Aplicación de un algoritmo para la detección de hipertensión arterial pulmonar en pacientes con enfermedad del tejido conectivo / Application of an Algorithm for the Detection of Pulmonary Arterial Hyertension in Patients with Connective Tissue Disease

Introducción: La hipertensión pulmonar (HP) es una complicación grave que se puede presentar en las enfermedades del tejido conectivo (ETC), múltiples causas pueden ser el origen de la misma. Por lo tanto, es imprescindible establecer un diagnóstico preciso para determinar la causa de la HP. Los algoritmos de diagnóstico precoz están dirigidos a la detección temprana de la HP en pacientes con ETC Objetivos: 1) detectar la presencia de HP en una población con diagnóstico de ETC mediante un algoritmo de detección precoz y 2) diagnosticar HAP asociada a ETC. Materiales y Métodos: Estudio descriptivo, prospectivo. Se incluyeron pacientes adultos en control y seguimiento reumatológico, con diagnóstico de ETC sintomática o esclerosis sistémica/enfermedad mixta del tejido conectivo (EMTC) sintomática como asintomática. A aquellos pacientes con alta sospecha clínico-ecocardiográfica de HP se les realizó cateterismo cardíaco derecho (CCD). Resultados: Se incluyeron 90 pacientes, 82 mujeres (91%) y 8 hombres (9%), con una edad media de 52 años. Presentaban esclerosis sistémica 54 (60%), artritis reumatoidea 18 (20%), EMTC 8 (9%), lupus eritematoso sistémico 8 (9%), Sjögren 1 (1%), polimiositis 1 (1%). La presencia de disnea fue referida en 60 pacientes (67%); un total de 12 pacientes (13%) presentaron alta presunción de HP y se les realizó un CCD, confirmándose el diagnóstico de HP en 9 (10%), siendo 7 del grupo I HAP y 2 del grupo II. Los pacientes con HP del grupo I se encontraban distribuidos según Clase funcional (CF), de la siguiente manera: uno en CF III, cinco en CF II y uno en CF I. Conclusiones: EI algoritmo utilizado permite diagnosticar HAP en pacientes con ETC en etapas termpranas.

Introduction: Pulmonary hypertension (PH) is a serious complication in connective tissue disease (CTD), although multiple causes can be the source of it. Therefore, it is essential to establish an accurate diagnosis to determine the cause of HP. Early detection algorithms are aimed to diagnose PH in patients with CTD in less advanced disease. Objectives: 1) To detect the presence of pulmonary hypertension (PH) in a population diagnosed with CTD by an early detection algorithm. 2) To diagnose Pulmonary arterial hypertension (PAH) associated to CTD. Materials and Methods: It's a descriptive, prospective study. Adult patients diagnosed with symptomatic CTD or symptomatic and asymptomatic systemic sclerosis, mixed connective tissue disease (MCTD) in the setting of rheumatologic control were included. Those patients with high clinical and echocardiographic suspicion of PH were catheterized (CCD). Results: 90 patients, 82 women (91%) were included, with a median age of 52 years. Fifty-flour (60%) corresponding to Systemic sclerosis, 18 (20%) to rheumatoid arthritis, 8 (9%) to MCTD, 8 (9%) to systemic lupus erythematosus, 1 (1%) to Sjögren and 1(1%) to polymyositis. Dyspnea was referred in 50 patients (67%); 12 patients (13%) had high presumption of HP and underwent a CCD, confirming the diagnosis of HP in 9 (10%). Sever belonged to PH Group I and 2 to group II. PH group I patients were distributed according to functional class (FC), as follows: 1 FC III, 5 FC II and 1 FC I. Conclusions: The used algorithm allows early PAH diagnosis in CTD.

Clinical characteristics and outcome of 107 adult patients with chronic Chagas disease and parasitological cure criteria.

BACKGROUND: The cure in adult patients with chronic Chagas disease and the relationship between parasitological and clinical evolution is still under debate. The aim of this study was to analyze the clinical, epidemiological and progression features of the disease in a patient population who became serologically negative either spontaneously or post-etiological treatment. METHODS: We included 107 patients over 20 years old with three different confirmed reactive anti-Trypanosoma cruzi serologic tests on admission, and a minimum of two years of follow-up. Patients were assigned to clinical groups according to Kuschnir. Change of clinical group was considered a heart disease progression criterion, and seronegative conversion of two or three as parasitological cure criterion. RESULTS: From 107 patients with parasitological cure, 82 had received treatment (77%) and 25 became spontaneously seronegative (23%). Forty-six (43%) and 61 (57%) patients had two and three negative serological tests, respectively. No differences in clinical groups, ECG, echocardiogram and heart disease progression were found in patients who became negative spontaneously or post-treatment. The clinical progression and ECG changes were observed in 5/107 (5%) and 11/107 (10%) respectively, in a mean of 10 years follow-up. CONCLUSIONS: Adults with chronic Chagas disease can cure, mostly post-etiological treatment, but also spontaneously, showing a favourable clinical outcome.

Allopurinol reduces antigen-specific and polyclonal activation of human T cells.

