Revisiting the History of Chagas Disease: "Live to tell"

Abstract In 1907, Carlos Chagas was designated to fight paludism in the Rio das Velhas region along the Central do Brasil railroad. During his field research, Chagas discovered a hematophagous insect ( Panstrongylus megitus ) carrying a new trypanosomatide, which he named Trypanosoma cruzi . On April 14th, 1909, he found the same parasite in the blood of a febrile child, submitting the announcement of his discoveries to the Brasil Médico scientific journal. Here, we discuss the early stages in the establishment of a new human morbid entity during the first decades after its discovery with a definite influence from its discoverer, Carlos Chagas, as well the first collaborators. Moreover, we cover the importance of the Center for the Study and Prophylaxis of Chagas Disease in Bambuí (MG), unraveling the most advanced developments in research within the disease's habitat and the widening perspectives for modern research that have emerged after the 1960s and continue to improve to this day. In this revisitation to the history of Chagas disease, we begin at Manguinhos (RJ ), making our way to Lassance (MG), where the discovery took place. Then, we travel back to Rio de Janeiro in the beginning of the twentieth century and Brazilian republic until the current day, revealing milestone publications that settled Chagas disease both as a source of pride for Brazilian medicine and as a challenge with important aspects that remain to be clarified. Any similarities to our country's politics and economy in the twentieth century are not mere coincidences.

Prevalence of Chagas heart disease in dilated cardiomyopathy / Prevalencia de cardiopatía chagásica en la miocardiopatía dilatada

Abstract Objectives: The main objective is to determine the prevalence of American trypanosomiasis in patients with dilated cardiomyopathy in a tertiary hospital in western Mexico. Methods: From January 1991 to February 2016, 387 consecutive patients with a confirmed diagnosis of dilated cardiomyopathy were included in the study. Cases with ventricular dilatation secondary to ischemic heart disease, valvular heart disease, hypertension, lung disease, pericardial disease, or congenital heart disease were excluded from the study. Diagnosis was made detecting antibodies against Trypanosoma cruzi with two different methods or parasite in blood. Results: Were included 387 patients with dilated cardiomyopathy, Chagas cardiomyopathy was confirmed in 6.9%, two patients in the acute phase (in one, suspected transfusion transmission was detected). Most patients were born in rural areas. About 96.2% showed congestive heart failure, only one patient with apical left ventricular aneurysm manifested palpitations. About 66% with right bundle branch block, left anterior fascicular block, or the association of both, in 14.8%, non-sustained ventricular tachycardia was found. Conclusions: Chagas cardiomyopathy is common in México, mainly in people who were born or lived during childhood in rural areas. It is a common cause of heart failure. Chagas’ heart disease should be suspected in patients receiving a blood transfusion, even without another epidemiological history.

Resumen Objetivo: El objetivo principal del estudio es conocer la prevalencia de tripanosomiasis americana en pacientes con cardiomiopatía dilatada, en un hospital de concentración en el occidente de México. Métodos: Desde enero de 1991 a febrero de 2016 se incluyeron 387 pacientes consecutivos con diagnóstico de cardiomiopatía dilatada, se excluyeron los casos con dilatación ventricular secundaria a cardiopatía isquémica, valvulopatías, hipertensión arterial sistémica, enfermedad pulmonar, enfermedad pericárdica o cardiopatías congénitas. El diagnóstico se realizó mediante la detección de anticuerpos anti-tripanosoma cruzi con 2 métodos positivos diferentes o con la detección del parásito en sangre. Resultados: Se incluyeron 387 paciente con cardiomiopatía dilatada, en el 6.9% se confirmó cardiopatía chagásica; dos pacientes en fase aguda (uno con sospecha de transmisión transfusional). La mayoría de los pacientes provenían de zonas rurales. El 96.2% de los casos presentó insuficiencia cardiaca congestiva, un paciente con aneurisma apical del ventrículo izquierdo solo manifestó palpitaciones. El 66% presentó bloqueo de la rama derecha del haz de His, hemibloqueo anterior izquierdo o la asociación de ambos, en el 14.8% se encontró taquicardia ventricular no sostenida. Conclusiones: La cardiopatía chagásica es frecuente en nuestro medio, principalmente en personas que nacieron o vivieron durante la infancia en áreas rurales. Es causa común de insuficiencia cardiaca. La cardiomiopatía chagásica debe sospecharse en pacientes que reciben transfusión sanguínea, incluso sin otros antecedentes epidemiológicos

