A Randomized, Controlled, Noninferiority, Multicenter Trial of Systemic vs Intralesional Treatment With Meglumine Antimoniate for Cutaneous Leishmaniasis in Brazil.

BACKGROUND: Meglumine antimoniate (MA) remains the main treatment for cutaneous leishmaniasis (CL). Uncontrolled studies suggest that intralesional MA (IL-MA) may be noninferior and safer than systemic MA (S-MA). METHODS: Multicenter, randomized, controlled, open-label, phase 3 clinical trial to evaluate the efficacy and toxicity of IL-MA in 3 infiltrations at 14-day intervals compared with S-MA (10-20 mg Sb5+/kg/day, 20 days) for CL, with noninferiority margin of 20%. Primary and secondary outcomes were definitive cure at day 180 and epithelialization rate at day 90 of treatment, respectively. A 2-year follow-up was performed to assess relapses and emergence of mucosal lesions. Adverse events (AEs) were monitored according to the Division of AIDS AE grading system. RESULTS: We evaluated 135 patients. The cure rates (95% confidence interval) for IL-MA and S-MA treatment were, respectively, 82.8% (70.5-91.4) and 67.8% (53.3-78.3) per protocol (PP) and 70.6% (58.3-81.0) and 59.7% (47.0-71.5) per intention to treat (ITT). The epithelialization rates of the IL-MA and S-MA treatment were, respectively, 79.3% (66.6-88 + 8) and 71.2% (57.9-82.2) PP and 69.1% (55.2-78.5) and 64.2% (50.0-74.2) ITT. AEs in the IL-MA and S-MA groups were, respectively, clinical, 45.6% and 80.6%; laboratory, 26.5% and 73.1%; and electrocardiogram, 8.8% and 25.4%. Ten participants in the S-MA group and 1 in the IL-MA group were discontinued due to severe or persistent AEs. CONCLUSIONS: IL-MA provides a similar cure rate and results in less toxicity compared with S-MA and may be used as first-line therapy for CL patients. CLINICAL TRIALS REGISTRATION: REBEC: RBR-6mk5n4.

Parasite species variation and impact of spatial displacement of the population on cutaneous leishmaniasis in Rio de Janeiro, Brazil.

BACKGROUND: Cutaneous leishmaniasis results from complex interactions between human beings, vectors and the environment. Parasitic species differ in epidemiological and geographical contexts. METHODS: We studied a retrospective cohort of 696 patients with cutaneous leishmaniasis treated at a reference centre in the state of Rio de Janeiro, Brazil, between 2000 and 2015. We analysed displacements due to work, leisure and migrations with identification of Leishmania species. RESULTS: The geographic distribution of autochthonous cases showed that >95% of infections occurred in urban areas. In the state of Rio de Janeiro, most cases were concentrated in the cities surrounding forest parks and nature conservation areas. The same applies to the city of Rio de Janeiro, where these infections occurred in the neighbourhoods surrounding some mountain and forest areas. The non-displacement group included 575 (82.6%) patients and the displacement group included 121 (17.4%) patients. Leishmania (Viannia) braziliensis predominated in both groups. Other species were found in the displacement group. CONCLUSIONS: The disordered urbanization of the state of Rio de Janeiro in recent decades has created conditions for the emergence of urban foci of transmission close to forest areas. Changes in the environment, movement of infected individuals and adaptation of sandflies may have contributed to this.

Bone sporotrichosis: 41 cases from a reference hospital in Rio de Janeiro, Brazil.

BACKGROUND: Bone sporotrichosis is rare. The metropolitan region of Rio de Janeiro is hyperendemic for zoonotic sporotrichosis and the bone presentations are increasing. METHODS: We studied a retrospective cohort of 41 cases of bone sporotrichosis, diagnosed from 1999-2016. The inclusion criteria was fungal culture isolation from any clinical specimen associated to bone involvement (radiography and/or computed tomography) compatible with fungal osteomyelitis or histopathological findings of bone material compatible with sporotrichosis. Molecular identification was performed when possible. RESULTS: Male patients represented 58.5% of the cases, with a cohort median age of 43 years. Immunosuppressive conditions were present in 68.3% of the patients, mostly HIV coinfection (51.2%). Multifocal bone involvement (more than one anatomical segment) was diagnosed in 61% of the patients, while 39% presented unifocal involvement. The bones of the hands were the most affected (58.5%), followed by the feet (41.5%) and tibia (26.8%). Multifocal group was characterized by a higher proportion of males (p = 0.0045) with immunosuppressive conditions (p = 0.0014). Amphotericin B followed by oral itraconazole was the main treatment, with a median time of 16.7 months (1.5 to 99.2 months), and cure of 53.7% of the patients (84.6% of immunocompetent and 39.3% of immunocompromised patients). Sequelae occurred in 12.2% of the patients-amputations (7.3%) and ankylosis (4.9%), while 22% died in the course of the disease. Sporothrix brasiliensis was the causative agent in all the 9 (22%) performed cases. CONCLUSIONS: Bone sporotrichosis is a chronic, challenging condition with prolonged treatment, often with poor results and sequelae.