Allopurinol is the most popular commercially available xanthine oxidase inhibitor and it is widely used for treatment of symptomatic hyperuricaemia, or gout. Although, several anti-inflammatory actions of allopurinol have been demonstrated in vivo and in vitro, there have been few studies on the action of allopurinol on T cells. In the current study, we have assessed the effect of allopurinol on antigen-specific and mitogen-driven activation and cytokine production in human T cells. Allopurinol markedly decreased the frequency of IFN-γ and IL-2-producing T cells, either after polyclonal or antigen-specific stimulation with Herpes Simplex virus 1, Influenza (Flu) virus, tetanus toxoid and Trypanosoma cruzi-derived antigens. Allopurinol attenuated CD69 upregulation after CD3 and CD28 engagement and significantly reduced the levels of spontaneous and mitogen-induced intracellular reactive oxygen species in T cells. The diminished T cell activation and cytokine production in the presence of allopurinol support a direct action of allopurinol on human T cells, offering a potential pharmacological tool for the management of cell-mediated inflammatory diseases.

Rol del bloqueo aldosterónico en la insuficiencia cardíaca crónica / Role of aldosterone blockade in chronic heart failure / Papel do bloqueio da aldosterona na insuficiência cardíaca crônica

El bloqueo de los efectos adversos del sistema renina-angiotensina-aldosterona (SRAA) ha sido un foco importante en el desarrollo de drogas para el tratamiento de la enfermedad cardiovascular en los últimos 30 años. Los niveles plasmáticos de aldosterona disminuyen en forma transitoria luego del inicio del tratamiento con inhibidores de la enzima convertidora de angiotensina (IECA) y se ha demostrado que la aldosterona ejerceefectos adversos sobre el sistema cardiovascular en forma independiente de la angiotensina II. En dos reuniones consecutivas 50 líderes de opinión se reunieron para discutir en forma crítica la evidencia actualmente disponible. El presente documento sintetiza las conclusiones que surgieron por consenso de la mesa: "Rol del bloqueo aldosterónico en la insuficiencia cardíaca crónica". El interés clínico en el bloqueo aldosterónico en pacientes tratados con IECA o antagonistas de los receptores de angiotensina (ARA) fue estimulado por el Estudio RALES (Randomized Aldactone Evaluation Study), que demostró que el antagonista de los receptores mineralocorticoides (RMC), espironolactona, redujo el riesgo de mortalidad de toda causa así como de hospitalizaciones por insuficiencia cardíaca (IC), en pacientes con IC severa (clase funcional III-IV, NYHA) y fracción de eyección disminuida. Recientemente, el estudio EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) encontró una reducción significativa en la mortalidad y hospitalización de toda causa en los pacientes con IC, con deterioro severo de la función ventricular y síntomas leves de IC, ampliando el espectro de las indicaciones terapéuticas actuales. Concluyendo que las indicaciones actuales para los bloqueantes de la aldosterona son, por lo tanto, claras para los pacientes con síntomas de IC moderados a severos (clase funcional III-IV, NYHA), con una disminución severa de la fracción de eyección del ventrículo izquierdo, a pesar del tratamiento farmacológico óptimo. La evidencia aportada por el estudio EMPHASIS-HF, indudablemente, contribuirá a un cambio en la práctica médica en relación a estos fármacos.

Blocking the adverse effects of the rennin-angiotensin system has been a major focus of drug development for the treatment of cardiovascular disease over the last 30 years. Plasma aldosterone levels are only transiently decreased suppressed after the initiation of angiotensin-converting enzyme (ACE) inhibitors treatment and has been shown that aldosterone causes adverse effects on the cardiovascular system independent of angiotensin II. In two consecutive meetings, 50 experts critically reviewed the available evidence. The present document reflects the consensus of the subject: "Role of aldosterone blockade in chronic heart failure". Clinical interest in blocking aldosterone in patients treated with ACE inhibitors or angiotensin receptor blockers (ARBs) was stimulated by the Randomized Aldactone Evaluation Study (RALES), which demonstrated that the mineralocorticoid (MC) antagonist spironolactone reduced the risk of all-cause mortality as well as hospitalizations for heart failure (HF) in patients with severe NYHA Class III-IV HF and a reduced left ventricular ejection fraction (LVEF). Recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial showed a greater reduction of all-cause death and all-cause hospitalizations among patients with heart failure reduced ejection fraction and mild symptoms (NYHA functional class II), thus expanding the spectrum of aldosterone antagonism. Concluding that the current indications for aldosterone blockade are therefore clear for patients with moderate to severe symptoms (NYHA functional class III-IV), who have a decrease LVEF and signs and symptoms of HF despite optimal background treatment. The evidence analyzed in the EMPHASIS-HF trial undoubtedly contribute to change medical practice with regard to the use of this drugs in the treatment of HF.

O bloqueio dos efeitos adversos do sistema renina-angiotensina-aldosterona (SRAA) tem sido o foco principal no desenvolvimento de drogas para o tratamento de doença cardiovascular nos últimos 30 anos. Os níveis plasmáticos da aldosterona temporariamente diminuem depois de início do tratamento com inibidores da enzima conversora da angiotensina (IECA) e tem mostrado-se que a aldosterona ter efeitos adversos sobre o sistema cardiovascular independente da angiotensina II. Em duas reuniões consecutivas, 50 líderes de opinião se reuniram para discutir criticamente as evidências atuais. O presente documento reflete o consenso sobre o assunto: "O papel do bloqueio da aldosterona na insuficiência cardíaca crônica". Interesse clínico no bloqueio da aldosterona em pacientes tratados com IECA ou antagonistas do receptor de angiotensina (ARA) foi estimulado pelo estudo RALES (Randomized Aldactone Evaluation Study), que demonstrou que o antagonista receptor mineralocorticóide (RMC), espironolactona, reduziu o risco de mortalidade por qualquer causa e hospitalizações por insuficiência cardíaca (IC) em pacientes com IC severa (classe funcional III-IV, NYHA) e fração de ejeção diminuída. Recentemente, o estudo EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) demonstrou uma redução significativa na mortalidade e hospitalização por todas as causas em pacientes com IC, com agravamento da função ventricular e com sintomas leves de IC, ampliando o espectro das atuais indicações terapêuticas. Concluindo que as indicações atuais para os bloqueadores de aldosterona são claras para os pacientes com sintomas moderados a severos (classe funcional IIIIV, NYHA) com uma diminuição acentuada da fração de ejeção, apesar do tratamento medicamentoso otimizado. A evidência fornecida pelo estudo EMPHASIS-HF, sem dúvida, contribuirá para uma mudança na prática médica em relação a estes fármacos.

