Tendência da mortalidade por Paracoccidioidomicose no Brasil ­ 1996 a 2020 / Mortality trends due to Paracoccidioidomycosis in Brazil ­ 1996 to 2020

Objetivo: Analisar a tendência da mortalidade por paracoccidioidomicose (PCM) e caracterizar o perfil sociodemográfico no Brasil e suas regiões geográficas numa série temporal de 25 anos. Métodos: Trata-se de estudo ecológico de séries temporais. Considerou-se como participantes do estudo a população brasileira dividida em faixas etárias, que tiveram como causa básica do óbito a PCM. Para calcular a variação percentual anual (VPA) dos coeficientes, na análise de tendência, foi utilizada a regressão de Prais-Winsten. Os coeficientes de mortalidade foram calculados a nível nacional, segundo as regiões geográficas, sexo e faixa etária e proporcional para as demais variáveis. Resultados: De acordo com os resultados deste estudo, ocorreram 2.101 óbitos por PCM no Brasil. A tendência ao longo dos 25 anos evidenciou um comportamento estável nas regiões Norte e Nordeste. Já no Sul, Sudeste e Centro-Oeste houve uma tendêndia de queda. A mortalidade média no Brasil foi de 84,04/100 mil hab., VPA -3,29 (IC 95% -2,43; -4,14). Levando em consideração a análise dos aspectos sociodemográficos, houve um predomínio de escolaridade ignorada (764; 36%), raça/ cor da pele branca (1.109; 53%), estado civil misto: casado (942; 45%) e solteiro (640; 30%), local de ocorrência do óbito predominantemente no âmbito hospitalar (1.852; 88%). Conclusão: Tanto no Brasil como nas regiões geográficas Sudeste, Sul e Centro-Oeste a mortalidade por PCM apresentou-se com tendência temporal decrescente. Já nas regiões Nordeste e Norte a tendência foi estacionária. O perfil sociodemográfico dos pacientes que foram a óbito apontou para sexo masculino, adultos, de baixa escolaridade, brancos e casados.

Objective: To analyze the trend in mortality from paracoccidioidomycosis (PCM) and characterize the sociodemographic profile in Brazil and its geographic regions in a 25-year time series. Methods: This is an ecological time series study. The study participants were the Brazilian population divided into age groups whose underlying cause of death was PCM. To calculate the annual percentage change (VPA) of the coefficients in the trend analysis, the Prais-Winsten regression was used. National mortality coefficients were calculated according to geographic regions, sex and age group and proportional to the other variables. Results: According to this study, there were 2,101 deaths from PCM in Brazil. The trend over the 25 years showed stable behavior in the North and Northeast regions. In the South, Southeast, and Midwest, there was a downward trend. The average mortality in Brazil was 84.04/100,000 inhab., VPA -3.29 (95% CI -2.43; -4.14). According to the analysis of sociodemographic aspects, there was a predominance of ignored schooling (764 deaths; 36%), white race/skin color (1,109; 53%), mixed marital status: married (942; 45%) and single (640; 30%), and place of death predominantly in the hospital environment (1,852; 88%). Conclusion: In Brazil and in the Southeast, South, andMidwest geographic regions, mortality from PCM showed a decreasing temporal trend. In the Northeast and North regions, the trend was stationary. The sociodemographic profile of the dying patients indicated males, adults, with low education, white, and married.

Hiperplasia pseudoepiteliomatosa: carcinoma escamocelular versus paracoccidioidomicosis oral, un caso con mirada dermatológica / Pseudoepitheliomatous hyperplasia: Squamous cell carcinoma versus oral paracoccidioidomycosis, a case from a dermatological perspective

La paracoccidioidomicosis es una micosis sistémica endémica en Latinoamérica. La presentación más frecuente compromete crónicamente los pulmones, la piel y las mucosas. Al inicio, este paciente presentó, por varios años, una lesión única en la mucosa oral que, en ausencia de otros síntomas, se relacionó con una neoplasia maligna, específicamente con un carcinoma escamocelular. La diferenciación entre los dos diagnósticos se hace mediante un examen directo, un estudio histopatológico y cultivos iniciales y subsecuentes. Sin embargo, tales estudios no fueron concluyentes. Después de varias consultas y pruebas, con los resultados del examen directo, la inmunodifusión y la PCR en tiempo real se confirmó el diagnóstico de paracoccidioidomicosis crónica multifocal. Este caso alerta sobre la ausencia de sospecha clínica de micosis endémicas, dada la presencia de lesiones mucocutaneas que pueden ser producidas por hongos como Paracoccidioides spp, y la importancia de considerarlas entre los diagnósticos diferenciales.

