Liposomal amphotericin B is more effective in polymorphic lesions of post kala-azar dermal leishmaniasis.

BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL) is thought to be the reservoir of infection for visceral leishmaniasis in South Asia. The development of strategies for the diagnosis and treatment of PKDL are important for the implementation of the visceral leishmaniasis elimination program. AIMS: Liposomal amphotericin B (L-AMB) has been an overwhelming success in the treatment of visceral leishmaniasis. However, the empirical three-week regimen of L-AMB proposed for PKDL was shown to be inadequate, especially in the macular variant. This study aimed to delineate response of the different variants of PKDL to L-AMB. METHODS: Skin biopsies were collected from PKDL cases at disease presentation and upon completion of treatment with L-AMB. Parasite DNA was detected by Internal Transcribed Spacer-1 PCR (ITS-1 PCR) and quantified by amplification of parasite kDNA. CD68 + macrophages were estimated in tissue sections by immunohistochemistry. RESULTS: Treatment with L-AMB decreased the parasite load by 97% in polymorphic cases but only by 45% in macular cases. The median parasite load (89965 vs 5445 parasites/µg of genomic DNA) as well as infiltration by CD68+ cells before treatment was much greater in the polymorphic cases. LIMITATIONS: Although monitoring of the parasite load for 12 months post-treatment would have been ideal, this was not possible owing to logistical issues as well as the invasive nature of biopsy collection procedure. CONCLUSION: A dramatic decrease in the parasite burden was noted in patients with polymorphic lesions. Although patients with macular disease also had a decrease in parasite burden, this was not as marked as in the polymorphic cases. There was also a significantly greater infiltration of CD68 + macrophages in polymorphic PKDL before therapy.

Case Report: Severe Visceral Leishmaniasis in a Patient with HIV Coinfection Undergoing Treatment for Erythema Nodosum Leprosum.

We report a case of visceral leishmaniasis (VL)/HIV coinfection in a patient undergoing regular antiretroviral therapy and treatment with thalidomide for erythema nodosum leprosum. He presented at a health service with high fever, chills, asthenia, pale skin, lower limb edema, hepatomegaly, and splenomegaly. Visceral leishmaniasis was confirmed by direct examination, and serological and molecular tests. Serum levels of Th1/Th2 cytokines were measured. The patient began treatment with liposomal amphotericin B, with good clinical response; however, VL recurred 6 months later. Treatment was reinitiated, maintaining secondary prophylaxis with liposomal amphotericin B. The patient showed clinical improvement with important recovery of CD4+ T-lymphocyte count.

Current and emerging medications for the treatment of leishmaniasis.

INTRODUCTION: Leishmaniasis is a vector-borne neglected tropical disease which manifests as visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), and mucocutaneous leishmaniasis (MCL). The current drugs are toxic, duration of treatment is long, there is regional variation in efficacy, and emergence of resistance is common. AREAS COVERED: This manuscript is based on literature derived from PubMed and reviews the current and emerging medications for the treatment of leishmaniasis. A single dose of liposomal amphotericin B (L-AmB) and multidrug therapy are the best options for VL in the Indian subcontinent (ISC), while a combination of pentavalent antimonials and paromomycin remains the treatment of choice for VL in Africa where efficacious and safe regimens are needed for HIV-VL coinfection. L-AmB at a total dose of 18-21 mg/kg is the recommended regimen for VL in the Mediterranean region, South America and for HIV-VL coinfection. Treatment of CL varies from observation, local or systemic therapy depending on severity of lesions, etiological species and its potential to develop into mucosal leishmaniasis. EXPERT OPINION: The monitoring of single-dose L-AmB and combination therapy in the ISC is essential. Effective short-course combination therapy is needed for the treatment of post-kala-azar dermal leishmaniasis and HIV-VL. Better evidence for treatment is still needed along with safer and shorter treatment options for CL and MCL.

Post-kala-azar dermal leishmaniasis and leprosy: case report and literature review.

BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis (VL), which may occur after or during treatment. It has been frequently reported from India and the Sudan, but its occurrence in South America has been rarely reported. It may mimic leprosy and its differentiation may be difficult, since both diseases may show hypo-pigmented macular lesions as clinical presentation and neural involvement in histopathological investigations. The co-infection of leprosy and VL has been reported in countries where both diseases are endemic. The authors report a co-infection case of leprosy and VL, which evolved into PKDL and discuss the clinical and the pathological aspects in the patient and review the literature on this disease. CASE PRESENTATION: We report an unusual case of a 53-year-old female patient from Alagoas, Brazil. She presented with leprosy and a necrotizing erythema nodosum, a type II leprosy reaction, about 3 month after finishing the treatment (MDT-MB) for leprosy. She was hospitalized and VL was diagnosed at that time and she was successfully treated with liposomal amphotericin B. After 6 months, she developed a few hypo-pigmented papules on her forehead. A granulomatous inflammatory infiltrate throughout the dermis was observed at histopathological examination of the skin biopsy. It consisted of epithelioid histiocytes, lymphocytes and plasma cells with the presence of amastigotes of Leishmania in macrophages (Leishman's bodies). The diagnosis of post-kala-azar dermal leishmaniasis was established because at this time there was no hepatosplenomegaly and the bone marrow did not show Leishmania parasites thus excluding VL. About 2 years after the treatment of PKDL with liposomal amphotericin B the patient is still without PKDL lesions. CONCLUSION: Post-kala-azar dermal leishmaniasis is a rare dermal complication of VL that mimics leprosy and should be considered particularly in countries where both diseases are endemic. A co-infection must be seriously considered, especially in patients who are non-responsive to treatment or develop persistent leprosy reactions as those encountered in the patient reported here.

