Successful treatment of diffuse cutaneous leishmaniasis caused by Leishmania amazonensis

Abstract Diffuse cutaneous leishmaniasis is a rare universal disease associated with an inadequate host cell immune response, caused by different species: infantum, aethiopica, major, mexicana, and others, which presents the challenge of a poor therapeutic response. In Brazil, it is caused by L. amazonensis. A case confirmed by histopathology with an abundance of vacuolated macrophages full of amastigotes and lymphocyte scarcity, identified by RFLP-ITS1PCR and in vitro decrease and exhaustion of the host cell immune response to L. amazonensis antigen, was treated early (3 months after the onset) with Glucantime (2 months) and allopurinol (29 months) with clinical cure, after a follow-up for 30 months after treatment.

PD-L1 May Mediate T-Cell Exhaustion in a Case of Early Diffuse Leishmaniasis Caused by Leishmania (L.) amazonensis.

Introduction: Diffuse cutaneous leishmaniasis (DCL) is a rare disease form associated with Leishmania (L.) amazonensis in South America. It represents the "anergic" pole of American Tegumentary Leishmaniasis, and the explanation for its resistance to treatment remains elusive. We aimed to study some possible immunological mechanisms involved in the poor DCL treatment response by evaluating some cell surface molecules obtained from a patient with DCL by flow cytometry. Case presentation: A 65-year-old DCL patient who initially failed to respond to the standard treatment for the disease showed vacuolated macrophages filled with amastigotes in lesion biopsy, and L. (L.) amazonensis was identified through ITS1PCR amplification. The Leishmania skin test and indirect immunofluorescence analysis revealed negative results. Peripheral blood from the patient was collected after a few months of treatment, when the patient presented with no lesion. Peripheral blood mononuclear cells were analyzed ex vivo and in vitro after 48 h of stimulation with soluble L. (L.) amazonensis antigen (SLA). Cell death, surface molecules, and intracellular molecules, such as IFN-γ and granzyme B, were analyzed in the cells using flow cytometry. Analysis of the surface markers showed an increased expression of the inhibitory molecule programmed death ligand 1 (PD-L1) in the monocytes restimulated with SLA (approximately 65%), whereas the negative controls were 35% positive for PD-L1. Conversely, compared with the negative controls, we observed a decrease in CD4+IFN-γ+ T cells (8.32 versus 1.7%) and CD8+IFN-γ+ T cells (14% versus 1%). We also observed a relevant decrease in the granzyme B levels in the CD8+ T cells, from 31% in the negative controls to 5% after SLA restimulation. Conclusion: The dysfunctional activation of PD-L1 inhibitory pathway after Leishmania antigen stimulation and reduced levels of IFN-gamma and granzyme B-producing cells could be closely related to unresponssiveness to standard drug treatment of DCL patient.

Case Report: Diffuse Cutaneous Leishmaniasis by Leishmania infantum in a Patient Undergoing Immunosuppressive Therapy: Risk Status in an Endemic Mediterranean Area.

This case report highlights the risk of severe cutaneous leishmaniasis (CL) by Leishmania infantum in patients undergoing immunosuppressant therapy who either live in an endemic area or are visiting in the transmission season. The case patient, resident in Majorca (Balearic Islands), presented 12 disseminated erythematous skin lesions, 1-6 cm in diameter, located on the scalp, cheek, umbilical region, and lower extremities 8 years after undergoing anti-tumor necrosis factor (TNF) therapy. Parasite presence in peripheral blood and high levels of specific antibodies were also observed, indicating a possible risk of CL shifting toward a visceral infection. However, once CL was diagnosed, anti-TNF therapy was discontinued and liposomal amphotericin B was administered, resulting in a complete healing of lesions, no Leishmania DNA detection in blood, and an important serological decrease in antibodies. The lack of data on the supposed epidemiological association between leishmaniasis and immunosuppressive therapy highlights the importance of implementing surveillance systems in endemic areas. No obvious relationship was found based on the data provided by the Balearic Islands Epidemiological System, in contrast with data reported in nearby endemic areas. This indicates that if the suspected association is to be clarified, greater efforts are needed to report information about concomitant diseases and therapies in leishmaniasis patients.