Paracoccidioidomycosis is a systemic mycosis endemic in Latin America. The most frequent form involves a chronic compromise of the lungs, skin, and mucosa. The patient started with a single oral lesion that lasted for several years. The absence of other symptoms pointed out a possible malignant neoplasm, specifically a squamous cell carcinoma. Differentiation between both diagnoses-fungal infection and carcinoma-depends on the results of the direct examination, the histopathological study, and the initial and subsequent cultures. However, in this case, those findings were not conclusive. The coexistence of both diagnoses is frequent and increases the diagnostic challenge. After several consultations and tests, direct examination, immunodiffusion and real-time PCR findings the multifocal chronic paracoccidioidomycosis diagnosis was confirmed. This case warns about a systematical absence of clinical suspicion of endemic mycoses before the appereance of mucocutaneous lesions, which can be produced by fungi like Paracoccidioides spp, and the importance of considering those mycoses among the differential diagnoses.

Un caso de paracoccidioidomicosis en laglándula suprarrenal bilateral / A case of paracoccidioidomycosisin the bilateral adrenal gland

La paracoccidioidomicosis es una micosis profunda. La afectación de la glándula suprarrenal es una forma de presentación rara que se asocia hasta un 10 a 15% de las insuficiencias supra renales y en algunas ocasiones puede ser la primera manifestación clínica de la patología. El objetivo del estudio es describir una presentación atípica de un paciente con diagnóstico de tumoración bilateral de la glándula supra renal, que en primer lugar se sospechó de un proceso tumoral de las glándulas supra renales y con la biopsia con punción guiada por ecografía se llegó al diagnóstico definitivo de paracocciodioidomicosis suprarrenal. Se realiza tratamiento con anfotericina B a una dosis de 50mg/día hasta una dosis acumulativa de 1500mg, con posterior seguimiento con itraconazol de 200 a 400mg/día por un periodo de 6 a 12 meses. Palabras Clave: paracoccidioidomicosis; glándulas suprarrenales; infecciones fúngicas invasoras

Paracoccidioidomycosis is aninvasive fungal infection.Involvement of the adrenal gland isa rare form of presentation that is associated with up to 10 to 15% of suprarenal insufficiencies and sometimes it can be the first clinical manifestation of the pathology. The objective of the study is to describean atypical presentation of a patient with a diagnosis of bilateral tumor of the suprarenal gland, that was suspected of a tumor process of the suprarenal glands and the definitive diagnosis with ultrasound-guided puncture biopsy was adrenal paracocciodioidomycosis.Treatment is carried out with amphotericin B at a dose of 50 mg/day up to a cumulative dose of 1500 mg, with subsequent follow-up with itraconazole of 200 to 400 mg/day for a period of 6 to 12 months. Key Words: paracoccidioidomycosis; adrenal glands; invasive fungal infections

Reporte de dos casos de neuro-paracoccidiomicosis / Report of two cases of neuro-paracoccidiomycosis

La paracoccidiodomicosis es la micosis sistémica más frecuente en América Latina. La afectación del sistema nervioso central (SNC) está descrita en un 10-27%. El objetivo es presentar dos pacientes del sexo masculino con neuroparacoccidiodomicosis internados en el Departamento de Medicina Interna del Hospital Nacional, uno en el año 2017 y el otro en el 2021. Ambos pacientes presentaron síntomas neurológicos con mejoría de las lesiones con anfotericina B. Los granulomas cerebrales de PCM pueden tener comportamiento pseudotumoral. La regresión de las lesiones fue completa con anfotericina B y trimetoprin sulfametoxasol en el primer caso y anfotericina B e itraconazol en el segundo caso.

Paracoccidioidomycosis is the most common systemic mycosis in Latin America. Central nervous system (CNS) involvement is described in 10-27%. The objective is to present two male patients with neuroparacoccidioidomycosis admitted to the Department of Internal Medicine of the National Hospital, one in 2017 and the other in 2021. Both patients presented neurological symptoms with improvement of the lesions with amphotericin B. The granulomas brain cells of PCM may have pseudotumor behavior. Regression of the lesions was complete with amphotericin B and trimethoprim sulfamethoxazole in the first case and amphotericin B and itraconazole in the second case.