A retrospective study of intravenous sodium stibogluconate alone and in combinations with allopurinol, rifampicin, and an immunomodulator in the treatment of Indian post-kala-azar dermal leishmaniasis.

BACKGROUND AND AIMS: A retrospective analysis of treatment outcome using recommended dose of sodium stibogluconate (SSG) alone and in combination with other antileishmanial drugs in adults with post-kala-azar dermal leishmaniasis (PKDL) attending as outpatients. METHODS: A total of 61 patients seen over ten years were included in the report. All had polymorphic lesions. Diagnosis was based on clinical picture, hailing from kala-azar (KA) endemic area, exclusion of other dermatoses, histopathology, and therapeutic response. Patients were distributed into two groups: Group I (n = 32), where SSG was given intravenously; in Group II (n = 29), they were allocated to one of four categories using SSG in combination with other drugs. In the first category, SSG was given along with allopurinol (n = 10); in second with rifampicin (n = 6); and in third with both allopurinol and rifampicin (n = 5). In the fourth category, SSG was administered with an immunomodulator (n = 8), Mw vaccine, known to enhance host Th1 response. RESULTS: Only 12 out of 61 patients completed treatment till histopathologic evidence of cure, five in Group I and seven in Group II, no patient being from third category. None had taken SSG without interruptions. Time taken for papulonodules to subside was similar in both groups, but erythema and induration subsided earlier in Group II. Group I patients attained cure after 120 injections while in Group II it took 95 injections in SSG + allopurinol and Mw vaccine categories respectively, and 110 with SSG + rifampicin. Nevertheless this was insufficient to facilitate compliance. Poor performance and high dropouts related to long duration of therapy, thrombophlebitis, difficulty in accessing veins, disabling rheumatic side-effects and practical problems. Liver, renal and pancreatic functions and ECG remained normal. CONCLUSION: No major advantage was obtained using allopurinol, rifampicin or Mw vaccine along with SSG as compared to SSG alone.

Immune response following miltefosine therapy in a patient with post-kala-azar dermal leishmaniasis.

We report a case of post-kala-azar dermal leishmaniasis in which real-time PCR was exploited to measure changes in cytokine transcripts in lesion tissue before and after oral miltefosine treatment. Unlike antimonial therapy elevated levels of IFNgamma transcripts were noted, whereas TNFalpha, IL-10 and transforming growth factor-beta declined similar to that observed after therapy with antimonials. A significant increase in IFNgamma and CD40 levels seen after miltefosine therapy could enhance parasite clearance. The patient remained normal after 18 months of follow-up.

Characterization of immunoglobulin G and its subclass response to Indian kala-azar infection before and after chemotherapy.

Serologic parameters of kala-azar were evaluated by Western blot analysis. Sera from kala-azar patients with confirmed diagnoses were screened for immunoglobulin G (IgG) and IgG subclass-specific reactivity against Leishmania donovani membrane antigen (LAg). Heterogeneous LAg-specific IgG reactivity with numerous proteins with molecular masses ranging from 18 to 190 kDa was observed. Though the individual band patterns were varied, seven polypeptides of approximately 31, 34, 51, 63, 72, 91, and 120 kDa were immunoreactive with all the sera tested from kala-azar patients. The band patterns of the immunoblots of sera from patients after treatment and clinical cure with sodium antimony gluconate revealed a decrease in the frequency of the bands. Still, recognition of the 63- and 120-kDa bands was 100%, and the 55- and 91-kDa fractions were recognized in 93% of the sera from cured individuals. Among the IgG subclasses, IgG1 reacted with the greatest number of polypeptides. The 63-kDa protein was again detected by all of the IgG subclasses of all the sera tested. Other fractions recognized by the subclasses of more than 70% of the serum samples included those of 47, 51, 55, and 78 kDa. Following treatment, 63- and 51-kDa bands were the most reactive with the IgG subclasses. LAg-associated cross-reaction with other reference human antisera revealed a mild reactivity of the 63-kDa polypeptide with some of the serum samples from leprosy, malaria, typhoid, tuberculosis, and healthy controls. Western blot analysis of LAg entrapped in liposomes, strong vaccine candidates against experimental visceral leishmaniasis, revealed a more restricted band pattern. The 63-kDa fraction revealed by all pre- and posttreatment sera showed almost negligible levels of cross-reaction with sera from patients with other diseases or from healthy controls. These observations provide insight into induced immunity during kala-azar infection for future application.