Chronic Chagas cardiomyopathy: a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the BENznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial

Chagas cardiomyopathy is the most frequent and most severe manifestation of chronic Chagas disease, and is one of the leading causes of morbidity and death in Latin America. Although the pathogenesis of Chagas cardiomyopathy is incompletely understood, it may involve several mechanisms, including parasite-dependent myocardial damage, immune-mediated myocardial injury (induced by the parasite itself and by self-antigens), and microvascular and neurogenic disturbances. In the past three decades, a consensus has emerged that parasite persistence is crucial to the development and progression of Chagas cardiomyopathy. In this context, antiparasitic treatment in the chronic phase of Chagas disease could prevent complications related to the disease. However, according to the results of the BENEFIT trial, benznidazole seems to have no benefit for arresting disease progression in patients with chronic Chagas cardiomyopathy. In this review, we give an update on the main pathogenic mechanisms of Chagas disease, and re-examine and discuss the results of the BENEFIT trial, together with its limitations and implications.

Transplante cardíaco na doença de Chagas / Heart transplantation in Chagas’ disease

Dentre as diversas etiologias da insuficiência cardíaca, a miocardiopatia chagásica é considerada a mais agressiva. Como não há tratamento capaz de reverter a evolução da doença o transplante cardíaco torna-se a únicaopção. Foram analisados 107 pacientes portadores da doença de Chagas submetidos a transplante cardíaco, com idades compreendidas entre 11 e 62 anos (42,7±15,3 anos). Os pacientesportadores de megaesôfago e megacólon sintomáticos são automaticamente excluídos dos programas de transplante devido a uma maior possibilidade de complicações no pós-operatório a curto e longo prazo. A expectativa de resultados inferiores para o transplante em chagásicos em relação às demais cardiomiopatias não foi confirmada e, paradoxalmente,se encontram melhores taxas de sobrevida. Notou-se uma mortalidade imediata de 17,7% (19 casos), sendo as principais causas de morte: infecção (6 casos, 31,5%), disfunção do enxerto (6 casos, 31,5%), rejeição (4 casos 21,1%), parada cardiorrespiratória súbita (2 casos 10,5%) e incompatibilidades ABO (1 caso 5,3%). Tardiamente ao transplante, 27 (25,2%) pacientes morreram, sendo as principais causas de morte: rejeição (6 casos, 22,2%), infecção (6 casos, 22,2%), linfoma (4 casos, 14,8%), Kaposi (2 casos, 7,4%), pericardite constritiva (2 casos, 7,4%) e reativação da doença de Chagas no sistemanervoso central (1 caso, 7,1%). Por fim, pode-se concluir que: 1) o transplante cardíaco ainda é a única forma capazde modificar a evolução natural da cardiomiopatia chagásica; 2) o diagnóstico precoce aliado à rápida introdução de benzonidazol leva a um reconhecimento de padrões histológicosnormais do miocárdio sem que haja sequelas e 3) as doses de imunossupressores empregadas devem ser inferiores às utilizadas em outras etiologias.