Multiparametric assay of screening for the diagnosis of mycoses of interest in Public Health: standardization of methodology / Ensaio multiparamétrico de triagem para diagnóstico de micoses de interesse em Saúde Pública: padronização da metodologia

The standardization and validation of a multiplex assay requires the combination of important parameters such as sensitivity and specificity, acceptable levels of performance, robustness, and reproducibility. We standardized a multiparametric Dot-blot aimed at the serological screening of paracoccidioidomycosis, histoplasmosis, and aspergillosis. A total of 148 serum were evaluated: 10 from healthy subjects, 36 from patients with paracoccidioidomycosis, 62 from patients with histoplasmosis, and 40 from patients with aspergillosis. It was found that the multiparametric Dot-blot showed a high percentage of cross-reactivity. However, when evaluated individually, in the serological screening of histoplasmosis, a good performance was observed when compared to the double immunodiffusion assay, considered the gold standard test, with 100% co-positivity and 83.3% co-negativity. The performance of serological screening for aspergillosis was not satisfactory when compared to double immunodiffusion, showing 71.4% co-positivity and 100% co-negativity. The evaluation of the stability of nitrocellulose membranes showed that membranes sensitized with H. capsulatum antigen remained stable for 90 days and those sensitized with A. fumigatus antigen for 30 days. We conclude that the use of crude antigens was not suitable for the standardization of the multiparametric Dot-blot assay, due to the high cross-reactivity, and that further tests should be performed with purified proteins (AU).

A padronização e validação de um ensaio multiplex requer a combinação de parâmetros importantes, como sensibilidade e especificidade, níveis aceitáveis de desempenho, robustez e reprodutibilidade. Este trabalho padronizou um Dot-blot multiparamétrico visando a triagem sorológica da paracoccidioidomicose, histoplasmose e aspergilose. Foram avaliadas 148 amostras de soro: 10 de indivíduos saudáveis, 36 de pacientes com paracoccidioidomicose, 62 de pacientes com histoplasmose e 40 de pacientes com aspergilose. Verificou-se que o Dot-blot multiparamétrico apresentou elevado percentual de reatividade cruzada. Entretanto, quando avaliado individualmente, na triagem sorológica da histoplasmose observou-se bom desempenho quando comparado ao ensaio de imunodifusão dupla, considerado o teste padrão ouro, com 100% de co-positividade e 83,3% de co-negatividade. O desempenho da triagem sorológica da aspergilose não foi satisfatório quando comparado a imunodifusão dupla, apresentando 71,4% de co-positividade e 100% de co-negatividade. A avaliação da estabilidade das membranas de nitrocelulose mostrou que membranas sensibilizadas com antígeno de H. capsulatum permaneceram estáveis por 90 dias e as sensibilizadas com antígeno de A. fumigatus, por 30 dias. Concluímos que o uso de antígenos brutos não foi adequado para a padronização do ensaio de Dot-blot multiparamétrico, devido ao alto índice de reatividade cruzada, e que novos testes devem ser realizados com proteínas purificadas (AU).

Paracoccidioidomicose afetando a mucosa bucal: relato de caso / Paracoccidioidomycosis affecting the buccal mucosa: case report / Paracoccidioidomicosis con afectación de la mucosa oral: relato de caso

Introdução: A paracoccidioidomicose é uma infecção micótica sistêmica com manifestações pulmonares primária que podem apresentar lesões cutâneas e orais. É mais comum no Brasil e em alguns outros países da América Latina, representando um importante problema de saúde pública devido às suas características potencialmente fatais. Relato de caso: Trabalhador rural de 53 anos, fumante e etilista, apresentando lesão ulcerada de aspecto moriforme em mucosa bucal direita. Realizou-se biópsia incisional cujo laudo histopatológico foi de paracoccidioidomicose. O paciente foi encaminhado ao médico infectologista para tratamento por meio de itraconazol (200mg por dia) por 18 meses. Após 03 meses de tratamento já apresentava regressão da lesão. Considerações Finais: Portanto, o objetivo deste trabalho é enfatizar a importância do cirurgião-dentista no reconhecimento das lesões oral e realização da biópsia para o correto diagnóstico e manejo desta doença por meio de um relato de caso clínico... (AU)

Paracoccidioidomycosis is a systemic mycotic infection with primary pulmonary manifestations that can present cutaneous and oral lesions. It is more common in Brazil and some other Latin American countries, representing an important public health problem due to its potentially fatal characteristics. Case report: 53-year-old rural worker, smoker and drinker, presenting an ulcerated lesion with a moriform aspect in the right oral mucosa. An incisional biopsy was performed, and the histopathological report was of paracoccidioidomycosis. The patient was referred to the infectious disease physician for treatment with itraconazole (200mg per day) for 18 months. After 03 months of treatment, he already had regression of the lesion. Final Considerations: Therefore, the objective of this paper is to emphasize the importance of the dentist in recognizing oral lesions and performing a biopsy for the correct diag... (AU)