Rol del bloqueo aldosterónico en la insuficiencia cardíaca crónica / Role of aldosterone blockade in chronic heart failure / Papel do bloqueio da aldosterona na insuficiÛncia cardíaca cr¶nica

El bloqueo de los efectos adversos del sistema renina-angiotensina-aldosterona (SRAA) ha sido un foco importante en el desarrollo de drogas para el tratamiento de la enfermedad cardiovascular en los últimos 30 años. Los niveles plasmáticos de aldosterona disminuyen en forma transitoria luego del inicio del tratamiento con inhibidores de la enzima convertidora de angiotensina (IECA) y se ha demostrado que la aldosterona ejerceefectos adversos sobre el sistema cardiovascular en forma independiente de la angiotensina II. En dos reuniones consecutivas 50 líderes de opinión se reunieron para discutir en forma crítica la evidencia actualmente disponible. El presente documento sintetiza las conclusiones que surgieron por consenso de la mesa: "Rol del bloqueo aldosterónico en la insuficiencia cardíaca crónica". El interés clínico en el bloqueo aldosterónico en pacientes tratados con IECA o antagonistas de los receptores de angiotensina (ARA) fue estimulado por el Estudio RALES (Randomized Aldactone Evaluation Study), que demostró que el antagonista de los receptores mineralocorticoides (RMC), espironolactona, redujo el riesgo de mortalidad de toda causa así como de hospitalizaciones por insuficiencia cardíaca (IC), en pacientes con IC severa (clase funcional III-IV, NYHA) y fracción de eyección disminuida. Recientemente, el estudio EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) encontró una reducción significativa en la mortalidad y hospitalización de toda causa en los pacientes con IC, con deterioro severo de la función ventricular y síntomas leves de IC, ampliando el espectro de las indicaciones terapéuticas actuales. Concluyendo que las indicaciones actuales para los bloqueantes de la aldosterona son, por lo tanto, claras para los pacientes con síntomas de IC moderados a severos (clase funcional III-IV, NYHA), con una disminución severa de la fracción de eyección del ventrículo izquierdo, a pesar del tratamiento farmacológico óptimo. La evidencia aportada por el estudio EMPHASIS-HF, indudablemente, contribuirá a un cambio en la práctica médica en relación a estos fármacos.(AU)

Blocking the adverse effects of the rennin-angiotensin system has been a major focus of drug development for the treatment of cardiovascular disease over the last 30 years. Plasma aldosterone levels are only transiently decreased suppressed after the initiation of angiotensin-converting enzyme (ACE) inhibitors treatment and has been shown that aldosterone causes adverse effects on the cardiovascular system independent of angiotensin II. In two consecutive meetings, 50 experts critically reviewed the available evidence. The present document reflects the consensus of the subject: "Role of aldosterone blockade in chronic heart failure". Clinical interest in blocking aldosterone in patients treated with ACE inhibitors or angiotensin receptor blockers (ARBs) was stimulated by the Randomized Aldactone Evaluation Study (RALES), which demonstrated that the mineralocorticoid (MC) antagonist spironolactone reduced the risk of all-cause mortality as well as hospitalizations for heart failure (HF) in patients with severe NYHA Class III-IV HF and a reduced left ventricular ejection fraction (LVEF). Recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial showed a greater reduction of all-cause death and all-cause hospitalizations among patients with heart failure reduced ejection fraction and mild symptoms (NYHA functional class II), thus expanding the spectrum of aldosterone antagonism. Concluding that the current indications for aldosterone blockade are therefore clear for patients with moderate to severe symptoms (NYHA functional class III-IV), who have a decrease LVEF and signs and symptoms of HF despite optimal background treatment. The evidence analyzed in the EMPHASIS-HF trial undoubtedly contribute to change medical practice with regard to the use of this drugs in the treatment of HF.(AU)

