, Passarini B. Diff use cutaneous dissemination of visceral leishmaniasis during human immunodefi ciency virus (HIV) infection, despite negligible immunodefi ciency: repeated failure of liposomal amphotericin B administration, followed by successful long-term pentamidine and paromomycin administration. Int J Antimicrob Agents 2008; 31: 590–92.

37 Perrin C, Taillan B, Hofman P, Mondain V, Lefi choux Y, Michiels JF. Atypical cutaneous histological features of visceral leishmaniasis in acquired immunodefi ciency syndrome. Am J Dermatopathol 1995; 17: 145–50.

38 Pourahmad M, Hooshmand F, Rahiminejad M. Cutaneous leishmaniasis associated with visceral leishmaniasis in a case of acquired immunodefi ciency syndrome (AIDS). Int J Dermatol 2009; 48: 59–61.

39 Santos-Oliveira JR, Da-Cruz AM, Pires LH et al. Atypical lesions as a sign of cutaneous dissemination of visceral leishmaniasis in a human immunodefi ciency virus-positive patient simultaneously infected by two viscerotropic leishmania species. Am J Trop Med Hyg 2011; 85: 55–59.

40 Alsina-Gibert M, Lopez-Lerma I, Martinez-Chamorro E, Herrero-Mateu C. Cutaneous manifestations of visceral leishmaniasis resistant to liposomal amphotericin B in an HIV-positive patient. Arch Dermatol 2006; 142: 787–89.

41 Barrio J, Lecona M, Cosin J, Olalquiaga FJ, Hernanz JM, Soto J. Leishmania infection occurring in herpes zoster lesions in an HIV-positive patient. Br J Dermatol 1996; 134: 164–66.

42 Castellano VM, Rodriguez-Peralto JL, Alonso S, Gomez-De la Fuente E, Ibarrola C. Dermatofi broma parasitized by leishmania in HIV infection: a new morphologic expression of dermal Kala Azar in an immunodepressed patient. J Cutan Pathol 1999; 26: 516–19.

43 Del Giudice P. Leishmania infection occurring in herpes zoster lesions in an HIV positive patient. Br J Dermatol 1996; 135: 1005–06.

44 Forsyth SF, Lawn SD, Miller RF, Fernando JJ, Lockwood DN, Vega-Lopez F. Multiple dermatofi broma-like lesions in a human immunodefi ciency virus-positive patient coinfected with visceral leishmaniasis. Br J Dermatol 2003; 148: 185–87.


Personal View

45 Gallego MA, Aguilar A, Plaza S, et al. Kaposi’s sarcoma with an intense parasitization by leishmania. Cutis 1996; 57: 103–05.

46 Garcia-Rio I, Dauden E, Ballestero-Diez M, Fraga J, Garcia-Diez A. Leishmaniasis and rheumatoid nodulosis in a patient with HIV infection. Actas Dermosifi liogr 2010; 101: 164–67 (in Spanish).

47 Hinojosa MC, Gonzalez MI, Martinez G, Gines A. Leishmanial parasitation of Kaposi’s sarcoma in a HIV patient. Rev Esp Quimioter 2011; 24: 54–55 (in Spanish).

48 Taillan B, Marty P, Schneider S, et al. Visceral leishmaniasis involving a cutaneous Kaposi’s sarcoma lesion and free areas of skin. Eur J Med 1992; 1: 255.

49 Ali A. Leishmaniases and HIV/AIDS co-infections: review of common features and management experiences. Ethiop Med J 2002; 40 (suppl 1): 37–49.

50 Kumar P, Sharma PK, Jain RK, Gautam RK, Bhardwaj M, Kar HK. Oral ulcer as an unusual feature of visceral leishmaniasis in an AIDS patient. Indian J Med Sci 2007; 61: 97–101.

51 Gonzalez-Anglada MI, Pena JM, Barbado FJ, et al. Two cases of laryngeal leishmaniasis in patients infected with HIV. Eur J Clin Microbiol Infect Dis 1994; 13: 509–11.

52 Grasa JM, Lorente J, Crego F, et al. Nasal leishmaniasis in an HIV-positive patient. Acta Otorrinolaringol Esp 2000; 51: 169–73 (in Spanish).

53 Villanueva JL, Torre-Cisneros J, Jurado R, Villar A, et al. Leishmania esophagitis in an AIDS patient: an unusual form of visceral leishmaniasis. Am J Gastroenterol 1994; 89: 273–75.

54 Bechade D, Seurat L, Discamps G, Taniere PH, Du Bourguet F. Multiple digestive involvement in visceral leishmaniasis in a patient with HIV infection: favourable course with itraconazole. Rev Med Interne 1996; 17: 234–37 (in French).

55 Bel Haj SM, Mekni A, Khanfi r M, et al. Unusual presentation of visceral leishmaniasis in an immunocompetent patient. Med Mal Infect 2006; 36: 167–69 (in French).