Coinfection of Leishmania guyanensis and Human Immunodeficiency Virus-Acquired Immune Deficiency Syndrome: Report of a Case of Disseminated Cutaneous Leishmaniasis in Ecuador.

AbstractReported herein is the first case of Leishmania-human immunodeficiency virus (HIV) coinfection in Ecuador. In Ecuador, HIV infections overlap endemic areas of leishmaniasis. Immunosuppression is a well-established risk factor for developing severe disease. This is a severe case of a 32-year-old man presenting with disseminated pleomorphic ulcers, papules, and cutaneous plaque-like lesions over his whole body. Numerous amastigotes were observed in both skin scrapings and biopsies. The sequence of the cytochrome b gene confirmed the presence of Leishmania guyanensis. The patient was treated but failed to respond to meglumine antimoniate and amphotericin B. Six months later, the patient died due to bacterial septic shock.

Disseminated Autochthonous Dermal Leishmaniasis Caused by Leishmania siamensis (PCM2 Trang) in a Patient from Central Thailand Infected with Human Immunodeficiency Virus.

AbstractSeveral case reports of autochthonous leishmaniasis in Thailand have been published since 1996. Most of the previous cases presented with visceral leishmaniasis (VL) and were mostly reported in southern part of Thailand. Recently, it has been evident that Leishmania martiniquensis is the main cause of Leishmania infection in Thailand. However, Leishmania siamensis (PCM2 Trang isolate) was found to be of a separate lineage with restricted distribution in southern Thailand and also a cause of disseminated dermal and visceral leishmaniasis in one published case. Here we report the first patient from central Thailand with human immunodeficiency virus infection presenting with disseminated dermal leishmaniasis. Polymerase chain reaction and DNA sequencing analysis (large subunit of RNA polymerase II and 18S ribosomal RNA internal transcribed spacer 1) from the tissue biopsy sample revealed the pathogen sequences to be highly homologous to PCM2 Trang strain previously reported from southern Thailand.

The antifungal compound butenafine eliminates promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis.

The production of ergosterol lipid, important for the Leishmania membrane homeostasis, involves different enzymes. This pathway can be blocked to azoles and allylamines drugs, such as Butenafine. The aim of the present work was to evaluate the anti-leishmanicidal activity of this drug in 2 major species of Leishmania responsible for causing the American tegumentar leishmaniasis (L. (L.) amazonensis and L. (V.) braziliensis). Butenafine eliminated promastigote forms of L. amazonensis and L. braziliensis with efficacy similar to miltefosine, a standard anti-leishmania drug. In addition, butenafine induced alterations in promastigote forms of L. amazonensis that resemble programmed cell death. Butenafine as well as miltefosine presented mild toxicity in peritoneal macrophages, however, butenafine was more effective to eliminate intracellular amastigotes of both L. amazonensis and L. braziliensis, and this effect was not associated with elevated levels of nitric oxide or hydrogen peroxide. Taken together, data presented herein suggests that butenafine can be considered as a prototype drug able to eliminate L. amazonensis and L. braziliensis, etiological agents of anergic diffuse and mucocutaneous leishmaniasis, respectively.

In vitro and in vivo antileishmania activity of sesquiterpene lactone-rich dichloromethane fraction obtained from Tanacetum parthenium (L.) Schultz-Bip.

The discovery of new treatments for neglected diseases, including leishmaniasis, is a substantial challenge for scientific research. Plant extracts have shown potential in the selective treatment of tropical diseases. The present study evaluated the in vitro and in vivo antileishmania effects of a sesquiterpene lactone-rich dichloromethane fraction (DF) obtained from the aerial parts of Tanacetum parthenium (L.) Schultz-Bip. In vitro studies of the DF indicated an IC50 of 2.40±0.76 µg mL(-1) against the promastigote form and 1.76±0.25 µg mL(-1) against the axenic amastigote form of Leishmania amazonensis. In vivo intramuscular treatment with DF decreased the growth and size of footpad lesions in mice. The DF also significantly decreased the parasite population compared with animals that were treated with the reference drug. Plasma malondialdehyde levels were increased slightly by the DF, attributable to its parthenolide-rich composition that causes cellular apoptosis, compared with the control group, demonstrating treatment efficacy without toxicity or genotoxicity. Because the isolation and purification of plant compounds are costly and time-consuming and generate low yields, extract fractions, such as the DF studied herein, represent a promising alternative for the treatment of leishmaniasis.

