Treatment of cutaneous leishmaniasis with a sequential scheme of pentamidine and tamoxifen in an area with a predominance of Leishmania (Viannia) guyanensis: A randomised, non-inferiority clinical trial.

OBJECTIVE: To determine whether a combination of a single intramuscular (IM) dose of pentamidine (7 mg/kg) followed by oral tamoxifen 40 mg/day for 20 days is non-inferior to three IM doses of pentamidine 7 mg/kg in the treatment of cutaneous leishmaniasis with a margin of 15%. METHODS: Phase II, randomised, controlled, open-label, non-inferiority clinical trial. Primary outcome was the complete healing of the lesions 6 months after starting treatment. Secondary outcomes were healing 3 months after starting treatment and determining the presence and severity of adverse effects (AE). RESULTS: The research was concluded with 49 patients; Leishmania (Viannia) guyanensis was the most frequent species isolated. In the primary outcome, 18 (72%) (95% CI: 52.4%-85.7%) of the 25 patients allocated to the intervention group and 24 (100%) (95% CI: 86.2%-100%) of the control group (p = 0.015) met the established criteria of cure. There was no AE with tamoxifen. CONCLUSION: Although a 72% cure rate presented by the combination of tamoxifen and pentamidine was lower than in the control group that achieved a 100% cure, it is still a safe and is a clinically relevant result. It indicates that the therapeutic scheme evaluated may be a promising option for populations in remote areas, however it should be further studied, in order to include a larger number of patients.

An open label randomized clinical trial comparing the safety and effectiveness of one, two or three weekly pentamidine isethionate doses (seven milligrams per kilogram) in the treatment of cutaneous leishmaniasis in the Amazon Region.

BACKGROUND: American Cutaneous Leishmaniasis (ACL), a vector borne disease, is caused by various species of Leishmania and in the Amazonas, Leishmania guyanensis is predominant. The recommended drugs for treatment of cutaneous leishmaniasis (CL) in Brazil are pentavalent antimonials, pentamidine isethionate (PI) and amphotericin B. Pentamidine was initially used as metanolsulfonate or mesylate (Lomidine) at a dose of 4 mg/kg/daily, containing 2.3mg of base. This drug was withdrawn from the market in the eighties, and currently is available as PI. The PI dose required to achieve an equivalent dose of pentamidine base is 7 mg/kg, rather than the 4 mg/kg that is currently recommended in Brazil. OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of PI in a single dose, two or three doses of 7 mg/kg body weight, intramuscularly, with an interval of seven days between each dose. MATERIALS AND METHODS: This study was conducted as a controlled, randomized, open-label clinical trial for a total number of 159 patients with CL. Individuals aged 16-64 years with one to six lesions of confirmed CL based on amastigotes visualization in direct examination of Giemsa stained of dermal scraping from the border of the lesion with no previous treatment for CL and no abnormal values for liver enzymes were eligible to participate in the study. Patients with history of diabetes, cardiac, renal, and hepatic disease as well as pregnant women were excluded. Cure was defined as complete healing in the diameters of the ulcers and lesions skin six months after the end of the treatment. RESULTS: From November 2013 to December 2015, 159 patients were screened and allocated in three groups for treatment with PI: i) 53 patients were treated with a single dose intramuscularly injection of 7 mg/kg body weight; ii) 53 received two doses of 7 mg/kg within an interval of seven days; and iii) 53 were treated with three doses of 7mg/kg with an interval of seven days between each dose. In 120 patients, L. guyanensis was identified. A cure rate of 45%, 81.1% and 96.2% were observed in the first, second and third group, respectively. The cure in the three PI dose group was higher compared to the single-dose (p<0.0001) and two-dose groups (p = 0.03). No serious adverse events occurred. CONCLUSION: The present study shows that PI is a safe drug and its efficacy varied with the number of doses. The administration of PI in patients with ACL, predominantly caused by L. guyanensis, was mostly efficient in three or two doses of 7 mg/kg. TRIAL REGISTRATION: ClinicalTrials.gov NCT02919605.

Sustained Presence of Cutaneous Leishmaniasis in Urban Manaus, the Largest Human Settlement in the Amazon.