La paracoccidioidomicosis es una infección micótica sistémica con manifestaciones pulmonares primarias que pueden presentar lesiones cutáneas y bucales. Es más común en Brasil y algunos otros países de América Latina, lo que representa un importante problema de salud pública debido a sus características potencialmente fatales. Caso clínico: trabajador rural de 53 años, fumador y bebedor, con lesión ulcerada de aspecto moriforme en mucosa oral derecha. Se realizó biopsia incisional y el informe histopatológico fue de paracoccidioidomicosis. El paciente fue remitido al médico de enfermedades infecciosas para tratamiento con itraconazol (200 mg al día) durante 18 meses. Después de 03 meses de tratamiento, ya tenía regresión de la lesión. Consideraciones finales: Por lo tanto, el objetivo de este trabajo es enfatizar la importancia del odontólogo en el reconocimiento de las lesiones bucales y la realización de una biopsia para el correcto diagnóstico y manejo de esta enfermedad a través de la presentación de un caso clínico... (AU)

Oral manifestations of systemic fungal infections: 25-year experience in an endemic region

Some mycoses are endemic. They develop through hematogenous spread, causing a generalized infection, usually with secondary mucosal involvement.The aim of this observational and retrospective study was to report the prevalence and characteristics of oral lesions in patients diagnosed with systemic fungal infections (SFI) over a 25-year period in southern Brazil. Demographic (age, sex, ethnicity, occupation) and clinical (anatomical location, symptoms,histopathological diagnosis and management) data from the medical records of patients with SFI were collected from 1995 to 2019. 34 cases of SFI were found, of which 31 (91.18%) were diagnosed as paracoccidioidomycosis (PCM) and 3 (8.82%) as histoplasmosis. Men were much more affected (n = 31; 91.18%), with an average age of 46.9 years. Most patients (n = 18; 58.06%) were Caucasian; 48% (n = 15) were farm/rural workers and the most affected region was the jugal mucosa (n = 13; 25.49%) followed by the alveolar ridge (n = 12; 23.52%). All patients with histoplasmosis were immunocompetent men (mean age: 52.67 years), and the palate was the most affected. All patients underwent incisional biopsy and were referred to an infectologist. The dentist has an essential role in the recognition of SFI, whose oral manifestations may be the first sign. SFI should be included in differential diagnosis in patients from endemic areas. In addition, the inevitable human mobility and globalization make knowledge of these mycosesnecessary worldwide, especially since advanced cases in immunocompromised patients can be fatal.

A scoping study of pulmonary paracoccidioidomycosis: severity classification based on radiographic and tomographic evaluation

The lungs have great importance in patients with paracoccidioidomycosis since they are the portal of entry for the infecting fungi, the site of quiescent foci, and one of the most frequently affected organs. Although they have been the subject of many studies with different approaches, the severity classification of the pulmonary involvement, using imaging procedures, has not been carried out yet. This study aimed to classify the active and the residual pulmonary damage using radiographic and tomographic evaluations, according to the area involved and types of lesions.

Paracoccidioidomicosis sistémica con compromiso del apéndice cecal en un niño: reporte de caso / Systemic paracoccidioidomycosis with compromise of the cecal appendix in a child: case report

RESUMEN La paracoccidioidomicosis es la micosis sistémica más prevalente en Latinoamérica. En niños la presentación clínica más frecuente es la forma juvenil o aguda/subaguda, que compromete principalmente los ganglios linfáticos y en menor proporción los órganos gastrointestinales. Presentamos el caso de un paciente de 10 años, sin comorbilidades, con dolor agudo en fosa iliaca derecha; además de historia de un mes de evolución de diarrea, fiebre, pérdida de peso e hipereosinofilia. Fue diagnosticado de apendicitis aguda secundaria a un cuadro de paracoccidioidomicosis sistémica, mediante histopatología del apéndice cecal y ganglios mesentéricos. Tuvo respuesta favorable al tratamiento con anfotericina B liposomal. A pesar de que la paracoccidioidomicosis sistémica con compromiso del apéndice cecal es infrecuente, debe considerarse como parte de los diagnósticos diferenciales en niños con linfadenomegalias generalizadas y procedentes de áreas endémicas.