Evaluación del transporte de glucosa, fármacos y del potencial de membrana como métodos pronósticos de quimioterapia en Leishmania spp / Evaluation of glucose transport, drugs and membrane potential as prognostic methods of chemotherapy in Leishmania spp

El fracaso terapéutico en leishmaniasis a menudo esta asociado a resistencia a los medicamentos por parte de los parásitos. Hasta ahora no se ha evaluado sistemáticamente si este fenotipo compromete u optimiza el metabolismo o la efectividad en leishmania, es decir, su competencia y adaptabilidad. Durante su ciclo de vida los parásitos deben ajustarse a condiciones de vida extremas, lo cual no es gratuito. Al presentarse conflictos que comprometen propiedades de leishmania esenciales para su supervivencia, surge un costo de adaptación. Sin embargo, tales compensaciones son el precio a pagar que garantizan la co-evolucion del binomio hospedero-parásito y el mantenimiento de la diversidad genética de leishmania. Comprender ese costo es imprescindible a fin de diseñar medidas de prognosis y control exitosas. Adicionalmente, el método vigente y confiable para evaluar resistencia en leishmania es el método in vitro macrofago-amastigote, el cual es oneroso y laborioso. Como parte de un proyecto sobre quimo-resistencia en Leismania, planteamos evaluar posibles parámetros bioquímicos que pudieran servir como marcadores celulares a ser usados para identificar parásitos con fenotipo quimioresistentes en aislados de pacientes y compararlos con cepas de referencia. Los resultados sugieren que algunos aislados:a) tienen incrementada la expresión transportadores ABC, b) utilizan glucosa de forma diferencial, c) tienen un potencial de membrana menos polarizado y d) expresan diferente sensibilidad a inhibidores clásicos de la función mitocondrial. En conjunto, los datos indican que los aislados estudiados expresan los mismos cambios fisiológicos ya descritos en parásitos de referencia quimioresistentes. Es decir, que los cambios explorados podrían constituir un patrón general asociado a este fenómeno leishmania, lo cual los valida como marcadores celulares de resistencia. En conclusion, se propone un nuevo enfoque al problema del tratamiento de la enfermedad ya que, además de las estrategias clásicas, se añadirían herramientas de pronostico del éxito de la quimioterapia.

Increase of NK cells and proinflammatory monocytes are associated with the clinical improvement of diffuse cutaneous leishmaniasis after immunochemotherapy with BCG/Leishmania antigens.

Diffuse cutaneous leishmaniasis (DCL) is characterized by disseminated lesions and the absence of a specific cellular immune response. Here, the immunochemotherapy outcome of a patient with DCL from Amazonian Brazil infected with Leishmania (Leishmania) amazonensis is presented. After several unsuccessful chemotherapy treatment regimens and many relapses, a monthly immunotherapy scheme of L. amazonensis PH8 plus L. (Viannia) braziliensis M2903 monovalent vaccines associated with Bacillus Calmette-Guerin (BCG) was established, one round of which also included an M2903 vaccine associated with intermittent antimonial treatment. Temporary healing of all lesions was achieved, although Leishmania skin tests were negative and interferon gamma was not detected in mononuclear cell cultures stimulated with Leishmania antigens. The frequencies of CD16 (+)CD56(+) NK cells (approximately 2x) and CD14 (+)CD16(+) proinflammatory monocytes (approximately 8x) increased in peripheral blood, and CD56 (+) lymphocytes were found infiltrating the lesions. An association between the increase of the frequency of innate immune system cells and the healing of lesions is shown, suggesting that this protocol of immunotherapy reduced the parasite load and activated NK cells and monocytes.

Diffuse cutaneous leishmaniasis: co-infection with human immunodeficiency virus (HIV).