Among the several etiologies of heart failure, the chagasic myocardiopathy is considered the most aggressive. Once there is no treatment capable of reverting the disease evolution, the heart transplantation becomes the only option. We analyzed 107 patients with Chagas disease submitted to heart transplantation, aged between 11 and 62 years (42.7 ± 15.3 years). Patients with symptomatic megacolon andmegaesophagus are automatically excluded from transplant programs due to a higher possibility of postoperative short and long term complications. The expectation of inferior results for the transplantation of chagasic patients in comparison with other myocardiopathies was not confirmed and, paradoxically, were found better survival rates. We noticed an immediatemortality rated in 17.7% (19 cases), whose main cause of death were: infection (6 cases, 31.5%), graft dysfunction (6 cases, 31.5%), rejection (4 cases 21,1%), sudden cardiopulmonary arrest (2 cases 10.5%) and ABO incompatibilities (1 case 5,3%). Late after transplant, 27 (25.2%) patients died, and the majorcauses were: rejection (6 cases, 22.2%), infection (6 casos, 22.2%), lymphoma (4 cases, 14.8%), Kaposi sarcoma (2 cases, 7.4%), constrictive pericarditis (2 cases, 7.4%) and Chagas disease reactivation in the central nervous system (1 case, 7.1%). Finally, the conclusions are: 1) heart transplantation is still the only way to modify the natural course of chagasicmyocardiopathy, 2) early diagnosis coupled to the rapid introduction of benzonidazol leads to a pattern recognition of normal myocardial histology without sequelae and 3) the doses of immunosuppressants used should be lower than those usedin other etiologies.

Transmisión oral de la enfermedad de chagas: con especial referencia a la patología de los casos del año 2009 / Oral transmission of chagas disease due to oral: with special reference to the pathology of the cases from the year 2009

La transmisión oral de la enfermedad de Chagas habitual en el ciclo selvático es una forma rará en el ser humano. En este último, se debe a la contaminación de las heces con Trypanosoma cruzi (Tcruzi) en los alimentos o a la manipulación infectada de los mismos. Más raramente a la ingesta de carne de reservorios infectados. En esta comunicación, se ponen en el tapete, los trabajos experimentales y naturales del investigador Díaz-Ungría quien demostró el importante papel que juega la mosca doméstica en la contaminación de los alimentos con las heces infectadas de los vectores. Igualmente, se destaca la importancia del perro como reservorio doméstico, todos los cuales podrían ser factores determinantes en la causa de los brotes agudos presentados en los dos últimos años en nuestro país. Se exponen las características de la miocarditis aguda chagásica como la expresión más constante de la forma aguda de la enfermedad por transmisión oral. Se destacan las medidas de prevención efectuadas por las autoridades sanitarias en estas circunstancias

Oral transmission of Chagas disease is common in the forest'cycle and is a rare form in humans. In the human is due to contamination of the stool with T.cruzi in food or infected by their manipulation. More rarely due to reservoirs infected T.cruzi meat intake. In this communication we described the natural and experimental works of the Díaz-Ungría researcher who demonstrated the important role played bi the house fly in the contamination of food with vectors infected faeces. It also highlights the importance of the dog as domestic reservoir, all of which could be determining factors in the cause of acute outbreaks in the past two years in our country. The features of acute Chagasic'myocarditis are exposed as the constant expression of the acute form of the disease by oral transmission. The prevention measures carried out by the health authorities in these circunstances are high lighted

Acometimento cardíaco em Casos de Doença de Chagas Aguda da Amazônia / Cardiac involvement in Acute Chagas' Disease Cases in the Amazon region

Descreve-se o acometimento cardíaco em cinco pacientes autóctones da Amazônia com diagnóstico de Doença de Chagas Aguda (DCA). Quatro desses pacientes apresentaram provável transmissão oral. Todos apresentaram algum grau de acometimento cardíaco, não havendo nenhum óbito.

The cardiac involvement of five patients from the Amazon region with Acute Chagas' Disease (ACD) is described. Four of these patients presented probable oral transmission. All of them presented some degree of cardiac involvement, but there were no deaths.