ABSTRACT Paracoccidioidomycosis, the most prevalent systemic mycosis in Latin America. In children the most common clinical presentation is the juvenile or acute/subacute form, which mainly involves the lymph nodes and in a lesser proportion the gastrointestinal organs. We present the case of a 10-year-old patient, without comorbidities, who presented acute right iliac fossa pain; in addition to a history of 1 month of evolution of diarrhea, fever, weight loss, and hypereosinophilia. Was diagnosed of acute appendicitis due to systemic paracoccidioidomycosis, through histopathology of the cecal appendix and mesenteric lymph nodes. Although systemic paracoccidioidomycosis with involvement of the cecal appendix is ​​rare, it should be considered as part of the differential diagnoses in children and young adults with generalized lymphadenomegaly from endemic areas.

Evaluación de la respuesta humoral inducida por la vacuna BBIBP-CorV mediante la determinación de anticuerpos neutralizantes en personal sanitario peruano / Evaluation of the humoral response induced by BBIBP-CorV vaccine by determining neutralizing antibodies in peruvian healthcare personnel

RESUMEN Objetivo. Determinar el título de anticuerpos frente al dominio de unión al receptor (RBD) de la proteína espiga (S) en personal de salud entre la 4.ª y 12.ª semana luego de haber recibido la vacuna BBIBP-CorV (Sinopharm). Materiales y métodos. Se incluyeron 168 trabajadores de salud de dos hospitales de la región, quienes cumplían el esquema completo con vacuna de Sinopharm, y se realizó la medición de anticuerpos en suero mediante la prueba Elecsys®Anti-SARS-CoV-2. Resultados. Todos los participantes desarrollaron anticuerpos frente al dominio RBD. El valor mínimo fue de 1,78 U/mL. En 70 (41,7%) participantes se encontraron niveles iguales o por encima de 250. La media geométrica fue de 82,6 (IC 95% 67,8-100,6). Las mujeres presentaron un mayor nivel de anticuerpos. El grupo de participantes en los que se midieron anticuerpos entre las semanas 4 y 7 posvacunación mostró niveles de anticuerpos significativamente mayores que los pacientes cuyas determinaciones fueron realizadas entre las 10 y 12 semanas posvacunación. Entre los pacientes con antecedente de COVID-19, los niveles de anticuerpos se encontraron en cifras iguales o por encima de 250 U/mL en el 88% de casos, en comparación con 6% entre aquellos sin antecedente de COVID-19, (p<0,001). Conclusión. Todos los participantes inmunizados con la vacuna BBIBP-CorV presentaron positividad a anticuerpos frente al RBD de la proteína S del SARS-CoV-2. Es necesario evaluar la correlación entre la magnitud de los títulos y la protección frente a COVID-19 y el tiempo de protección conferido por la vacuna.

ABSTRACT Objective. To determine the titer of antibodies against the receptor binding domain (RBD) of the spike protein (S) in health personnel between the 4th and 12th week after receiving the BBIBP-CorV vaccine (Sinopharm). Materials and methods. We included a total of 168 healthcare workers from two hospitals in the region, who complied with the complete Sinopharm vaccine schedule; serum antibodies were measured using the Elecsys® Anti-SARS-CoV-2 test. Results. All participants developed antibodies to the RBD domain. The lowest antibody titer level was 1.78 U/mL. Levels equal to or above 250 were found in 70 (41.7%) participants. The geometric mean was 82.6 (95% CI: 67.8-100.6). Women had higher antibody levels. Participants whose antibodies were measured between 4- and 7-weeks post-vaccination showed significantly higher antibody levels than patients whose antibody levels were measured between 10- and 12-weeks post-vaccination. Among patients with a history of COVID-19, antibody levels were found to be at or above 250 U/mL in 88% of cases, compared to 6% among those without a history of COVID-19, (p<0.001). Conclusion. All participants immunized with BBIBPCorV vaccine were positive for antibodies against the SARS-CoV-2 spike protein RBD. The correlation between the titer level and protection against COVID-19, as well as the length of the protection provided by the vaccine, needs to be evaluated.

Multifocal Pseudotumorous Form of Neuroparacoccidioidomycosis in an Immunocompetent Patient: A Clinicopathological Review Based on a Case Report