Cutaneous leishmaniasis is a disease caused by intracellular protozoal parasites belonging to the genus Leishmania. Immune suppression caused by HIV infection is an important factor for atypical presentation and widespread progression of cutaneous leishmaniasis. Diffuse (disseminated) cutaneous leishmaniasis and HIV co-infection is emerging as an extremely serious new disease. A 38-year-old HIV-positive man presented with a 12-month history of a progressive papule and nodular eruptions on face and extremities with infiltrations of nasal and oral mucosa. We report the case due to its atypical, widespread muco-cutaneous presentation masquerading as lepromatous leprosy.

Diffuse cutaneous leishmaniasis responds to miltefosine but then relapses.

BACKGROUND: Diffuse cutaneous leishmaniasis (DCL), although rare, is profoundly incapacitating. At present there is no successful treatment for this progressive protozoan infection, which is associated with the absence of specific cell-mediated immunity (CMI) to Leishmania. This disease shares features with visceral leishmaniasis (VL), including specific CMI inactivity during active disease and a heavy parasitic burden, but VL responds well to treatment. Miltefosine is the first orally administered drug which has shown efficacy in the treatment of VL; it has not been adequately evaluated in the treatment of DCL. OBJECTIVES: To evaluate the efficacy of miltefosine in the treatment of DCL, using clinical, parasitological, histopathological and immunological criteria. METHODS: Sixteen patients with DCL were treated with miltefosine, 2.0-2.5 mg kg(-1) daily, for variable periods of time (75-218 days). Patients were hospitalized for the first month and evaluated every 2 weeks until the termination of treatment with routine laboratory chemistry, percentage clinical improvement, presence of parasites in skin smears, growth of parasites in culture medium and in hamsters, histopathological characteristics of the granulomas, adverse side-effects, and reactivity to leishmanin skin test antigen. Further cycles of treatment were given in some of these patients, particularly after suspension of treatment was followed by relapse. RESULTS: Patients showed dramatic clinical improvement and reduction in the parasite burden by day 15 after the initiation of treatment, which continued while treatment was maintained. By day 45, 15 patients showed 80-90% clinical improvement. Nevertheless, suspension of treatment was followed by the development of new lesions in all but one patient. Inoculation in hamsters was observed to be the most sensitive technique to detect persisting parasites. Adverse events were very mild. CONCLUSIONS: Miltefosine produced a dramatic clinical and parasitological response in patients with DCL and improvement continued during drug administration, but with a single exception all patients presented new lesions after suspension of treatment. There was no histological or skin test evidence to suggest the development of CMI during treatment, which may be an indispensable criterion for the evaluation of potentially effective drugs against DCL.

Diffuse cutaneous leishmaniasis in an HIV-positive patient in western Africa.

A 36-year-old HIV1-positive woman presented with a 6-month history of a progressive papular and nodular eruption of the face and subsequent extensive spread to the rest of the skin. The diagnosis of diffuse cutaneous leishmaniasis was established by direct examination and skin biopsy. This atypical form had a dramatic improvement after a 21-day treatment with meglumine antimoniate. This clinical form may be confused with other endemic diseases in western Africa, especially leprosy.

Tratamiento con miltefosina de la leishmaniosis cutánea diseminada / Miltefosine for disseminated cutaneous leishmaniasis

La leishmaniosis cutánea diseminada es una forma escasa de leishmaniosis, que se caracteriza por la diseminación sanguínea del parasito que lleva a la aparición de múltiples nódulos y placas en la piel de todo el cuerpo y aun de la mucosa nasal. Se diferencia de la leishmaniosis cutánea difusa en que la alteración de la inmunidad celular es menor y las lesiones pueden tener una descamación epidérmica, en cambio en la leishmaniosis difusa las lesiones son nodulares y hay una anergia celular específica contra el parásito. En este artículo se describe el caso de un paciente colombiano con Leishmaniosis cutánea diseminada causada por L(V) panamensis que inicialmente tuvo falla terapéutica al ser tratado con Glucantime y Anfotericina B y quien curó de sus lesiones al recibir tratamiento con Miltefosine.