Chagas disease cardiomyopathy: current concepts of an old disease

Chagas disease continues to be a significant public health problem, as ca. 10 million people are still infected with T. cruzi in Latin America. Decades after primary infection, 30 percent of individuals can develop a form of chronic inflammatory cardiomyopathy known as Chagas disease cardiomyopathy (CCC). Data from both murine models and human studies support the view that an autoimmune response as well as a parasite-driven immune response involving inflammatory cytokines and chemokines may both play a role in generating the heart lesions leading to CCC. This review aims to summarize recent advances in the understanding of the immunopathogenesis of Chagas disease cardiomyopathy.

A doença de Chagas continua sendo importante problema de saúde pública uma vez que cerca de 10 milhões de indivíduos ainda estão infectados pelo T. cruzi. Décadas após a infecção primária, aproximadamente 30 por cento dos indivíduos podem desenvolver uma cardiomiopatia inflamatória crônica, a chamada Cardiomiopatia Chagásica Crônica (CCC). Dados de modelos murinos e de estudos em humanos apóiam a visão de que tanto respostas auto-imunes como as determinadas pelo parasita em conjunto com citocinas e quimiocinas inflamatórias participam da geração das lesões cardíacas típicas da CCC. A presente revisão tem como objetivo sumarizar os recentes avanços no entendimento da imunopatogênese da Cardiomiopatia Chagásica Crônica.

Case-control study of factors associated with chronic Chagas heart disease in patients over 50 years of age

A case-control study on chronic Chagas heart disease (CCHD) was carried out between 1997 and 2005. Ninety patients over 50 years of age were examined for factors related to (CCHD). Fourty-six patients (51.1 percent) with Chagas heart disease (anomalous ECG) were assigned to the case group and 44 (48.9 percent) were included in the control group as carriers of undetermined forms of chronic disease. Social, demographic (age, gender, skin color, area of origin), epidemiological (permanence within an endemic zone, family history of Chagas heart disease or sudden death, physical strain, alcoholism, and smoking), and clinical (systemic hypertension) variables were analyzed. The data set was assessed through single-variable and multivariate analysis. The two factors independently associated with heart disease were age - presence of heart disease being three times higher in patients over 60 years of age (odds ratio, OR: 2.89; confidence interval of 95 percent: 1.09-7.61) - and family history of Chagas heart disease (OR: 2.833, CI 95 percent: 1.11-7.23). Systemic hypertension and gender did not prove to hold any association with heart disease, as neither did skin color, but this variable showed low statistical power due to reduced sample size.

An overview of chagasic cardiomyopathy: pathogenic importance of oxidative stress

Há evidências que sugerem que as miocardites chagásicas são devidas aos danos induzidos pelo estresse oxidativo, podendo contribuir para a evolução da doença de Chagas. Em doenças infecciosas, a formação de espécies reativas do oxigênio (ROS) é, principalmente, derivada de danos celulares mediados pela invasão e replicação do patógeno e por reações citotóxicas mediadas pelo sistema imune. No entanto, como as ROS são formadas e sua função no estresse oxidativo na cardiomiopatia chagásica (CCM) não estão completamente elucidadas. Nesta revisão, nós discutimos as evidências para o aumento do estresse oxidativo na doença de Chagas, com ênfase nas anormalidades mitocondriais, na disfunção da cadeia de transporte de elétrons e seu papel na manutenção do estresse oxidativo no miocárdio. Discutimos ainda, os resultados da literatura que relatam as conseqüências da manutenção do estresse oxidativo na patogênese da CCM.

Probabilidade de ocorrência de morte súbita cardíaca na cardiomiopatia chagásica e não chagásica / Probably of sudden cardiac death in Chagas and non-Chagas' disease