56 Garcia-Samaniego J, Laguna F. Intestinal leishmaniasis in AIDS patients. Rev Esp Enferm Dig 1997; 89: 145 (in Spanish).

57 Jablonowski H, Szelenyi H, Borchard F, Dohring-Schwerdtfeger E, Hengels KJ. Visceral leishmaniasis with gastrointestinal involvement in a 30-year-old HIV infected patient. Z Gastroenterol 1994; 32: 405–07 (in German).

58 Jawhar NM. Visceral leishmaniasis with an unusual presentation in an HIV positive patient. Sultan Qaboos Univ Med J 2011; 11: 269–72.

59 Laguna F, Garcia-Samaniego J, Moreno V, Gonzalez-Lahoz JM. Prevalence of gastrointestinal leishmaniasis in Spanish HIV-positive patients with digestive symptoms. Am J Gastroenterol 1994; 89: 1606.

60 Laguna F, Soriano V, Valencia E, Gonzalez-Lahoz JM. Gastrointestinal leishmaniasis in patients infected with the human immunodefi ciency virus. Rev Clin Esp 1994; 194: 510–11 (in Spanish).

61 Lemaistre AI, Chapel F, Cie P, Jeantils V, Guettier C. Unusual vascular lesions in the course of a colonic leishmaniasis in an HIV positive patient. Ann Pathol 1997; 17: 200–02 (in French).

62 McBride MO, Fisher M, Skinner CJ, Golden R, Main J. An unusual gastrointestinal presentation of leishmaniasis. Scand J Infect Dis 1995; 27: 297–98.

63 Mediavilla Garcia JD, Lopez-Gomez M, Corrales Torres AJ, Ortiz FF, Jimenez-Alonso J. Esophago-gastric leishmaniasis in a patient with HIV infection. Rev Clin Esp 1992; 191: 335–36 (in Spanish).

64 Pesce A, Saint-Paul MC, Vinti H, et al. Gastric leishmaniasis in a patient with acquired immunodefi ciency syndrome. Presse Med 1990; 19: 178 (in French).

65 Sanchez LA, Ferrero OL, Baraia-Etxaburu J, et al. Visceral leishmaniasis with duodenal involvement in an HIV patient. Rev Esp Enferm Dig 2001; 93: 740–41 (in Spanish).

66 Santos G, I, Fernandez BM. Gastric leishmaniasis associated with human immunodefi ciency virus infection. Rev Clin Esp 1999; 199: 332 (in Spanish).

67 Sebastian JJ, Garcia S, Soria MT, Pac J, Vicente J, Uribarrena R. Visceral leishmaniasis diagnosed by colonoscopy. J Clin Gastroenterol 1997; 25: 691–92.

68 Zimmer G, Guillou L, Gauthier T, Iten A, Saraga EP. Digestive leishmaniasis in acquired immunodefi ciency syndrome: a light and electron microscopic study of two cases. Mod Pathol 1996; 9: 966–69.

69 Alex S, Criado C, Fernandez-Guerrero ML, et al. Nephrotic syndrome complicating chronic visceral leishmaniasis: re-emergence in patients with AIDS. Clin Nephrol 2008; 70: 65–68.

70 Clevenbergh P, Okome MN, Benoit S, et al. Acute renal failure as initial presentation of visceral leishmaniasis in an HIV-1-infected patient. Scand J Infect Dis 2002; 34: 546–47.

71 de Valliere S, Mary C, Joneberg JE, et al. AA-amyloidosis caused by visceral leishmaniasis in a human immunodefi ciency virus-infected patient. Am J Trop Med Hyg 2009; 81: 209–12.

72 Navarro M, Bonet J, Bonal J, Romero R. Secondary amyloidosis with irreversible acute renal failure caused by visceral leishmaniasis in a patient with AIDS. Nefrologia 2006; 26: 745–46 (in Spanish).

73 Matheron S, Cabie A, Parquin F, et al. Visceral leishmaniasis and HIV infection: unusual presentation with pleuropulmonary involvement, and eff ect of secondary prophylaxis. AIDS 1992; 6: 238–40.

74 Mofredj A, Guerin JM, Leibinger F, Masmoudi R. Visceral leishmaniasis with pericarditis in an HIV-infected patient. Scand J Infect Dis 2002; 34: 151–53.

75 Munoz-Rodriguez FJ, Padro S, Pastor P, et al. Pleural and peritoneal leishmaniasis in an AIDS patient. Eur J Clin Microbiol Infect Dis 1997; 16: 246–48.

76 Canalias J, Falco J, Martin J, Jurado I. Macronodular hepatic granulomas due to visceral leishmaniasis in an AIDS patient: imaging fi ndings. J Comput Assist Tomogr 1997; 21: 677–79.