Contribution of Leishmania braziliensis antigen-specific CD4+ T, CD8+ T, NK and CD3+CD56+NKT cells in the immunopathogenesis of cutaneous leishmaniasis patients: Cytotoxic, activation and exhaustion profiles.

The pathogenesis of cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis is dictated mainly by the immune-mediated-tissue inflammation developed. The understanding of the immunological mechanisms that generate tissue damage or resolution of lesions is the key to the development of effective vaccine protocols and proper therapeutic schemes. It is clear that the specific immune response mediated by T cells is responsible for the beneficial outcome of the disease, however, the roles of CD4+ T, CD8+ T, NK and NKT cell subpopulations in immunopathogenesis of CL need to be elucidated. Peripheral blood cells from patients before, during and after the antimonial therapy, as well as healthy individuals (HI) were cultured with (LbAgS) or without (NS) L. braziliensis antigens (LbAg). Afterwards, the frequencies of LbAg-specific-cytotoxic CD8+ T, CD4+ T, NK and CD3+CD56+ NKT cells, as well as their activation and exhaustion profiles, were defined by flow cytometry. We observed higher frequencies of CD8+ T, NK and CD3+CD56+ NKT cells and lower frequencies of CD4+ T lymphocytes in LbAgS cell cultures from patients before treatment. The specific response to LbAg resulted in an expansion of cytotoxic-activated CD4+ T, CD8+ T, and NK cells, before and during treatment, indicating specificity in the response by these cells against L. braziliensis. Furthermore, comparing the differences of frequencies of cytotoxic-activated CD4+T, CD8+T, and NK cells, among before and during treatment patients and HI groups, we conclude that these cell populations are in charge of immune response elicited by antimonial therapy. Interestingly, we also observed that NK cells were induced by LbAg to an exhaustion profile during all clinical stages of the disease. The increased antigen-specific activation and cytotoxic activity are in line with the strong inflammatory response described in this disease, a likely cause of tissue damage. These findings reinforce the involvement of these distinct cytotoxic-activated cell populations in the immunopathogenesis of CL, showing a character of specificity in this immune response.

Clinical features and therapeutic response in adult and pediatric patients with American tegumentary leishmaniasis in Rio de Janeiro.

BACKGROUND: American tegumentary leishmaniasis (ATL) is a neglected disease with wide territorial distribution. Knowledge is scarce in children and adolescents. This study aims to compare the clinical features and response to antimony treatment in pediatric and adult patients with cutaneous leishmaniasis. METHODS: A retrospective cohort study was performed with 659 patients who attended a reference centre in Rio de Janeiro, Brazil, from 2000 to 2015. The pediatric cohort consisted of 131 (20%) patients and the adult cohort consisted of 528 (80%) patients. RESULTS: The epidemiological profile, antimony therapeutic response and incidence of adverse events (AE) were different in the pediatric cohort compared with the adult cohort. Mucosal form was less frequent in the pediatric cohort (RR:0.49, p=0.011). Lesions in the head, neck and trunk were more frequent in the pediatric cohort (RR:1.49, p=0.043). The effectiveness of antimony treatment was superior in the pediatric cohort (88.3% vs 76.6%) with a shorter healing time (RR:0.49, p=0.009). Pediatric patients had lower proportions of moderate to severe AE compared with adults (RR:0.45, p=0.027). Clinical AE predominated in the adult cohort (RR:0.40, p=0.000) and laboratory AE in the pediatric cohort (RR:1.50, p=0.023). CONCLUSIONS: This study adds to the body of knowledge on differences that exist between different age groups in ATL.

Cutaneous tuberculosis in Rio de Janeiro, Brazil: description of a series of 75 cases.