Disseminated cutaneous leishmaniasis is a rare presentation characterized by hematogenous dissemination of the parasite that causes the appearance of multiple nodules and plaques in the skin of the whole body and even including the nasal mucous membrane. It differs from diffuse cutaneous leishmaniasis because the alteration in cellular immunity is lower and the lesions may have epidermal desquamation. On the other hand, diffuse cutaneous leishmaniasis presents nodular lesions and a specific anergy in the immune response directed against the parasite. This article describes the case of a Colombian patient with disseminated cutaneous leishmaniasis caused by L. (V) panamensis. The initial treatments with Glucantime® and Amphotericin B failed, but his lesions healed after treatment with miltefosine.

[Diffuse cutaneous leishmaniasis in a patient with AIDS]. / Leishmaniasis cutánea difusa en un paciente con sida.

OBJECTIVE: A patient with a leishmaniasis-Aids co-infection was presented and discussed.. METHODS AND RESULTS: A 29-year -old soldier, coming from the Province of San José del Guaviare, Colombia, complained of a weight loss of 18 kgs in the previous ten months as well as a two-month-old cutaneous leision. Elisa and Western blot tests were positive for HIV infection. LT CD4 were 92/mm3. He had a generalized erythematous, psoriasiform dermal lesion, which, upon biopsy, revealed an abundance of phagocytosed microorganisms that stained black with Gomory's technique. Disseminated histoplasmosis was diagnosed. The patient received anti-retroviral therapy and itraconazole, without regression of the lesions. Amphotericin B was beneficial but the lesions recurred several months later, more numerous, nodular and with occurrence in the oral mucosa. Nine months after the initial diagnosis additional skin biopsies and review of the previous biopsies established that the patient had diffuse cutaneous leishmaniasis. The leishmania parasite did not grow in culture. Miltefosine produced marked improvement, but the lesions recurred and were cured finally with 52 Glucantime injections administered for two months. Presently, the patient remains in good condition 21 months after diagnosis of leishmaniasis. CONCLUSIONS: Diffuse cutaneous leishmaniasis may be a common clinical manifestation when leishmaniasis and AIDS co-occur. Its treatment is difficult and must include an antiparasitic drug as well as prophylactic, and anti-retroviral therapy. Leishmania amastigotes typically are not Gomory-positive and can be differentiated from Histoplasma by morphology, immunohistochemistry, culture, antibody-specific response and PCR. The leishmaniasis-AIDS co-infection enhances invasive capacity for both causal microorganisms. Increasing case numbers can be expected in Colombia, due to the high frequency of both diseases.

Disseminated cutaneous leishmaniasis.

Disseminated cutaneous leishmaniasis DCL is a condition rarely seen in the Middle East. We report a case of disseminated cutaneous leishmaniasis in a 60-years-old lady. The patient first presented 1996 with an initial lesion, which started on the butterfly area of the face and spread, probably due to immunosuppression, to involve the whole face. The lesions consisted of nodules, which did not ulcerate. The histology showed abundance of macrophages filled with amastigotes L-D bodies. The patient was started on oral zinc sulphate 10 mg/kg in 3 divided doses daily. The condition showed gradual improvement. Repeated biopsies showed upgrading of the histopathological picture. After 6-months of treatment there was complete clearance of the condition. The patient was followed up for 6-years with no recurrence. However, she presented with a new lesion on the butterfly area again in February 2003. The biopsy again showed abundance of macrophages filled with amastigotes L-D bodies. A 4-months course of zinc sulphate 10 mg/kg in 3 divided doses daily resulted in complete clearance of the lesions. Zinc sulphate might represent a new treatment for this condition that has no adequate treatment until now.

Leishmaniose tegumentar americana associada à AIDS: relato de quatro casos / American cutaneous leishmaniasis associated with HIV/AIDS: report of four clinical cases

A co-infecção leishmaniose tegumentar americana e AIDS é de relato recente na literatura, observando-se diversidade quanto ao comportamento clínico e imunológico destes pacientes. Relatamos quatro casos acompanhados no Hospital Universitário de Brasília, com diagnóstico de infecçäo por parasitas do gênero Leishmania e pelo vírus da imunodeficiência humana, ilustrando diferentes apresentaçöes clínicas, evoluções e respostas terapêuticas