O bloqueio dos efeitos adversos do sistema renina-angiotensina-aldosterona (SRAA) tem sido o foco principal no desenvolvimento de drogas para o tratamento de doenþa cardiovascular nos últimos 30 anos. Os níveis plasmáticos da aldosterona temporariamente diminuem depois de início do tratamento com inibidores da enzima conversora da angiotensina (IECA) e tem mostrado-se que a aldosterona ter efeitos adversos sobre o sistema cardiovascular independente da angiotensina II. Em duas reuni§es consecutivas, 50 líderes de opiniÒo se reuniram para discutir criticamente as evidÛncias atuais. O presente documento reflete o consenso sobre o assunto: "O papel do bloqueio da aldosterona na insuficiÛncia cardíaca cr¶nica". Interesse clínico no bloqueio da aldosterona em pacientes tratados com IECA ou antagonistas do receptor de angiotensina (ARA) foi estimulado pelo estudo RALES (Randomized Aldactone Evaluation Study), que demonstrou que o antagonista receptor mineralocorticóide (RMC), espironolactona, reduziu o risco de mortalidade por qualquer causa e hospitalizaþ§es por insuficiÛncia cardíaca (IC) em pacientes com IC severa (classe funcional III-IV, NYHA) e fraþÒo de ejeþÒo diminuída. Recentemente, o estudo EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) demonstrou uma reduþÒo significativa na mortalidade e hospitalizaþÒo por todas as causas em pacientes com IC, com agravamento da funþÒo ventricular e com sintomas leves de IC, ampliando o espectro das atuais indicaþ§es terapÛuticas. Concluindo que as indicaþ§es atuais para os bloqueadores de aldosterona sÒo claras para os pacientes com sintomas moderados a severos (classe funcional IIIIV, NYHA) com uma diminuiþÒo acentuada da fraþÒo de ejeþÒo, apesar do tratamento medicamentoso otimizado. A evidÛncia fornecida pelo estudo EMPHASIS-HF, sem dúvida, contribuirá para uma mudanþa na prática médica em relaþÒo a estes fármacos.(AU)

Impact of aetiological treatment on conventional and multiplex serology in chronic Chagas disease.

BACKGROUND: The main criterion for treatment effectiveness in Chagas Disease has been the seronegative conversion, achieved many years post-treatment. One of the main limitations in evaluating treatment for chronic Chagas disease is the lack of reliable tests to ensure parasite clearance and to examine the effects of treatment. However, declines in conventional serological titers and a new multiplex assay can be useful tools to monitor early the treatment impact. METHODOLOGY/PRINCIPAL FINDINGS: Changes in antibody levels, including seronegative conversion as well as declines in titers, were serially measured in 53 benznidazole-treated and 89 untreated chronic patients in Buenos Aires, Argentina with a median follow-up of 36 months. Decrease of titers (34/53 [64%] treated vs. 19/89 [21%] untreated, p<0.001) and seronegative conversion (21/53, [40%] treated vs. 6/89, [7%] untreated, p<0.001) in at least one conventional serological test were significantly higher in the benznidazole-treated group compare with the untreated group. When not only complete seronegative conversion but also seronegative conversion on 2 tests and the decreases of titers on 2 or 3 tests were considered, the impact of treatment on conventional serology increased from 21% (11/53 subjects) to 45% (24/53 subjects). A strong concordance was found between the combination of conventional serologic tests and multiplex assay (kappa index 0.60) to detect a decrease in antibody levels pos-treatment. CONCLUSIONS/SIGNIFICANCE: Treatment with benznidazole in subjects with chronic Chagas disease has a major impact on the serology specific for T. cruzi infection in a shorter follow-up period than previously considered, reflected either by a complete or partial seronegative conversion or by a significant decrease in the levels of T. cruzi antibodies, consistent with a possible elimination or reduction of parasite load.

The impact of socioeconomic conditions on chronic Chagas disease progression.

INTRODUCTION AND OBJECTIVES: The extent to which a patient's socioeconomic conditions determine the persistence or control of chronic Chagas disease has not been previously investigated. The aim of this study was to evaluate the effect of socioeconomic conditions on clinical and serologic measures of disease progression. METHODS: Data on the following socioeconomic variables were obtained by questioning as part of medical history taking at admission: birth in a rural area, time of residence in endemic and urban areas (in years), overcrowding index (i.e. number of inhabitants/number of bedrooms), absence of toilet facilities, years of education, employed or unemployed, and health insurance coverage (i.e. private contributory medical insurance cover). The study endpoints for the Cox regression analysis were: consistently negative results on serologic tests and on tests for markers of cardiomyopathy progression by the end of the study. RESULTS: The study included 801 Argentine patients (mean age 42 years) who were followed up for a mean of 10 years between 1990 and 2005. After adjustment for age and antiparasitic treatment, negative seroconversion was associated with a short time of residence in an endemic area (hazard ratio [HR]=0.97; 95% confidence interval [CI], 0.96-0.99; P=.004), a low overcrowding index (HR=0.82; 95% CI, 0.70-0.97; P=.022) and medical insurance cover (HR=1.46; 95% CI, 1.01-2.09; P=.04). After adjustment for age, sex, ECG abnormalities and antiparasitic treatment, a low rate of cardiomyopathy progression was associated with more years of education (HR=0.88; 95% CI, 0.80-0.97; P=.01) and higher medical insurance cover (HR=0.49; 95% CI, 0.30-0.81; P=.005). CONCLUSIONS: Socioeconomic conditions had a significant effect on chronic Chagas disease progression which was independent of antiparasitic treatment and clinic characteristics.

El impacto de las condiciones socioeconómicas en la evolución de la enfermedad de Chagas crónica / The impact of socioeconomic conditions on chronic Chagas disease progression