BACKGROUND: Brazil is one of the highest tuberculosis (TB) burden countries of the world. Cutaneous tuberculosis (CTB) is a rare form of extrapulmonary manifestation of tuberculosis. This study aimed to describe the clinico-evolutive, laboratory and therapeutic aspects of CTB cases among patients from a cohort with TB in Rio de Janeiro, Brazil. METHODS: Cases of diagnosed CTB with microbiologic confirmation or clinical response to anti-tuberculous treatment associated with positive smear or histopathological findings between the years 2000 and 2016 were selected. RESULTS: Seventy-five patients with CTB were included, most were women (58.7%) with a median age of 42 years. CTB diagnosis was based on culture in only 42.7% of the cases. Scrofuloderma represented 50.7% of the cases, followed by erythema induratum of Bazin (EIB) (18.7%), tuberculous gumma (13.3%), lupus vulgaris (8%), TB verrucosa cutis (4%), orificial TB (2.7%) and associated forms (2.7%). Other TB presentations were pulmonary (22.7%), mammary (6.6%) and osteoarticular (4%). All patients who completed the treatment (97.3%) had their lesions healed. Only two patients (2.6%) needed to change the therapy due to adverse reactions. Fifty percent of EIB patients presented recurrence. CONCLUSIONS: These data highlight the diversity of CTB presentations and the importance of the skin to assist in early identification and treatment of TB. More studies are necessary to improve the knowledge on EIB for a better approach towards these patients, mainly in cases of recurrence.

CD3+CD4negCD8neg (double negative) T lymphocytes and NKT cells as the main cytotoxic-related-CD107a+ cells in lesions of cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis.

BACKGROUND: Cutaneous leishmaniasis (CL) is caused by Leishmania (Viannia) braziliensis, which infects dermal macrophages and dendritic cells, causing an intense immune-mediated-tissue inflammation and a skin ulcer with elevated borders that can heal spontaneously or after antimonial therapy. The resolution of lesions depends on an adaptive immune response, and cytotoxic cells seem to have a fundamental role in this process. The aim of this study is to better understand the role of cytotoxicity mediated mechanisms that occur during the immune response in the CL lesion milieu, considering distinct cytotoxic-related CD107a+ cells, such as CD8+, CD4+, CD4neg CD8neg (double-negative, DN) and CD4+CD8+ (double-positive, DP) T lymphocytes, as well as NK and NKT cells. METHODS: Lesion derived cells were assessed for T cell subpopulations and NK cells, as well as CD107a expression by flow cytometry. In addition, cytometric bead array (CBA) was used to quantify cytokines and granzyme B concentrations in supernatants from macerated lesions. RESULTS: Flow cytometry analyses revealed that NKT cells are the major CD107a-expressing cell population committed to cytotoxicity in CL lesion, although we also observed high frequencies of CD4+ and DN T cells expressing CD107a. Analysing the pool of CD107a+-cell populations, we found a higher distribution of DN T cells (44%), followed by approximately 25% of NKT cells. Interestingly, NK and CD8+ T cells represented only 3 and 4% of the total-CD107a+-cell pool, respectively. CONCLUSIONS: The cytotoxicity activity that occurs in the lesion milieu of CL patients seems to be dominated by DN T and NKT cells. These findings suggest the need for a reevaluation of the role of classical-cytotoxic NK and CD8+ T cells in the pathogenesis of CL, implicating an important role for other T cell subpopulations.

Exfoliative erythroderma and palmoplantar hyperkeratosis associated with Majocchi's granuloma by Trichophyton tonsurans in a patient with AIDS.

BACKGROUND: Dermatophytoses are skin superficial mycoses in which clinical manifestations are directly related to the virulence of the infecting microorganism or the host immunity. CASE REPORT: We describe a severe case of dermatophytosis associated with exfoliative erythroderma, substantial palmoplantar keratoderma, onychodystrophy affecting all nails, diffuse non-scarring alopecia and tissue fungal invasion by Trichophyton tonsurans, which led us to the diagnosis of AIDS. Direct examination and culture for fungi from skin scraping from two different sites were performed. Biopsy and histopathological exam were also performed on three different sites. Direct examination of the lesions' scraping revealed septate hyaline hyphae and arthroconidia, identified as Trichophyton tonsurans by culture in glucose Sabouraud agar and Mycosel agar. A scalp biopsy revealed follicular fungal invasion and Majocchi's granuloma. Due to the severity of the presentation we requested an anti-HIV serology, which was positive. The patient was treated with itraconazole, 200mg/day, for 120 days, which promoted a complete regression of the lesions. CONCLUSIONS: Severe and atypical forms of dermatophytosis could lead to a diagnosis of AIDS.

