Directrices para el tratamiento de las leishmaniasis en la región de las américas - 2 ed / Guidelines for the treatment of leishmaniasis in the region of the Americas - 2 ed

Las leishmaniasis son enfermedades infecciosas desatendidas de gran importancia en la Región de las Américas debido a su morbilidad, mortalidad y amplia distribución geográfica. De las tres formas clínicas principales, la cutánea es la más común y la visceral es la forma más grave, ya que puede causar la muerte de hasta 90% de las personas que no reciban tratamiento. En el 2013, la Organización Panamericana de la Salud (OPS) elaboró recomendaciones para el tratamiento de las leishmaniasis en la Región de las Américas utilizando la metodología de clasificación de la valoración, la elaboración y la evaluación de las recomendaciones (GRADE, por su sigla en inglés). No obstante, dada la evidencia acumulada desde entonces, se hizo necesario revisar esas recomendaciones. En esta segunda edición se presentan las recomendaciones actualizadas sobre el tratamiento de las leishmaniasis, y se detallan los esquemas y los criterios de indicación del tratamiento en el contexto regional. Estas directrices presentan modificaciones sustanciales con respecto a la primera edición. En el caso de la leishmaniasis cutánea, se ha eliminado el ketoconazol de las opciones terapéuticas, el número de especies de Leishmania para las que hay evidencia sólida de la eficacia de la miltefosina ha aumentado de dos a cuatro y la recomendación de administrar antimoniales intralesionales ahora es fuerte. Con respecto a la leishmaniasis mucosa, se incluye una recomendación fuerte sobre el uso de antimoniales pentavalentes con o sin pentoxifilina oral. Por lo que respecta a la leishmaniasis visceral, la recomendación fuerte sobre el uso de antimoniales pentavalentes y desoxicolato de anfotericina B ahora es condicional. También hay evidencia contundente en contra del uso de miltefosina en pacientes con leishmaniasis causada por Leishmania infantum. Otros cambios importantes son el desglose de las recomendaciones según si se trata de pacientes adultos o pediátricos, la inclusión de las especies de Leishmania y, en el caso de los pacientes inmunocomprometidos, la introducción de una recomendación fuerte contra el uso de antimoniales pentavalentes. Esta segunda edición es una versión revisada de la publicación Leishmaniasis en las Américas: recomendaciones para el tratamiento: https://iris.paho.org/handle/10665.2/7704

Exuberant case of verrucous cutaneous leishmaniasis

Abstract Cutaneous leishmaniasis represents a public health problem that affects 85 countries. It is an endemic disease in Brazil, having an important socioeconomic impact. An exuberant case of cutaneous leishmaniasis is reported herein. A 28-year-old male patient with Down syndrome had had verrucous plaques on the back for over a year, with progressive growth. PCR of a lesion sample was positive for Leishmania braziliensis. The patient's condition was classified as atypical cutaneous leishmaniasis. He was successfully treated with amphotericin B and miltefosine. The treatment remains a challenge, given the toxicity and low cure rate of the currently recommended drugs.

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.

Cellular infiltrate in cutaneous leishmaniasis lesions and therapeutic outcome

Abstract Background: The treatment of cutaneous leishmaniasis is a challenge. A better understanding of the in situ mechanisms involved in the evolution and cure of the disease is essential for the development of new therapies. Objective: Correlate histopathological and immunological characteristics of cutaneous leishmaniasis lesions with clinical outcome after different treatment regimens. Methods: The authors analyzed cellular infiltration and immunohistochemistry staining for CD4, CD8 and IL-17 in biopsy samples from 33 patients with cutaneous leishmaniasis before treatment. All patients were recruited in a randomized clinical trial at Corte de Pedra (Bahia-Brazil) and assigned to receive Glucantime®, Glucantime® + Oral Tamoxifen or Glucantime® + Topical Tamoxifen. Patients were followed for 2 to 6 months to define disease outcome. Results: A similar expression of CD4, CD8 and IL-17 was observed in lesion samples regardless of clinical outcome. In general, a higher amount of CD8 cells were observed compared with CD4 cells. An important observation was that all patients whose cellular infiltrate did not contain plasma cells were cured after treatment. Study limitations: Isolated quantification of TCD8 and IL-17 using immunohistochemistry is insufficient to analyze the role of these molecules in the immunopathogenesis of cutaneous leishmaniasis. In addition, the expansion of the immunohistochemistry panel would allow a more complete analysis of the immune response in situ. Conclusions: The absence of plasma cells in cutaneous leishmaniasis lesions was related to a favorable therapeutic outcome.