Introducción y objetivos. Las condiciones socioeconómicas del huésped no han sido evaluadas como determinantes de la persistencia o el control de la enfermedad de Chagas crónica. El objetivo fue valorar el impacto de las condiciones socioeconómicas sobre la evolución clínica y serológica. Métodos. Las variables socioeconómicas en estudio fueron obtenidas por interrogatorio como parte de la historia clínica de ingreso: nacimiento en área rural, tiempo de residencia en área endémica y urbana (años), índice de hacinamiento (número de habitantes/número de dormitorios), ausencia de instalaciones sanitarias, años de educación, ocupación/desocupación y cobertura social (planes de asistencia médica por aportación privada). La negativización de las pruebas serológicas y los indicadores de progresión de la cardiopatía al concluir el estudio fueron los puntos finales de evaluación para el análisis de regresión de Cox. Resultados. Se incluyó a 801 pacientes, de 42 años de edad y 10 años de seguimiento promedio, en Argentina, entre los años 1990 y 2005. Un aumento de la seroconversión negativa, ajustada para edad y tratamiento etiológico, se asoció con un menor tiempo de residencia en área endémica (hazard ratio [HR] = 0,97 [0,96-0,99]; p = 0,004), menor índice de hacinamiento (HR = 0,82 [0,70-0,97]; p = 0,022) y mayor cobertura social (HR = 1,46 [1,01-2,09]; p = 0,04). Una disminución de la progresión de la cardiopatía, ajustada para edad, sexo, electrocardiograma anormal y tratamiento etiológico, se observó en pacientes con más años de educación (HR = 0,88 [0,80-0,97]; p = 0,01) y con cobertura social (HR = 0,49 [0,30-0,81]; p = 0,005). Conclusiones. Las condiciones socioeconómicas mostraron un significativo impacto sobre la evolución de la enfermedad de Chagas crónica independientemente del tratamiento antiparasitario y las características clínicas (AU)

Introduction and objectives. The extent to which a patient’s socioeconomic conditions determine the persistence or control of chronic Chagas disease has not been previously investigated. The aim of this study was to evaluate the effect of socioeconomic conditions on clinical and serologic measures of disease progression. Methods. Data on the following socioeconomic variables were obtained by questioning as part of medical history taking at admission: birth in a rural area, time of residence in endemic and urban areas (in years), overcrowding index (ie, number of inhabitants/number of bedrooms), absence of toilet facilities, years of education, employed or unemployed, and health insurance coverage (ie, private contributory medical insurance cover). The study endpoints for the Cox regression analysis were consistently negative results on serologic tests and on tests for markers of cardiomyopathy progression by the end of the study. Results. The study included 801 Argentine patients (mean age, 42 years) who were followed up for a mean of 10 years between 1990 and 2005. After adjustment for age and antiparasitic treatment, negative seroconversion was associated with a short time of residence in an endemic area (hazard ratio [HR] = 0.97; 95% confidence interval [CI], 0.96-0.99; P=.004), a low overcrowding index (HR=0.82; 95% CI, 0.70-0.97; P=.022) and medical insurance cover (HR=1.46; 95% CI, 1.01-2.09; P=.04). After adjustment for age, sex, ECG abnormalities, and antiparasitic treatment, a low rate of cardiomyopathy progression was associated with more years of education (HR=0.88; 95% CI, 0.80-0.97;P=.01) and higher medical insurance cover (HR=0.49; 95% CI, 0.30-0.81; P=.005). Conclusions. Socioeconomic conditions had a significant effect on chronic Chagas disease progression which was independent of antiparasitic treatment and clinic characteristics (AU)

Mejoría clínica y serológica de pacientes con enfermedad de Chagas crónica tratados con benznidazol / Improvement of clinic and serological long-term evolution of chronic Chagas disease patients treated with benznidazole

Objetivos: Comparar la evolución alejada de pacientes crónicos tratados con benznidazol y sin tratamiento. Métodos: Se incluyeron 1835 pacientes con enfermedad de Chagas crónica y más de 1 año de seguimiento. El punto final principal de evaluación fue la progresión de la miocardiopatía y los puntos finales secundarios incluyeron los cambios electrocardiográficos y la negativización serológica. Los resultados del tratamiento se evaluaron en un modelo multivariado (Cox) ajustados para la edad, sexo, síntomas y ECG. Los pacientes tratados recibieron 5 mg/kg de peso/día de benznidazol oral, durante 30 días (760 pacientes) o continuaron sin tratamiento (1075 pacientes). Resultados: La edad, los síntomas y el ECG anormal fueron predictores independientes de progresión de la miocardiopatía. El tratamiento con benznidazol redujo la progresión de la cardiopatía (HR 0.63; IC 95%: 0.47-0.95; p = 0.02), la mortalidad (HR 0.54; IC 95%: 0.30-0.97; p = 0.04) y los cambios del ECG (HR 0.59; IC 95%: 0.44-0.79; p < 0.001), mientras que aumentó la frecuencia de negativización completa de la serología (HR 1.78; IC 95%: 1.16-2.73; p = 0.008). Conclusiones: El tratamiento con benznidazol mostró un beneficio clínico y serológico sobre la evolución de la enfermedad de Chagas crónica.

Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities.

Chagas disease is caused by a parasite, Trypanosoma cruzi, transmitted primarily by a triatomine insect and affects approximately 8 million people in Latin American countries. The principal aim of the management of the disease is to avoid the development of cardiomyopathy and transmission by blood transfusion, congenital and organ transplants. Currently, benznidazole is the only etiological treatment commercially available for the disease until new and better drugs can be developed and tested. Benznidazole has been used even though it does not have all the conditions of an ideal drug. The efficacy and tolerance of benznidazole is inversely related to the age of the patient, while its side effects are more frequent in elderly patients. The side effects are systematically evaluated only in controlled studies designed for that purpose. However, the true clinical impact of the side effects could be different, considering that the treatment is for a short duration (between 30 and 60 days) and only carried out once. In this article, we discuss the benefits and risks of the treatment with benznidazole from a clinical point of view to be considered for the management of the treatment of chronic adult Chagas disease patients in the current medical practice.