O cardioversor-desfibrilador implantável (CDI) tem demonstrado sua eficácia no tratamento das arritmias das arritmias ventriculares responsáveis pela morte súbita cardíaca. Entretanto, a probabilidade de ocorrência dessas arritmias na cardiomiopatia chagásica é desconhecida. O objetivo deste estudo foi comparar a probabilidade da não ocorrência de morte súbita cardíaca por arritmia ventricular na cardiomiopatia chagásica e não chagásica. Foram selecionados 53 pacientes (idade média de 52,9 +- 12,8 anos, 48 do sexo masculino) portadores de CDI recuperados de morte súbita, 11 com Doença de Chagas (grupo I) e 42 com cardiomiopatia de outras etiologias (grupo II). Foram definidas como fatais as arritmias ventriculares com intervalo RR inferior a 315 ms. Foi comparada a probabilidade de não ocorrência de morte súbita cardíaca por estas arritmias nos dois grupos, utilizando a curva de Kaplan-Meyer. Após 22,7 +- 20,2 meses de seguimento médio, a probabilidade acumulada da não ocorrência de morte súbita por arritmia ventricular fatal foi nitidamente inferior no grupo I (p=0,0097-log rank test).

Cardiopatía crónica endémica rural chagásica o crónica común en chagásicos y no chagásicos / Rural endemic chronic cardiopathy or common cardiopathy among chagasic and non chagasic people

Se presentan evidencias de que la cardiopatía crónica rural en adultos no es diferente entre los chagásicos crónicos que entre los no chagásicos. Se conjuntaron los resultados epidemiológicos de LabMICE (una encuesta de prevalencia (1978-1983); un estudio de caso-control (1986-1988); y un estudio clínico de cohorte y de sobrevivencia (1978-1989) con las investigaciones clínicas de Diego Dávila y colaboradores (1988-2002). Ambos grupos pertenecen a la Universidad de Los Andes. Las inferencias de ambos contestan interrogantes que plantearon anatomopatólogos venezolanos entre 1937 y 1985. También están de acuerdo con publicaciones internacionales de 1970 a 2000. Los trabajos sugieren que existe una cardiopatía crónica endémica rural que es común entre seropositivos y seronegativos a T. cruzi en el medio rural. Parece claro que el Chagas crónico no es problema de salud pública, pero sí es prevalente una cardiopatía crónica que amerita nuevas investigaciones. Se invita a grupos de investigación interesados a usar el blanco comunitario de datos para deslindar el mito y la realidad en la cardiopatía rural crónica venezolana.

Chaga's disease: pathology of chronic lesions

The morphologic features of the indeterminate and the chronic cardiac forms of Chaga's disease, and their clinical correlations, are briefly reviewed. The significance of mild focal myocarditis as the main change of the indeterminate form, the myocardial inflammation and fibrosis of the chronic cardiac form, plus the involvement of the conducting system, are particulary considered.

Enfermedad de Chagas en el grupo familiar de un caso crónico de curso fatal en un área sin triatominos del departamento de Ica Perú / Chagas disease in the familial group of a chronic case with fatal course in an area free of triatomines at Ica department, Peru

El propósito de esta comunicación es presentar dos casos de enfermedad de Chagas en el grupo familiar de un caso índice, procedente de Arequipa región sudoccidental del Perú, el cual es una área endémica. El caso índice sufrió una muerte súbita por cardiomiopatía chagásica en una localidad sin triatominos del departamento de Ica. Su hermana y su sobrino mostraron anticuerpos IgG específicos contra Trypanosoma cruzi por Inmunoensayo Enzimático (ELISA) e Inmunofluorescencia Indirecta (IFI), ambos familiares tenían antecedentes de haber vivido en el valle endémico de Vítor (Arequipa). Nuestros resultados enfatizan la importancia de la investigación epidemiológica en el grupo familiar de un caso crónico en áreas de bajo riesgo

Farmacología molecular de la enfermedad de Chagas / Molecular pharmacology of the chagas disease