The Amazon is responsible for approximately 40% of the American tegumentary leishmaniasis (ATL) in Brazil. Herein the sustained presence of ATL in Manaus, the largest settlement in the Amazon, was investigated. Records of notification of historic cases, and data from cases prospectively enrolled in the Tropical Medicine Foundation of the Amazonas State were used. Geographic coordinates of prospective patients' living sites were used to detect inner-city clusters of ATL. Infecting Leishmania species was determined by polymerase chain reaction. Among prospectively enrolled subjects, 94.8% were infected with Leishmania (Viannia) guyanensis, 76.7% were male, 30.2% were 0-20 years old, and 69.8% had an urban residence. Historic cases showed a profile similar to that of prospectively enrolled subjects. Several clusters of ATL, widely distributed within the city of Manaus, could be detected. In conclusion, there was a high frequency of disease in young age groups and cases clustered in urban neighborhoods. It cannot be determined from these data whether transmission of these cases occurred within or outside the city of Manaus.

Polymorphisms in the TOLLIP Gene Influence Susceptibility to Cutaneous Leishmaniasis Caused by Leishmania guyanensis in the Amazonas State of Brazil.

INTRODUCTION: The clinical outcome to Leishmania-infection is determined by the individual adaptive immune T helper cell responses and their interactions with parasitized host cells. An early development of a proinflammatory immune response (Th1 response) is necessary for Leishmania-infection resolution. The Toll-interacting protein (TOLLIP) regulates human Toll-like receptors signaling pathways by down regulating the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and inducing the ant-inflammatory cytokine interleukin-10 (IL-10). Polymorphisms in the TOLLIP gene are associated with infectious diseases. MATERIAL AND METHODS: The polymorphisms rs5743899 and rs3750920 in the TOLLIP gene were genotyped by polymerase chain reaction and restriction fragment length polymorphism (RFLP) analysis in 631 patients with cutaneous leishmaniasis (CL) caused by L. guyanensis and 530 individuals with no history of leishmaniasis. RESULTS: The G and T alleles of the rs5743899 and rs3750920 were more common in patients with CL than in healthy individuals (P = 2.6 x10(-8) ; odds ratio [OR], 1.7 [ 95% confidence interval (CI) 1.4-2.0] and P = 1.9 x10(-8) ; OR, 1.6 [95% CI 1.4-1.9] respectively). The r2 and D' linkage disequilibrium between the two polymorphisms are 0.05 and 0.473 with a confidence bounds of 0.37 to 0.57 respectively. CONCLUSION: The two polymorphisms are independently associated with an increased risk of developing CL.

A historical overview of leprosy epidemiology and control activities in Amazonas, Brazil.

Leprosy is an ancient infectious disease caused by Mycobacterium leprae. According to comparative genomics studies, this disease originated in Eastern Africa or the Near East and spread with successive human migrations. The Europeans and North Africans introduced leprosy into West Africa and the Americas within the past 500 years. In Brazil, this disease arrived with the colonizers who disembarked at the first colonies, Rio de Janeiro, Salvador and Recife, at the end of the sixteenth century, after which it was spread to the other states. In 1854, the first leprosy cases were identified in State of Amazonas in the north of Brazil. The increasing number of leprosy cases and the need for treatment and disease control led to the creation of places to isolate patients, known as leprosaria. One of them, Colonia Antônio Aleixo was built in Amazonas in 1956 according to the most advanced recommendations for isolation at that time and was deactivated in 1979. The history of the Alfredo da Matta Center (AMC), which was the first leprosy dispensary created in 1955, parallels the history of leprosy in the state. Over the years, the AMC has become one of the best training centers for leprosy, general dermatology and sexually transmitted diseases in Brazil. In addition to being responsible for leprosy control programs in the state, the AMC has carried out training programs on leprosy diagnosis and treatment for health professionals in Manaus and other municipalities of the state, aiming to increase the coverage of leprosy control activities. This paper provides a historical overview of leprosy in State of Amazonas, which is an endemic state in Brazil.