Evaluación inmunológica del tratamiento con benznidazol en la enfermedad de Chagas crónica / Immunological Assessment of Benznidazol Therapy in Chronic Chagas Disease

Para determinar el efecto del tratamiento con benznidazol sobre las células T de memoria específica para Trypanosoma cruzi, se seleccionaron 47 pacientes con tres reacciones serológicas positivas para T. cruzi, sin cardiopatía y edades comprendidas entre los 30 y los 50 años. El tratamiento se realizó con benznidazol en dosis de 5 mg/kg/d por 30 días. Se efectuó una evaluación serológica, inmunológica y clínica pretratamiento (tiempo 0) y a los 2, 6 y 12 meses postratamiento. Posteriormente, los controles se hicieron anualmente. La respuesta de linfocitos T frente a un lisado de amastigotas de T. cruzi se evaluó por la técnica de ELISPOT para IFN-ã. La frecuencia de linfocitos T de memoria productores de IFN-ã específicos para T. cruzi disminuyó significativamente en el grupo tratado (n = 33) versus el no tratado (n = 14) 12 meses después del seguimiento. Once de 25 (44%) pacientes que recibieron benznidazol negativizaron la respuesta para IFN-ã. Cuatro de los 11 (36%) pacientes con ELISPOT (+) que negativizaron la respuesta por ELISPOT para IFN-ã también negativizaron la serología convencional a los 2 años postratamiento. Durante el seguimiento no se observaron alteraciones clínicas. Estos hallazgos muestran que el benznidazol es capaz de modular la respuesta celular T de memoria específica para T. cruzi. La medición de la frecuencia de linfocitos T de memoria productores de IFN-ã podría constituir un ensayo más sensible y precoz para determinar el impacto/eficacia del tratamiento específico contra este parásito.

To determine the effect of benznidazol therapy on memory T cells specific for Trypanosoma cruzi, 47 patients between 30 and 50 years old and three positive serological tests for T. cruzi without cardiopathy were selected. Benznidazol was administered in a dose of 5 mg/kg/d during 30 days. Serological, immunological and clinical assessment was performed at basal (time 0) and at 2, 6 and 12 months following treatment, and once a year thereafter. IFN-ã ELISPOT assay was used to evaluate T cell responses against a T. cruzi lysate obtained from amastigotes. The frequency of IFN-ã - producing memory T lymphocytes specific for T. cruzi was significantly lower in the treatment group (n=33) compared to the control group (n=14) 12 months after the therapy. IFN- ã response became negative in 11 patients in the treatment group (44%). Among these 11 patients, conventional serology also became negative in 4 patients (36%) after 2 years of treatment. No clinical manifestations occurred during follow-up. These findings show that benznidazol is capable of modulating T cell responses specific for T. cruzi. Measuring the frequency of memory T lymphocytes producing IFN-ã might become a more sensitive test to determine earlier the impact and/or efficacy of the specific treatment against this parasite.

[Predictors of heart failure in chronic chagasic cardiomyopathy with asymptomatic left ventricular dysfunction]. / Predictores de insuficiencia cardiaca en la miocardiopatía chagásica crónica con disfunción asintomática del ventrículo izquierdo.

INTRODUCTION AND OBJECTIVES: The development of asymptomatic left ventricular dysfunction signifies a worsening of chronic chagasic cardiomyopathy. Our objective was to identify factors that predict the development of heart failure and all-cause mortality. METHODS: The study included 95 patients with an echocardiographic diagnosis of asymptomatic left ventricular dysfunction. The patients' clinical, electrocardiographic and echocardiographic characteristics were recorded. Factors associated with the development of heart failure were evaluated by Cox regression modeling. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Receiver operating characteristic (ROC) curves were used to evaluate the sensitivity and specificity of continuous variables identified as significant in the regression analysis. RESULTS: Patients (mean age, 55 [11] years) were followed up for a median of 63 months (interquartile range, 32-110 months). Univariate analysis showed that there were significant differences in mild and severe systolic dysfunction, age on admission, and E-point-to-septal separation, while the only significant predictors of heart failure found on Cox regression analysis were severe systolic dysfunction (HR=3.53; 95% CI, 1.21-10.30; P=.021) and E-point-to-septal separation (HR=1.12; 95% CI, 1.02-1.23; P=.014). The mortality rate was 3% (3/95) in patients who continued to have asymptomatic left ventricular dysfunction and 37% (10/27) in those who developed heart failure. CONCLUSIONS: The E-point-to-septal separation and the presence of severe systolic dysfunction can serve as predictors of heart failure in patients with chronic chagasic cardiomyopathy and asymptomatic left ventricular dysfunction.

Predictores de insuficiencia cardiaca en la miocardiopatía chagásica crónica con disfunción asintomática del ventrículo izquierdo / Predictors of heart failure in chronic chagasic cardiomyopathy with asymptomatic left ventricular dysfunction