Neuroparacoccidiodimycosis (NPDM) is an uncommon granulomatous disease, which more frequently affects immunocompromised male patients over 30 years of age in the course of chronic lung disease. Paracoccidioides brasiliensis (PB) is an endemic fungus in Brazil, and grows as thick-walled yeast (with round to oval bodies) measuring 10 µm to 60 µm in diameter. Neuroparacoccidiodimycosi may develop many years after transmission and/or primary lung involvement. The authors describe a case of NPDM affecting a male patient, 52 years of age, farmer, heavy smoker, with clinical complaint of headache, asthenia, seizures, and prostration in the previous nine months. Upon physical examination, the patient presented regular general condition, without other relevant physical alterations. Computed tomography (CT) showed multiple bilateral pulmonary nodules associated to enlargement of the mediastinal lymph node. Magnetic resonance imaging (MRI) and CTscans of the central nervous system showed six heterogeneous nodular lesions compromising the frontal and parietal lobes, the largest one measuring 3.8 3.2 3.2 cm. The hypothesis of a neoplastic process compromising the lung and brain was considered. A biopsy of the mediastinal lymph node showed epithelioid granulomas, which exhibited round, thin-walled fungal structures in Grocott silver stain. The stereotactic biopsy of the frontal lesion was constituted by necrotic tissue admixed with some round to oval, thin-walled fungi measuring 10 µm to 60 µm, compatible with PB (identified on Grocott silver stain/confirmed in culture). The diagnosis of NPDM was then established. The employed therapeutic regimen was intravenous amphotericin B, itraconazole, and sulfamethoxazole-trimetropin. After ninety days of clinical follow-up, no episodes of seizures/neurological deficits were identified, and a marked decrease in the number and size of the lung and brain lesions were found.

Disseminated paracoccidioidomycosis in a liver transplant patient

Abstract Paracoccidioidomycosis is an endemic systemic mycosis caused by Paracoccidioides brasiliensis complex and P. lutzii. It is a rare disease in non-HIV-induced immunosuppressed individuals. In organ transplant recipients, it is more frequently associated with immunosuppression after kidney transplantation. In a liver transplant patient, only one case has been published in the literature to date. The present report comprises the case of a 47-year-old female patient with disseminated skin lesions associated with signs and symptoms of systemic involvement of paracoccidioidomycosis that manifested one year after liver transplantation and under an immunosuppression regimen with tacrolimus and mycophenolate mofetil.

Insulina modula migração celular e a secreção de citocinas na vigência da infecção pulmonar por Paracoccidioides brasiliensis em camundongos diabéticos e não-diabéticos / Insulin modulates cell migration and cytokines secretion during pulmonary infection caused by Paracoccidioides brasiliensis in diabetic and non-diabetic mice

Diabetes mellitus (DM) compreende um conjunto de doenças metabólicas de grande importância e incidência mundial. Nele, o DM do tipo 1 é caracterizado pela destruição de células pancreáticas produtoras de insulina, e dentre seus sintomas, a disfunção imunológica relacionada à falta de insulina foi observada por diversos estudos, descrevendo pacientes diabéticos como mais susceptíveis a infecções e complicações decorrentes destas. Paracoccidioidomicose (PCM) é uma enfermidade sistêmica causada por fungos da espécie Paracoccidioides sp., bastante importante no Brasil e endêmica em toda a América Latina. Este trabalho utiliza um modelo de carência relativa de insulina (DM experimental) para estudar a intervenção da insulina em um modelo de micose pulmonar causada por P. brasiliensis, analisando o processo de migração celular (expressão de moléculas de adesão por imunohistoquímica e fenótipo dos leucócitos do pulmão por citometria de fluxo), os mecanismos moleculares (produção/liberação de citocinas por cytometric bead array), intracelulares (vias de sinalização por Western blot), e a atividade fagocítica e microbicida dos macrófagos alveolares. Em resultados observamos que, comparados aos não-diabéticos, camundongos tornados diabéticos apresentam maior susceptibilidade evidenciada por menor atividade fagocítica e reduzidas secreções de interferon-γ e de interleucina-12 na fase inicial da inflamação, que leva a uma resposta menos efetiva com menor expressão de molécula de adesão de células vasculares, reduzidas populações de linfócitos TCD4+, TCD8+, células natural killer, culminando em inflamação crônica resultante da proliferação aumentada do fungo nos pulmões (aumento de interferon-γ e fator necrótico tumoral-ß). Vemos ainda que o tratamento de insulina em animais diabéticos restaurou as secreções de citocinas pró-inflamatórias e a atividade fagocítica de macrófagos em 24 horas de infecção, e aumentou a celularidade, a expressão de moléculas de adesão de células vasculares-1 e restaurou as populações de linfócitos B, de células natural killer e de células coestimuladas por CD80, além de reduzir a inflamação crônica no pulmão. Estes dados em conjunto nos permitem inferir que a insulina modulou o ambiente inflamatório de animais tornados diabéticos de formas diferentes em estágios iniciais e tardios da infecção pelo isolado Pb18 do Paracoccidioides brasiliensis