Plantar ulcer as an atypical manifestation of cutaneous leishmaniasis

Abstract Cutaneous leishmaniasis is characterized by ulcers with raised edges and a granular bottom, mainly on the lower limbs. This is a case report of a male patient with an ulcer on the left plantar region. The diagnosis was confirmed by positive PCR for L. braziliensis and the presence of amastigotes of Leishmania sp. in the histopathological examination. After treatment with Glucantime, the patient showed full healing of the ulcer. The unusual location of the ulceration calls attention to atypical presentations of leishmaniasis, and the importance of histopathological examination and PCR, leading to the appropriate diagnosis and treatment.

Ramsey hunt syndrome after antimonial treatment for American Cutaneous Leishmaniasis

Abstract Ramsay Hunt Syndrome (RHS), also known as herpes zoster oticus, is caused by the reactivation of varicella zoster virus (VZV) in the geniculate ganglion of the facial nerve. Herein, we report a case of Ramsey Hunt Syndrome in a patient after antimonial treatment for Cutaneous Leishmaniasis. The patient presented with microvesicles grouped on an erythematous base, starting in the neck and ascending towards the scalp margin on the right side of the head. The patient also developed grade V peripheral facial palsy the day after initiating the herpes zoster treatment, this outcome corroborated the assumption of Ramsey Hunt Syndrome.

Acute uveitis: A rare adverse effect of miltefosine in the treatment of post-kala-azar dermal leishmaniasis

Abstract Post-kala-azar dermal leishmaniasis is a skin disorder occurring in 5-10% of visceral leishmaniasis patients after treatment with miltefosine,the first-line drug for this skin disorder. We reported a case of acute anterior uveitis,a rare adverse effect, experienced by a patient treated with miltefosine for post-kala-azar dermal leishmaniasis. This adverse effect developed after 15 days of miltefosine consumption, and the patient himself discontinued the treatment. The ophthalmic complication was completely resolved with antibiotics and steroid eye drops. After recovery from the ophthalmic complication, the patient was successfully treated with liposomal amphotericin B for the skin lesions.

Efficacy of imiquimod 5% cream as first-line management in cutaneous leishmaniasis caused by Leishmania mexicana

Abstract Cutaneous leishmaniasis (CL) involves several differential diagnoses as it lacks a gold standard diagnostic test. Its diagnosis is easier in endemic regions; however, many cases come from travelers to endemic areas. A 22-year-old patient, who had recently visited Oaxaca, Mexico, developed two asymptomatic ulcers weeks later on the left auricle and the nose. Leishmania mexicana was identified using polymerase chain reaction. The patient was treated with imiquimod 5% cream three times/week, providing favorable results after 12 weeks, without relapse 2 months after therapy. To our knowledge, this is the first case of CL due to L. mexicana effectively treated with imiquimod.

Unusual manifestation of genital cutaneous leishmaniasis in an immunocompetent patient from São Paulo, Brazil: A case report

Abstract A 31-year-old male patient developed an ulcer on the glans penis that evolved for three months without healing. We diagnosed it as leishmaniasis using polymerase chain reaction. No immunosuppression or associated diseases were observed. The patient was treated with meglumine antimoniate that cured the lesion in a month post-treatment. Here, we report this case of cutaneous leishmaniasis lesion at the unusual location of glans penis in an immunocompetent individual. The lesion likely developed due to the bite of a vector, highlighting the need for considering cutaneous leishmaniasis among differential diagnosis of sexually transmitted diseases in areas endemic for leishmaniasis.

Treatment of tegumentary leishmaniasis in two hemodialysis patients with end-stage renal disease using two series of pentamidine

Abstract In this study, we present two cases of cutaneous leishmaniasis in patients with end-stage renal disease, who were treated solely with intramuscular pentamidine. In such cases, treatment implies a fine line between therapeutic efficacy and toxicity. This is suggestive of a knowledge gap; however, findings indicate that this is still the fastest and safest alternative to the treatment with antimonials. Also, it can help avoid the side effects that occur upon using antimonials.