Introducción y objetivos. La disfunción ventricular izquierda asintomática representa un estadio de mala evolución en la miocardiopatía chagásica crónica. Nuestro objetivo fue establecer los posibles predictores de progresión hacia la insuficiencia cardiaca y mortalidad total. Métodos. Se incluyó a 95 pacientes con diagnóstico ecocardiográfico de disfunción ventricular izquierda asintomática. Las variables estudiadas fueron clínicas, electrocardiográficas y ecocardiográficas. Para evaluar la progresión hacia la insuficiencia cardiaca se utilizó un modelo de regresión de Cox. Se calcularon las hazard ratio (HR) y sus intervalos de confianza del 95%. La curva receiver operating characteristic (ROC) se utilizó para valorar la sensibilidad y la especificidad de las variables continuas con significación en la regresión. Resultados. El tiempo de seguimiento presentó una mediana de 63 meses y un rango intercuartílico de 32-110 meses, con una edad promedio de 55 ± 11 años. El deterioro leve y severo de la función sistólica, la edad al ingreso y la distancia E-septum mostraron diferencias significativas en el análisis univariable, mientras que la disfunción sistólica severa (p = 0,021; HR = 3,53 [1,21-10,3]) y la distancia E-septum (p = 0,014; HR = 1,12 [1,02-1,23]) fueron las únicas variables predictoras de insuficiencia cardiaca en el análisis de regresión de Cox. La mortalidad fue del 3% (3/95) de los pacientes que permanecieron con disfunción ventricular izquierda asintomática y el 37% (10/27) de los pacientes que evolucionaron hacia la insuficiencia cardiaca. Conclusiones. La distancia E-septum y el deterioro severo de la función sistólica pueden ser predictores de insuficiencia cardiaca en pacientes con miocardiopatía chagásica crónica y disfunción ventricular izquierda asintomática (AU)

Introduction and objectives. The development of asymptomatic left ventricular dysfunction signifies a worsening of chronic chagasic cardiomyopathy. Our objective was to identify factors that predict the development of heart failure and all-cause mortality. Methods. The study included 95 patients with an echocardiographic diagnosis of asymptomatic left ventricular dysfunction. The patients' clinical, electrocardiographic and echocardiographic characteristics were recorded. Factors associated with the development of heart failure were evaluated by Cox regression modeling. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Receiver operating characteristic (ROC) curves were used to evaluate the sensitivity and specificity of continuous variables identified as significant in the regression analysis. Results. Patients (mean age, 55 [11] years) were followed up for a median of 63 months (interquartile range, 32­110 months). Univariate analysis showed that there were significant differences in mild and severe systolic dysfunction, age on admission, and E-point-to-septal separation, while the only significant predictors of heart failure found on Cox regression analysis were severe systolic dysfunction (HR=3.53; 95% CI, 1.21­10.30; P=.021) and E-point-to-septal separation (HR=1.12; 95% CI, 1.02­1.23; P=.014). The mortality rate was 3% (3/95) in patients who continued to have asymptomatic left ventricular dysfunction and 37% (10/27) in those who developed heart failure. Conclusions. The E-point-to-septal separation and the presence of severe systolic dysfunction can serve as predictors of heart failure in patients with chronic chagasic cardiomyopathy and asymptomatic left ventricular dysfunction (AU)

Readmisión hospitalaria en un centro ambulatorio quirúrgico / Readmission to an ambulatory surgery center

Introducción: La readmisión hospitalaria de pacientes ambulatorios se ha convertido en una importante medición de la calidad de un centro ambulatorio. Estudiando sus causas y los factores que la predisponen, evaluamos el objetivo principal del centro, los equipos profesionales y la organización operativa. La incidencia de readmisión en cirugía ambulatoria varía del 0,11 por ciento al 2,4 por ciento. Objetivo: Determinar la incidencia, las causas y los factores predictivos de readmisión hospitalaria en cirugía ambulatoria. Material y métodos: Durante 9 años, se analizaron en forma retrospectiva y consecutiva todos los pacientes sometidos a cirugía en un centro de atención ambulatoria. Resultados: Se incluyeron 2495 pacientes ambulatorios. El índice de readmisión fue del 0,76 por ciento (19/2495 pacientes). Las causas de readmisión fueron divididas en cuatro categorías: quirúrgicas 42,10 por ciento, anestésicas 36,85 por ciento, falta de tiempo de recuperación 15,80 por ciento y sociales 5,25 por ciento. En el análisis multivariado, los factores predictivos independientes de readmisión hospitalaria, con significancia estadística fueron: tiempo quirúrgico, cirugía general y anestesia general [OR e IC95 por ciento 1,02, (1,02-1,03); 3,52, (1,24-9,97); y lO, (1,21-82,49), respectivamente]. Conclusión: La incidencia de readmisiones es baja y aceptable para una unidad quirúrgica ambulatoria. Las complicaciones que exigen el rápido traslado en ambulancia desde el quirófano hasta una unidad de cuidados intensivos de otra institución tienen una alta probabilidad de originar demandas legales, sea por su gravedad y también por la falta de contención de los familiares del paciente, quienes cuestionan abiertamente la capacidad operativa del centro ambulatorio en estos tipos de complicaciones.

Readmisión hospitalaria en un centro ambulatorio quirúrgico / Readmission to an ambulatory surgery center