La enfermedad de Chagas es una parasitosis exclusiva del continente americano. Es endémica en 21 países, con 18-20 millones de personas infectadas y 100 millones en riesgo de infección. En Venezuela la enfermedad de Chagas es una enfermedad reemergente cuya frecuencia alcanza en algunas comunidades rurales el 22 por ciento. La prevención de la transmisión de la enfermedad de Chagas es un proceso sencillo, consiste en el control y eliminación del vector mediante rociamientos sistemáticos de las viviendas en las zonas endémicas y a través de políticas habitacionales, donde se sustituya los ranchos por viviendas higiénicas consolidadas. La enfermedad de Chagas no tiene tratamiento y los pacientes infectados con T. cruzi inexorablemente evolucionan hacia la miocardiopatía chagásica crónica cuya manifestación sindromática más frecuente es la insuficiencia cardíaca congestiva y/o las arritmias cardíacas, de difícil tratamiento y cuyo desenlace más frecuente es la muerte súbita. En los últimos años importantes avances han sido realizados en la fisiopatología de las miocardiopatías no chagásicas, cuyas bases moleculares parecen semejarse a la de las bases de la miocardiopatía chagásica crónica.En el presente trabajo se presenta una revisión de los eventos moleculares que parecen estar involucrados en la génesis y desarrollo de la miocardiopatía chagásica crónica, planteándose que la miocardiopatía chagásica crónica se inicia como un desbalance en los factores humorales y neurales que afectan el miocardio, el cual es causado por mediadores de la respuesta inmune, los cuales inician y mantienen una cascada de eventos, que afectan los elementos involucrados en las señales transmembranas, como por ejemplo; receptores para neurotransmisores (colinérgicos y adrenérgicos), sistemas transductores de la señal (proteína G) y efectores de la señal (canales iónicos o segundos mensajeros). Finalmente, se sugiere que el conocimiento de estos factores permitiría planear racionalmente estrategias terapéuticas no tripanomicidas

Avaliaçäo do tratamento especifíco para Trypanosoma cruzi em crianças, na evoluçäo da fase indeterminada / Specific treatment evaluation for Trypanosoma cruzi in children, in the evolution of the indeterminate phase

Doze pacientes com idades entre 7 a 12 anos, na forma indeterminada da doença de Chagas, com sorologia e xenodiagnóstico positivos, receberam tratamento específico. Dois pacientes tomaram 7mg/kg de nifurtimox durante 60 e 90 dias e 10 usaram 5-7mg/kg de benznidazol durante 60 dias. A evoluçäo clínica foi verificada através de exame clínico, eletrocardiograma, exame radiológico contrastado do esôfago. Após o tratamento somente uma (8,3 por cento) paciente apresentou todos os exames negativos. Oito deles foram avaliados após oito anos do tratamento e 4 acompanhados durante 20 anos. Sete (58,4 por cento) permaneceram na forma indeterminada e 4 (33,3 por cento) chagásicos progrediram clinicamente para cardiopatia grau II e/ou esofagopatia, apesar do tratamento precoce. Säo necessários estudos com maior número de crianças na fase indeterminada e acompanhamento a longo prazo para se estabelecer a influência do tratamento específico na evoluçäo da doença de Chagas

Infección humana por trypanosoma cruzi en Chile: algunas estimaciones epidemiológicas y de los costos de la atención y tratamiento del paciente chagásico / Trypanosoma cruzi human infection in Chile: some estimates on epidemiology and care and treatment costs of the chagasic patient

According to the gathered information from the 1992 Chile census and an extensive epidemiological field study of Chagasïdisease in rural-periurban sections of the seven most northern regions where this malady is endemic, the following epidemiological outline arises: Total population in the country 13,348,401. Population in endemic regions 8,824,205 (urban 8,050,700 rural 773,505). Number of infected 142,000 (16,7 percent). Total number of cardiopathies 26,554 (18,7 percent). In considering the regime of fees for health attentions of the National Health Funds- including hospitalization, laboratory test and surgical interventions- in its minimal prices plus the value of medicaments, it is posible to produce some estimates onf the cost of attention and treatment, in U.S. dollars, of the chagasic patient. Average annual cost of a patient with chronic chagasic cardiopathy U.S.$ 439,29 to U.S.$ 584,25 If these values are multiplied by 26,554 give rise to a figure ranging from U.S.$ 11,644,906 to U.S.$ 15,514,474