In vivo antileishmanial activity of Annona mucosa extracts

Abstract INTRODUCTION: Leishmaniasis, a disease caused by a parasite endemic to large areas of tropical and subtropical countries, is a growing public health problem. METHODS: Male BALB/c mice were infected with Leishmania amazonensis and treated with extracts isolated from Annona mucosa. RESULTS: Treated groups had significantly reduced footpad swelling. The group treated intraperitoneally with hexane extract showed footpad swelling similar to groups treated with Pentamidine® and Glucantime®. Groups treated with dichloromethane extract and hexane extract presented the recovering phenotype associated with reduced parasite levels. CONCLUSIONS: Extracts of A. mucosa are promising sources of novel antileishmanial compounds.

Metformin promotes susceptibility to experimental Leishmania braziliensis infection

BACKGROUND Metformin (MET) is a hypoglycemic drug used for the treatment of diabetes, despite interference in host immunity against microorganisms. Cutaneous infection caused by pathogens such as Leishmania braziliensis (Lb), the agent responsible for cutaneous leishmaniasis (CL) in Brazil, represents an interesting model in which to evaluate the effects associated with MET. OBJECTIVE To evaluate the modulatory effect of MET in Lb infection. MATERIAL AND METHODS Experimental study of Lb infection and MET treatment in BALB/c mice and Raw 264.7 macrophages. FINDINGS MET treatment interfered with lesion kinetics, increased parasite load and reduced macrophage proliferation. Low concentrations of MET in Lb culture allow for the maintenance of stationary parasite growth phase. Lb-infected cells treated with MET exhibited increased parasite load. While both MET and Lb infection alone promoted the production of intracellular reactive oxygen species (ROS), reduced levels of ROS were seen in MET-treated Lb-infected macrophages. MAIN CONCLUSION Experimental treatment with MET interfered with the kinetics of cutaneous ulceration, increased Lb parasite load, altered ROS production and modulated cellular proliferation. Our experimental results indicate that MET interfere with the evolution of CL.

Efficacy of the 7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline derivative against infection caused by Leishmania amazonensis

Abstract INTRODUCTION: The drugs currently available for leishmaniasis treatment have major limitations. METHODS: In vitro and in vivo studies were performed to evaluate the effect of a quinoline derivative, Hydraqui (7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline, against Leishmania amazonensis. In silico analyses of absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were performed. RESULTS: Hydraqui showed significant in vitro anti-amastigote activity. Also, Hydraqui-treated mice exhibited high efficacy in lesion size (48.3%) and parasitic load (93.8%) reduction, did not cause hepatic and renal toxicity, and showed appropriate ADMET properties. CONCLUSIONS: Hydraqui presents a set of satisfactory criteria for its application as an antileishmanial agent.

FLI1 gene influences lesion size and skin test may predict therapeutic response in cutaneous leishmaniasis

Genes associated with wound healing have been shown to be risk factors for cutaneous leishmaniasis (CL) which is caused by Leishmania braziliensis. In this study, we examined whether the genes previously associated with CL influenced the clinical outcome. Patients were genotyped and retrospectively classified as responders, who were cured with a single course of pentavalent antimony (Sbv), or as refractories, who did not respond to Sbv. Patients characterised as responders showed a stronger response to the leishmanin skin test (LST) when compared to the refractory subjects (p = 0.0003). Furthermore, we observed an association between the FLI1 CC genotype and an increased size of ulcers (p = 0.0170). We suggest that the leishmanin skin test may be a predictive tool for therapeutic outcome and reinforce FLI1 as a potential influencer of susceptibility and lesion size in CL.

Neurohistoplasmosis y leishmaniasis cutánea en paciente inmunocompetente / Neurohistoplasmosis and cutaneous leishmaniasis in an immunocompetent patient