A historical overview of leprosy epidemiology and control activities in Amazonas, Brazil

Leprosy is an ancient infectious disease caused by Mycobacterium leprae. According to comparative genomics studies, this disease originated in Eastern Africa or the Near East and spread with successive human migrations. The Europeans and North Africans introduced leprosy into West Africa and the Americas within the past 500 years. In Brazil, this disease arrived with the colonizers who disembarked at the first colonies, Rio de Janeiro, Salvador and Recife, at the end of the sixteenth century, after which it was spread to the other states. In 1854, the first leprosy cases were identified in State of Amazonas in the north of Brazil. The increasing number of leprosy cases and the need for treatment and disease control led to the creation of places to isolate patients, known as leprosaria. One of them, Colonia Antônio Aleixo was built in Amazonas in 1956 according to the most advanced recommendations for isolation at that time and was deactivated in 1979. The history of the Alfredo da Matta Center (AMC), which was the first leprosy dispensary created in 1955, parallels the history of leprosy in the state. Over the years, the AMC has become one of the best training centers for leprosy, general dermatology and sexually transmitted diseases in Brazil. In addition to being responsible for leprosy control programs in the state, the AMC has carried out training programs on leprosy diagnosis and treatment for health professionals in Manaus and other municipalities of the state, aiming to increase the coverage of leprosy control activities. This paper provides a historical overview of leprosy in State of Amazonas, which is an endemic state in Brazil.

Leishmaniasis and AIDS coinfection / Coinfeccao leishmaniose e AIDS

Cutaneous leishmaniasis and HIV coinfection has been reported in Brazil since the initial description of AIDS in the country. We report an HIV-positive patient under antiretroviral treatment who presented with cutaneous leishmaniasis which was successfully treated with meglumine antimoniate.

A coinfecção leishmaniose cutânea e HIV tem sido descrita no Brasil desde o início da endemia de Aids no país. É relatado caso de paciente masculino, HIV positivo, em uso de terapia antirretroviral, que apresentou quadro de leishmaniose cutânea, tratada com antimoniato de meglumina.

Leishmaniasis and AIDS coinfection.

Cutaneous leishmaniasis and HIV coinfection has been reported in Brazil since the initial description of AIDS in the country. We report an HIV-positive patient under antiretroviral treatment who presented with cutaneous leishmaniasis which was successfully treated with meglumine antimoniate.

Histoplasmosis and AIDS co-infection.

This report concerns an AIDS patient presenting systemic and cutaneous manifestations of histoplasmosis. A histopathological and mycological examination of the skin lesion confirmed the diagnosis. In AIDS patients histoplasmosis arises mainly when the T-CD4+ cell count is less than 50 cells/mm3. In such cases, histoplasmosis can be severe and if left untreated can lead to death, as occurred with this patient.

Coinfecção histoplasmose e Aids / Histoplasmosis and AIDS co-infection

Apresenta-se um caso de coinfecção histoplasmose e Aids, com lesões cutâneas predominantemente papulosas e comprometimento sistêmico. O exame histopatológico e micológico de lesão cutânea confirmou o diagnóstico. Em doentes com Aids, a histoplasmose surge, principalmente, quando a contagem de células T-CD4-positivas é inferior a 50 células/mm³. Nesses casos, a histoplasmose pode ser grave e, se não tratada adequadamente, levar ao êxito letal, como no paciente relatado.

This report concerns an AIDS patient presenting systemic and cutaneous manifestations of histoplasmosis. A histopathological and mycological examination of the skin lesion confirmed the diagnosis. In AIDS patients histoplasmosis arises mainly when the T-CD4+ cell count is less than 50 cells/mm3. In such cases, histoplasmosis can be severe and if left untreated can lead to death, as occurred with this patient.

Randomized controlled clinical trial to access efficacy and safety of miltefosine in the treatment of cutaneous leishmaniasis Caused by Leishmania (Viannia) guyanensis in Manaus, Brazil.

Miltefosine has been used in the treatment of several new world cutaneous leishmaniasis (CL) species with variable efficacy. Our study is the first evidence on its clinical efficacy in Leishmania (Viannia) guyanensis. In this phase II/III randomized clinical trial, 90 CL patients were randomly allocated (2:1) to oral miltefosine (2.5 mg/kg/day/28 days) (N = 60) or parenteral antimony (15-20 mg/Sb/kg/day/20 days) (N = 30) according to age groups: 2-12 y/o and 13-65 y/o. Patients were human immunodeficiency virus (HIV) noninfected parasitological proven CL without previous treatment. Definitive cure was accessed at 6 months follow-up visit. No severe adverse events occurred. Vomiting was the most frequent adverse event (48.3%) followed by nausea (8.6%) and diarrhea (6.7%). Cure rates were 71.4% (95% confidence interval [CI] = 57.8-82.7) and 53.6% (95% CI = 33.9-72.5) (P = 0.05) for miltefosine and antimonial, respectively. There were no differences in cure rates between age groups within the same treatment arms. Miltefosine was safe and relatively well tolerated and cure rate was higher than antimony.