Diabetes mellitus comprehends a group of metabolic diseases of great importance and incidence worldwide. Type 1 diabetes mellitus is characterized by destruction of insulin producing-pancreatic cells and, among its symptoms, an impaired immunological function has been observed in many studies having diabetic patients described as more susceptible to infections and complications resulted of them. Paracoccidioidomycosis is a systemic disease caused by fungi of Paracoccidioides spp. , also of great importance in Brazil and endemic in the whole Latin America. This work uses a model of experimental T1DM to investigate the intervention of insulin in a model of murine PCM induced by Paracoccidioides brasiliensis, analyzing the process of cell migration (adhesion molecules expression, leukocyte phenotyping), molecular mechanisms (production and secretion of cytokines), intracellular mechanisms (signaling pathways) and phagocytic and microbicidal activities in alveolar macrophages. In results, compared to controls, we observed higher susceptibility in diabetic mice to PCM, evidenced by reduced phagocytic activity and reduced levels of interferon-γ and interleukin-12 on initial stages of infection, and a less effective inflammation with lesser expression of adhesion molecules, reduced migration of TCD4+, TCD8+, NK cells and B lymphocytes, resulting in chronic inflammation caused by higher fungal proliferation in lungs (higher interferon-γ and tumours necrosis factor-α levels). In addition, we saw treatment with insulin in diabetic animals restored secretion of pro-inflammatory cytokines and phagocytic activity on early stages and allowed higher cellularity, higher expression of vascular cells adhesion molecule-1 and restored populations of B lymphocytes, NK cells and the expression of costimularoty molecule CD80, also reducing the chronic inflammation in lungs. Taken together, these data lead us to suggest insulin modulated the inflammatory microenvironment in lungs of mice rendered diabetic, in different forms on earlier and later stages of an infection by Pb18 isolate

Trends and patterns of mortality arising from fungal infections in Brazil in a period of 11 years / Tendências e padrões de mortalidade em decorrência de infecções fúngicas no Brasil, em um período de 11 anos

Objective: To investigate the mortality attributed to fungal infections, in Brazil between 2003 and 2013. Methods: This ecological study relied on official data collected from the Sistema de Informação Sobre Mortalidade ­ Mortality Information System database. The mycoses were identified by the 10th revision of the International Classification of Diseases, which included categories B35­B49 in its first chapter. Results: Overall, 11,991,935 deaths were reported in the aforementioned period. The deaths of 4,192 individuals were primarily attributed to mycoses. High annual mortality rates were observed in all Brazilian regions, except in the Northeast. The main recorded mycoses were paracoccidioidomycosis (35.6%) and cryptococcosis (24.1%). There was a downward trend in the number of deaths due to paracoccidioidomycosis. In addition, 10,925 death certificates listed mycoses as an associated cause of death. Cryptococcosis (89.7%) and histoplasmosis (89.4%) were the most common mycoses associated with deaths in HIV patients. Conclusions: There was a downward trend in the number of deaths stemming from invasive fungal infections. However, opportunistic mycoses follow been a significant cause of death, especially in HIV patients.

Objetivo: Investigar a mortalidade atribuída para as infecções fúngicas, no Brasil, entre 2003 e 2013. Métodos: Trata-se de um estudo ecológico, em que os dados foram obtidos do Sistema de Informação sobre Mortalidade (SIM), disponíveis na plataforma do DATASUS. As micoses foram identificadas por meio da 10ª revisão da Classificação Internacional de Doenças (CID-10), a qual incluiu as categorias B35-B49 no primeiro capítulo da CID-10. Resultados: No total, 11.991.935 óbitos foram notificados no período do estudo. Os óbitos de 4,192 indivíduos foram atribuídos às micoses. Foram observadas elevadas taxas de mortalidade em todas as regiões brasileiras, com exceção do Nordeste. As principais micoses registradas foram paracoccidioidomicose (35,6%) e criptococose (24,1%). Houve uma tendência na redução do número de óbitos em relação à paracoccidioidomicose. Além disso, em 10.925 declarações de óbitos informavam que as micoses foram causas associadas ao óbito. Criptococose (89,7%) e Histoplasmose (89,4%) foram as micoses mais comumente associadas ao óbito, principalmente em pacientes HIV positivos. Conclusões: Houve uma tendencia na diminuição dos óbitos por infecções fúngicas invasivas. Entretanto, micoses oportunistas continuam sendo importantes causas de morte, especialmente em indivíduos HIV positivos.