La histoplasmosis y la leishmaniasis son enfermedades olvidadas, endémicas en Argentina, y generalmente se asocian a inmunocompromiso. Presentamos el caso de un varón de 16 años, inmunocompetente, con histoplasmosis del sistema nervioso central y leishmaniasis cutánea. Inicialmente, el paciente presentó una lesión en la pierna de un mes de evolución seguida de paraparesia leve, diagnosticada como un proceso de desmielinización mediante estudios de imágenes. El cuadro fue tratado con altas dosis de corticoides y en 72 horas evolucionó a paraparesia grave con lesiones nodulares en las vértebras cervicales, observadas en las imágenes de resonancia magnética nuclear. Se aisló Histoplasma capsulatum de líquido cefalorraquídeo, genotípicamente identificado como perteneciente a la especie filogenética LamB. El paciente recibió tratamiento intravenoso con anfotericina B deoxicolato durante 30 días y posteriormente fluconazol e itraconazol oral durante un año. A los tres meses de iniciado el tratamiento con antifúngicos se reactivó la lesión de la pierna y en el examen directo se observaron amastigotes de Leishmania. La leishmaniasis cutánea fue tratada con antimoniato de meglumina intramuscular. La respuesta clínica al tratamiento de ambas enfermedades fue favorable.

Histoplasmosis and leishmaniasis are neglected and endemic diseases in Argentina, and generally are found associated with immunosuppression. We report the case of an immunocompetent 16-years-old man with simultaneous occurrence of central nervous system histoplasmosis and cutaneous leishmaniasis. Upon admission, the patient showed a one-month old skin lesion in a leg and mild paraparesis. Imaging studies detected thickening and edema in the spinal cord and the cerebrospinal fluid analysis was within normal range. The case was diagnosed as a demyelinating disorder and treated with high-dose short-term steroids. Seventy-two hours later the patient showed severe paraparesis and nuclear magnetic resonance imaging revealed nodular lesions in the spinal cord. Histoplasma capsulatum belonging to the phylogenetic species LamB was isolated from cerebrospinal fluid samples. The patient received intravenous antifungal therapy with amphotericin B for 30 days, followed by oral fluconazole and itraconazole for one year. Three months after initiation of antifungal treatment, the cutaneous lesion recrudesced and Leishmania amastigotes were observed on microscopic examination. The cutaneous leishmaniasis was treated with intramuscular meglumine antimoniate. The patient´s outcome was favorable after treatment for both diseases.

American tegumentary leishmaniasis: severe side effects of pentavalent antimonial in a patient with chronic renal failure

Abstract: Pentavalent antimonials are the first-line drug treatment for American tegumentary leishmaniasis. We report on a patient with chronic renal failure on hemodialysis who presented with cutaneous lesions of leishmaniasis for four months. The patient was treated with intravenous meglumine under strict nephrological surveillance, but cardiotoxicity, acute pancreatitis, pancytopenia, and cardiogenic shock developed rapidly. Deficient renal clearance of meglumine antimoniate can result in severe toxicity, as observed in this case. These side effects are related to cumulative plasma levels of the drug. Therefore, second-line drugs like amphotericin B are a better choice for patients on dialysis.

Disseminated leishmaniasis: clinical, pathogenic, and therapeutic aspects

Abstract: Disseminated leishmaniasis is a severe and emerging form of American tegumentary leishmaniasis. Disseminated leishmaniasis is defined by the presence of more than 10 polymorphic cutaneous lesions, distributed over more than two noncontiguous parts of the body. Nasal mucosal involvement is observed in almost half of cases. Disseminated leishmaniasis patients present with a decreased production of Th1 cytokines in the peripheral blood due to the attraction of leishmania- activated T cells to the multiple cutaneous lesions. Disseminated leishmaniasis development is poorly understood and is related to a complex network involving environmental, host immune response, and parasite factors, in which L. braziliensis polymorphism plays an important role. Disseminated leishmaniasis is a challenging disease to cure, presenting a high failure rate of 75% to pentavalent antimony therapy. Despite its importance and severity, this form of American tegumentary leishmaniasis has been poorly studied and documented, deserving greater attention from professionals working in endemic areas.

First report of treatment failure in a patient with cutaneous leishmaniasis infected by Leishmania (Viannia) naiffi carrying Leishmania RNA virus: a fortuitous combination?

Abstract We report the case of a 32-year-old man from Rio de Janeiro, who was infected in the Amazon region of Brazil by Leishmania (Viannia) naiffi. Generally, patients with L. naiffi cutaneous leishmaniasis exhibit a good therapeutic response to either pentavalent antimonials or pentamidine. However, after pentamidine treatment, this patient's infection evolved to therapeutic failure. To understand this clinical outcome, we investigated the presence of the Leishmania RNA virus (LRV) in parasites isolated from the cutaneous lesion; herein, we discuss the possible association between a poor response to pentamidine therapy and the presence of the LRV.