77 Fernandez-Miranda C, Colina F, Delgado JM, Lopez-Carreira M. Diff use nodular regenerative hyperplasia of the liver associated with human immunodefi ciency virus and visceral leishmaniasis. Am J Gastroenterol 1993; 88: 433–35.

78 Mondain-Miton V, Toussaint-Gari M, Hofman P, et al. Atypical leishmaniasis in a patient infected with human immunodefi ciency virus. Clin Infect Dis 1995; 21: 663–65.

79 Federal HIV/AIDS Prevention and Control Offi ce, Federal Ministry of Health. Guidelines for management of opportunistic infections and antiretroviral treatment in adolescents and adults in Ethiopia. March 2008. http://www.who.int/hiv/pub/guidelines/ethiopia_art.pdf (accessed Feb 5, 2013).

80 de Faria FB, Barroca H. Fine needle aspiration of a lymph node in an HIV patient with chronic infection by leishmania: a case report. Acta Cytol 2010; 54 (5 suppl): 946–48.

81 Harms G, Zenk J, Martin S et al. Localized lymphadenopathy due to leishmanial infection. Infection 2001; 29: 355–56.

82 Ignatius R, Loddenkemper C, Woitzik J, Schneider T, Harms G. Localized leishmanial lymphadenopathy: an unusual manifestation of leishmaniasis in a traveler in southern Europe. Vector Borne Zoonotic Dis 2011; 11: 1213–15.

83 Sharma SK, Das ML, Rijal S, Sah SP, Koirala S. Lymphatic leishmaniasis—fi rst case report from Nepal. Southeast Asian J Trop Med Public Health 2001; 32: 749–50.

84 Tallada N, Raventos A, Martinez S, Compano C, Almirante B. Leishmania lymphadenitis diagnosed by fi ne-needle aspiration biopsy. Diagn Cytopathol 1993; 9: 673–76.

85 de Beer P, el Harith A, Deng LL, Semiao-Santos SJ, Chantal B, van Grootheest M. A killing disease epidemic among displaced Sudanese population identifi ed as visceral leishmaniasis. Am J Trop Med Hyg 1991; 44: 283–89.

86 Bielory BP, Lari HB, Mirani N, Kapila R, Fitzhugh VA, Turbin RE. Conjunctival squamous cell carcinoma harboring leishmania amastigotes in a human immunodefi ciency virus-positive patient. Arch Ophthalmol 2011; 129: 1230–31.

87 Canet JJ, Julia J, Martinez-Lacasa J, Garau J. Clinical microbiological case: esophageal lesion in an AIDS patient. Clin Microbiol Infect 2003; 9: 421, 463–66.

88 Diego MJ, Omar M, Jimenez-Alonso J, Miranda C, Aliaga L. Visceral leishmaniasis with small intestine and colon involvement in a patient with HIV infection. Enferm Infecc Microbiol Clin 1995; 13: 377–78 (in Spanish).

89 Zijlstra EE, Musa AM, Khalil EA, el-Hassan IM, el-Hassan AM. Post-kala-azar dermal leishmaniasis. Lancet Infect Dis 2003; 3: 87–98.

90 Lynen L. Clinical HIV/AIDS care guidelines for resource-poor settings. Médecins Sans Frontières. 2006. http://telemedicine.itg.be/telemedicine/Uploads/MSFGuidelines2006JuneMSF.pdf (accessed Feb 5, 2013).


Personal View

91 WHO. IMAI acute care: interim guidelines for fi rst-level facility health workers at health centre and district outpatient clinic. 2009. http://www.who.int/hiv/pub/imai/acute_care.pdf (accessed Feb 5, 2013).

92 WHO. IMAI/IMCI chronic care with ARV therapy and prevention: interim guidelines for fi rst-level facility health workers at health centers and district outpatient clinic. 2007. http://www.who.int/hiv/pub/imai/Chronic_HIV_Care7.05.07.pdf (accessed Feb 5, 2013).

93 WHO. IMAI district clinician manual: hospital care for adolescents and adults – guidelines for the management of illnesses with limited resources. 2011 http:\\www.who.int/hiv/topics/capacity/en/ (accessed Feb 5, 2013).

94 Sudan HIV/AIDS working group. Tackling the HIV challenge in Sudan: the way forward. 2008. http://www.shawg.org/Documents/the%20way%20forward%202008.pdf (accessed Feb 5, 2013).

95 Ministry of Health. National manual for the management of HIV related opportunistic infection and conditions. A healthcare workers’ manual. 2008. http://nascop.or.ke/library/ARTguidelines/NationalManualforthemanagementofHIVrelatedOIs.pdf (accessed Feb 5, 2013).

96 WHO. Antiretroviral therapy for HIV Infection in adults and adolescents: recommendations for a public health approach. 2006. http://www.who.int/hiv/pub/guidelines/adult/en/index.html (accessed Feb 5, 2013).