Gene expression of Paracoccidioides virulence factors after interaction with macrophages and fibroblasts

BACKGROUND Paracoccidioidomycosis (PCM) is a systemic mycosis with high prevalence in Latin America that is caused by thermodimorphic fungal species of the Paracoccidioides genus. OBJECTIVES In this study, we used quantitative polymerase chain reaction (qPCR) to investigate the expression of genes related to the virulence of Paracoccidioides brasiliensis (Pb18) and P. lutzii (Pb01) strains in their mycelial (M) and yeast (Y) forms after contact with alveolar macrophages (AMJ2-C11 cell line) and fibroblasts (MRC-5 cell line). METHODS The selected genes were those coding for 43 kDa glycoprotein (gp43), enolase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 14-3-3 protein (30 kDa), phospholipase, and aspartyl protease. FINDINGS In the Pb18 M form, the aspartyl protease gene showed the highest expression among all genes tested, both before and after infection of host cells. In the Pb18 Y form after macrophage infection, the 14-3-3 gene showed the highest expression among all genes tested, followed by the phospholipase and gp43 genes, and their expression was 50-fold, 10-fold, and 6-fold higher, respectively, than that in the M form. After fibroblast infection with the Pb18 Y form, the 14-3-3 gene showed the highest expression, followed by the phospholipase and aspartyl protease genes, and their expression was 25-fold, 10-fold, and 10-fold higher, respectively, than that in the M form. Enolase and aspartyl protease genes were expressed upon infection of both cell lines. After macrophage infection with the Pb01 Y form, the 14-3-3 gene showed the highest expression, followed by the phospholipase and aspartyl protease genes, and their expression was 18-fold, 12.5-fold, and 6-fold higher, respectively, than that in the M form. MAIN CONCLUSIONS In conclusion, the data show that the expression of the genes analysed may be upregulated upon fungus-host interaction. Therefore, these genes may be involved in the pathogenesis of paracoccidioidomycosis.

Serological diagnosis of paracoccidioidomycosis using a Paracoccidioides spp. comercial antigen and the counterimmunoelectrophoresis method

ABSTRACT Purpose: In-house Paracoccidioides spp. antigens are commonly used in the serological diagnosis of paracoccidioidomycosis (PCM). The sensitivity and specificity of a commercial Paracoccidioides spp. antigen was assessed for PCM serological testing. Method: Counterimmunoelectrophoresis and double immunodiffusion were used to evaluate the Paracoccidioides ID Antigen reagent in sera from PCM cases and patients with other diseases. Results: All active PCM sera (n=24) were reactive using counterimmunoelectrophoresis (sensitivity = 100%), including 11 cases of infection by P. brasiliensis sensu stricto and one by P. americana. Fifteen (88%) out of 17 sera from patients on treatment or cured were reactive, including one case of P. lutzii infection. One to three bands of antigen-antibody precipitate were observed on the agarose gel, with a predominance of two to three bands in the test with untreated PCM sera or at the beginning of antifungal therapy. All sera from patients with histoplasmosis (n=7), aspergillosis (n=5), and other diseases (n=27) tested negative (specificity = 100%). The overall sensitivity and specificity using the commercial antigen and double diffusion test were 75% and 100%, respectively. Conclusion: The commercial antigen performed satisfactorily and may contribute to the dissemination of the use of serological tests for the PCM diagnosis.

Epidemiology of paracoccidioidomycosis in Venezuela: a retrospective study from 1954 to 2019

BACKGROUND Paracoccidioidomycosis (PCM) is a systemic mycosis endemic to Latin America. Etiological agents are Paracoccidioides species that diverge phylogenetically throughout South America. OBJECTIVES This study aimed to document the epidemiology of PCM in Venezuela. METHODS We have performed a retrospective cross-sectional descriptive study in 31,081 clinical records of patients from two reference centres during 65 years (1954-2019). FINDINGS PCM diagnosis was confirmed in 745 patients. Chronic PCM was the most prevalent form (90.06% cases); 80.67% were male and the most affected age range was 41-60. Farming and construction were the most prevalent occupation and Miranda State had a higher prevalence. Lung and skin were the most affected organs, followed by oral manifestations. Direct examination, culture and serology showed a high sensibility, and no statistical difference was observed among the diagnostic tools. Out of 17 Paracoccidioides isolates genotyped from Venezuela, one was typed as Paracoccidioides americana and 16 as Paracoccidioides venezuelensis. MAIN CONCLUSIONS Clinical manifestations observed, information about the epidemiology and molecular profile is essential not only for diagnosis but also for understanding therapeutic responses to mycotic drugs and prognosis. Therefore, it is necessary to sequence all positive isolated strains in order to confirm the dominance of P. venezuelensis in Venezuela.