Post-kala-azar dermal leishmaniasis in the Sudan: clinical presentation and differential diagnosis.

Post-kala-azar dermal leishmaniasis (PKDL) is a common complication following kala-azar (visceral leishmaniasis). In a prospective study in a village in the endemic area for kala-azar in the Sudan, 105 of 183 (57%) kala-azar patients developed PKDL. There was a significantly higher PKDL rate (69%) in those who received inadequate and irregular treatment of kala-azar than in those who were treated with stibogluconate 20 mg kg-1 daily for 15 days (35%). The group of patients who developed PKDL did not differ from those who did not develop PKDL with regard to age and sex distribution, reduction in spleen size, and conversion in the leishmanin skin test (LST). In a clinical study, 416 PKDL patients were analysed and divided according to grade of severity. Severe PKDL was more frequent in younger age groups (P < 0.001); there was an inverse correlation between grade and conversion in the LST (P < 0.01). In 16% of patients tested, parasites were demonstrated in inguinal lymph node or bone marrow aspirates, indicating still visceral disease (para-kala-azar dermal leishmaniasis); there was no correlation between the presence of parasites and grade of severity. Conversion rates in the LST were lower than in those who did not have demonstrable parasites (11% and 37%, respectively; P < 0.01). In the absence of reliable and practical diagnostic tests, PKDL may be diagnosed on clinical grounds and differentiated from other conditions, of which miliaria rubra was the most common. Differentiation from leprosy was most difficult.

Diagnostic and prognostic potential of a competitive enzyme-linked immunosorbent assay for leishmaniasis in India.

A Leishmania donovani species-specific monoclonal antibody (monoclonal antibody D2) was evaluated for its diagnostic and prognostic potential by a competitive enzyme-linked immunosorbent assay (C-ELISA) in sera from Indian patients with visceral leishmaniasis (VL) and seven patients with post-kala-azar dermal leishmaniasis (PKDL). These results were compared with those obtained by microscopy with Giemsa-stained tissue smears and a direct enzyme-linked immunosorbent assay (direct ELISA) with crude parasite antigen. Of 121 patients with clinically diagnosed VL examined, 103 (85.1%) were positive and 11 (9.1%) were negative by all three methods. An additional 7 (5.8%) who were negative by microscopy were positive by both C-ELISA and direct ELISA. Seven PKDL patients were also examined and were found to be positive by all three methods. Analysis of the chemotherapeutic response to sodium antimony gluconate of these 110 serologically positive VL patients showed that 57 (51.8%) were drug responsive and 53 (48.2%) were drug resistant. The C-ELISA with sera from 20 longitudinally monitored VL patients before and after chemotherapy showed a significant decrease in percent inhibition of monoclonal antibody D2 in drug-responsive patients. However, in drug-unresponsive patients, the percent inhibition of D2 was unchanged or was slightly increased. Our results therefore indicate (i) the applicability of L. donovani species-specific monoclonal antibody D2 for sensitive and specific serodiagnosis by C-ELISA, (ii) that the C-ELISA is more sensitive than microscopy, especially for early diagnosis, (iii) that L. donovani is still the main causative agent of VL, irrespective of the chemotherapeutic response, and (iv) that the C-ELISA can be used to evaluate the success of drug treatment.

Post-kala-azar dermal leishmaniasis mimicking leprosy: experience with 4 patients, with some unusual features in 1.

We report on 4 cases of post-kala-azar dermal leishmaniasis (PKDL). History of kala-azar was available in all 4 patients. Slit-skin smears (SSS) for leishmania donovani (LD) bodies were negative in all 4. In 3 patients hypopigmented lesions were present over the face. Papules and nodules over his lips, tongue, scrotum and dactylitis were some unusual features observed in 1 patient. Histopathological examination showed LD bodies in 2 patients; histopathology was nonspecific in the other 2. All the patients were treated with sodium stibogluconate, 20 mg/kg/day. Infiltrated papules and nodules had subsided by 3 months, while hypopigmented macules took longer to improve. In 3 patients there had previously been a misdiagnosis as leprosy sufferers and they had been treated with antileprosy drugs. Clinical and histopathological differences between PKDL and leprosy are discussed.

Post kala-azar dermal leishmaniasis in the Sudan: clinical features, pathology and treatment.

The clinical features, pathology, immune responses, diagnosis and treatment of post kala-azar dermal leishmaniasis (PKDL) in the Sudan are described and discussed. The disease is characterized by maculopapular or nodular lesions on the face, limbs or trunk. Lesions appear during or within months after the treatment of visceral leishmaniasis, but in 2 of 19 patients there was no previous history of kala-azar. PKDL may be confused with leprosy both clinically and pathologically. Similarities and differences between the 2 diseases are discussed. Unlike visceral leishmaniasis, the peripheral lymphoid cells of patients with PKDL respond to Leishmania antigen and some are leishmanin positive. The response to intravenous sodium stibogluconate (20 mg/kg for 30 d) was reasonably good but some patients required repeated or more prolonged treatment. Ketoconazole in a dose of 10 mg/kg daily for 4 weeks had no effect on PKDL.