Hand atrophy in a leprosy patient--treatment with polymethylmethacrylate.

Leprosy, an infectious disease caused by Mycobacterium leprae, affects mostly the skin and peripheral nerves. The polymethylmethacrylate has been used as bone cement, knee and intraocular implants as a bioexpansor, filling the area where it is applied. We describe the case of a Brazilian male with tuberculoid leprosy who developed muscular wasting between the metacarpals of both hands. Ten years after leprosy treatment, he was submitted to five applications of 10% polymethylmethacrylate. The treatment was successful, improving the appearance of his hands leading to a positive impact on the patient's life.

Leprosy and HIV coinfection: a clinical, pathological, immunological, and therapeutic study of a cohort from a Brazilian referral center for infectious diseases.

BACKGROUND: Although awareness of the relevance of leprosy and human immunodeficiency virus (HIV) coinfection is increasing worldwide, several aspects of this co-occurrence are not fully understood. METHODS: We describe clinical, pathological, immunological, and therapeutic long-term follow-up of a cohort of 25 individuals with leprosy and HIV infection from Manaus, Amazonas. RESULTS: Careful description of our cohort indicates a higher prevalence of leprosy in an HIV-positive population than that in the general population. We also observed upgrading shifting of leprosy clinical forms after initiation of highly active antiretroviral therapy and multidrug therapy and an impact of HIV infection on leprosy granuloma formation, among other features. CONCLUSION: Taken together, these new insights allow the proposition of a classification system that includes (1) leprosy and HIV true coinfection, (2) opportunistic leprosy disease, and (3) leprosy related to highly active antiretroviral therapy.

Lobomycosis.

A case of lobomycosis in a patient from the Brazilian Amazon region is presented. Lobomycosis is a subcutaneous mycosis caused by the yeast Lacazia loboi. It often affects adult males and has been reported in dolphins. Therapeutical options for localized lesions, such as the ones shown by the patient in this report, are eletrocoagulation, surgical exeresis, and cryotherapy. Disseminated lesions may be treated with Itraconazole or combination therapy with Clofazimine. There is still no curative therapy for disseminated lesions of lobomycosis.

Tegumentary leishmaniasis as the cause of immune reconstitution inflammatory syndrome in a patient co-infected with human immunodeficiency virus and Leishmania guyanensis.

We report a case of immune reconstitution inflammatory syndrome (IRIS) in a 32-year-old man infected with human immunodeficiency virus and Leishmania guyanensis. Three months after initiation of highly active anti-retroviral therapy (HAART), the patient had disseminated cutaneous leishmaniasis and started anti-leishmanial therapy. The patient's leishmaniasis manifestations during HAART ranged form an anergic response (46 CD4+ T cells/microL) to a disseminated cutaneous leishmaniasis (112 CD4+ T cells/microL). Eight weeks later (168 CD4+ T cells/microL, skin biopsy specimens showed inflammatory infiltrates with no detectable amastigotes. The patient then became comatose. Prednisone therapy (60 mg/day) was initiated with a significant improvement within 48 hours. Three months later (CD4+ T cell count = 184 cell/microL), localized, classic, cutaneous leishmaniasis developed in the patient and anti-leishmanial treatment was re-introduced. On that occasion, frequency of T regulatory cells was 1.82% of all CD4+ cells. Our data suggest a pivotal role for CD4+ T cells in the onset of IRIS and lesion ulceration and their association with a low frequency of T regulatory cells.

Exfoliative cytology as a rapid diagnostic tool for lobomycosis.

Lobomycosis is a common subcutaneous mycosis in South America. It is caused by Lacazia loboi. We report two cases of lobomycosis which were diagnosed by exfoliative cytology without any special staining. We highlight this diagnostic tool as a simple, low-cost, painless, non-invasive and fast method for the diagnosis of lobomycosis.