Is There Any Difference between the In Situ and Systemic IL-10 and IFN-γ Production when Clinical Forms of Cutaneous Sporotrichosis Are Compared?

Fungus of the Sporothrix schenckii complex can produce skin lesions in humans, commonly lymphocutaneous (LC) and fixed (F) forms of sporotrichosis. Some authors have suggested that clinical forms are influenced by differences in virulence and genetic profile of isolates. But little is known about the role of immune response in determining the clinical outcome of sporotrichosis. To verify the profile of systemic and in situ IFN-γ and IL-10 expression in sporotrichosis patients, and consequently to detect any difference between the two compartments and/or clinical presentation, we quantified the number of IFN-γ and IL-10 producer peripheral blood mononuclear cells stimulated with S. schenckii antigen (Ss-Ag) by Elispot, and quantified cytokines expression by in situ immunohistochemistry in the same patient. Three groups were formed: 1- LC (n = 9); 2- F (n = 10); 3- healthy individuals (n = 14). All sporotrichosis patients produced high amounts of systemic IFN- γ when compared to uninfected individuals. No differences were observed between LC and F groups. Regarding in situ IL-10 expression, a difference between LC and F groups was observed: LC lesions presented higher amounts of IL-10 than F lesions differently from systemic IL-10 which showed similarities. Our data suggests that LC lesions present higher IL-10 expression which could be related to regulatory mechanisms for compensating the tissue injury, however favoring fungal persistence in the lesions. Surprisingly, there were no differences in systemic and in situ IFN- γ expression between CL and F patients, although it was significantly higher expressed in these patients than in healthy individuals.

Exfoliative erythroderma and palmoplantar hyperkeratosis associated with Majocchi's granuloma by Trichophyton tonsurans in a patient with AIDS / Eritrodermia exfoliativa e hiperqueratosis palmoplantar asociada con granuloma de Majocchi por Trichophyton tonsurans en un paciente con sida

Background. Dermatophytoses are skin superficial mycoses in which clinical manifestations are directly related to the virulence of the infecting microorganism or the host immunity. Case report. We describe a severe case of dermatophytosis associated with exfoliative erythroderma, substantial palmoplantar keratoderma, onychodystrophy affecting all nails, diffuse non-scarring alopecia and tissue fungal invasion by Trichophyton tonsurans, which led us to the diagnosis of AIDS. Direct examination and culture for fungi from skin scraping from two different sites were performed. Biopsy and histopathological exam were also performed on three different sites. Direct examination of the lesions’ scraping revealed septate hyaline hyphae and arthroconidia, identified as Trichophyton tonsurans by culture in glucose Sabouraud agar and Mycosel agar. A scalp biopsy revealed follicular fungal invasion and Majocchi's granuloma. Due to the severity of the presentation we requested an anti-HIV serology, which was positive. The patient was treated with itraconazole, 200mg/day, for 120 days, which promoted a complete regression of the lesions. Conclusions. Severe and atypical forms of dermatophytosis could lead to a diagnosis of AIDS (AU)

Antecedentes. Las dermatofitosis son micosis cutáneas superficiales cuyas manifestaciones clínicas están relacionadas directamente con la virulencia del microorganismo involucrado y la inmunidad del huésped. Caso clínico. Se describe un caso grave de dermatofitosis asociado con eritrodermia exfoliativa, con apreciable queratodermia palmoplantar, onicodistrofia de las 20uñas, alopecia no cicatricial difusa e invasión fúngica del tejido por Trichophyton tonsurans, lo cual permitió establecer el diagnóstico de sida. Se llevó a cabo exploración directa y cultivo de hongos de dos muestras tomadas por raspado en dos localizaciones distintas. También se llevaron a cabo una biopsia de piel y un estudio histopatológico de tres localizaciones. En la exploración directa del raspado de las lesiones se observaron hifas tabicadas hialinas y artroconidios; en el cultivo en agar Sabouraud con glucosa y agar Mycosel se aisló Trichophyton tonsurans. La biopsia de cuero cabelludo mostró una invasión fúngica folicular y la existencia de un granuloma de Majocchi. La gravedad del cuadro motivó la solicitud de la serología para el VIH, que fue positiva. Se trató al paciente con 200mg/día de itraconazol durante 120días, lo que llevó a la remisión completa de las lesiones. Conclusiones. Una dermatofitosis grave o atípica podría considerarse enfermedad reveladora de sida (AU)