Introducción: La readmisión hospitalaria de pacientes ambulatorios se ha convertido en una importante medición de la calidad de un centro ambulatorio. Estudiando sus causas y los factores que la predisponen, evaluamos el objetivo principal del centro, los equipos profesionales y la organización operativa. La incidencia de readmisión en cirugía ambulatoria varía del 0,11 por ciento al 2,4 por ciento. Objetivo: Determinar la incidencia, las causas y los factores predictivos de readmisión hospitalaria en cirugía ambulatoria. Material y métodos: Durante 9 años, se analizaron en forma retrospectiva y consecutiva todos los pacientes sometidos a cirugía en un centro de atención ambulatoria. Resultados: Se incluyeron 2495 pacientes ambulatorios. El índice de readmisión fue del 0,76 por ciento (19/2495 pacientes). Las causas de readmisión fueron divididas en cuatro categorías: quirúrgicas 42,10 por ciento, anestésicas 36,85 por ciento, falta de tiempo de recuperación 15,80 por ciento y sociales 5,25 por ciento. En el análisis multivariado, los factores predictivos independientes de readmisión hospitalaria, con significancia estadística fueron: tiempo quirúrgico, cirugía general y anestesia general [OR e IC95 por ciento 1,02, (1,02-1,03); 3,52, (1,24-9,97); y lO, (1,21-82,49), respectivamente]. Conclusión: La incidencia de readmisiones es baja y aceptable para una unidad quirúrgica ambulatoria. Las complicaciones que exigen el rápido traslado en ambulancia desde el quirófano hasta una unidad de cuidados intensivos de otra institución tienen una alta probabilidad de originar demandas legales, sea por su gravedad y también por la falta de contención de los familiares del paciente, quienes cuestionan abiertamente la capacidad operativa del centro ambulatorio en estos tipos de complicaciones. (AU)

Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial.

BACKGROUND: Benznidazole is effective for treating acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages remains uncertain. OBJECTIVE: To compare long-term outcomes of patients with nonacute Chagas disease treated with benznidazole versus outcomes of those who did not receive treatment. DESIGN: Clinical trial with unblinded, nonrandom assignment of patients to intervention or control groups. SETTING: Chagas disease center in Buenos Aires, Argentina. PATIENTS: 566 patients 30 to 50 years of age with 3 positive results on serologic tests and without heart failure. MEASUREMENTS: The primary outcome was disease progression, defined as a change to a more advanced Kuschnir group or death. Secondary outcomes included new abnormalities on electrocardiography and serologic reactivity. INTERVENTION: Oral benznidazole, 5 mg/kg of body weight per day for 30 days (283 patients), or no treatment (283 patients). RESULTS: Fewer treated patients had progression of disease (12 of 283 [4%] vs. 40 of 283 [14%]; adjusted hazard ratio, 0.24 [95% CI, 0.10 to 0.59]; P = 0.002) or developed abnormalities on electrocardiography (15 of 283 [5%] vs. 45 of 283 [16%]; adjusted hazard ratio, 0.27 [CI, 0.13 to 0.57]; P = 0.001) compared with untreated patients. Left ventricular ejection fraction (hazard ratio, 0.97 [CI, 0.94 to 0.99]; P < 0.002) and left ventricular diastolic diameter (hazard ratio, 2.45 [CI, 1.53 to 3.95]; P < 0.001) were also associated with disease progression. Conversion to negative results on serologic testing was more frequent in treated patients than in untreated patients (32 of 218 [15%] vs. 12 of 212 [6%]; adjusted hazard ratio, 2.1 [CI, 1.06 to 4.06]; P = 0.034). LIMITATIONS: Nonrandom, unblinded treatment assignment was used, and follow-up data were missing for 20% of patients. Loss to follow-up was more common among patients who were less sick. Two uncontrolled interim analyses were conducted. CONCLUSIONS: Compared with no treatment, benznidazole treatment was associated with reduced progression of Chagas disease and increased negative seroconversion for patients presenting with nonacute disease and no heart failure. These observations indicate that a randomized, controlled trial should now be conducted.

[Clinical predictors of chronic chagasic myocarditis progression]. / Indicadores clínicos de progresión de la miocarditis chagásica crónica.

INTRODUCTION AND OBJECTIVES: Previous prognostic studies of Chagas' disease have focused on mortality associated with end-stage cardiopathy (i.e., heart failure). Our aim was to identify indicators of progression in early-stage Chagas' heart disease. MATERIAL AND METHOD: The study included 856 patients with 3 positive anti-Trypanosoma cruzi test results. Those with heart failure were excluded. Patients were divided into 3 clinical groups: those without heart disease (Group I); those with heart disease but without left ventricular enlargement (Group II); and those with left ventricular enlargement but without heart failure (Group III). The endpoint was progression to a more severe clinical stage or death due to cardiovascular disease. A Cox regression model was used to derive a clinical risk score from clinical, electrocardiographic and echocardiographic variables. RESULTS: At study entry, the patients' mean age was 43.7 years. They were followed up for a mean of 8 years. The following were predictors of heart disease progression: age at entry (HR=1.05; 95% CI, 1.02-1.07; P<.001), left ventricular systolic diameter (HR=1.06; 95% CI, 1.04-1.09; P<.001), intraventricular conduction abnormalities (HR=1.85; 95% CI, 1.02-3.36; P=.04), and sustained ventricular tachycardia (HR=3.97; 95% CI, 1.65-9.58; P=.002). Treatment with benznidazole reduced the risk of progression (HR=0.40; 95% CI, 0.23-0.72; P=.002). The devised clinical risk score was effective in stratifying the likelihood of cardiopathy progression. CONCLUSIONS: Specific clinical indicators and a derived clinical risk score can be used to predict the progression of chronic chagasic myocarditis in patients without heart failure.

Indicadores clínicos de progresión de la miocarditis chagásica crónica / Clinical predictors of chronic chagasic myocarditis progression

Introducción y objetivos. Los estudios de pronóstico efectuados sobre la mortalidad de la cardiopatía se han centrado en la etapa final de la enfermedad (insuficiencia cardíaca). Nuestro objetivo fue establecer los indicadores de progresión de la enfermedad de Chagas en estadios tempranos. Material y método. Se incluyó a 856 pacientes con 3 pruebas reactivas anti-Trypanosoma cruzi y se excluyó a los pacientes con insuficiencia cardíaca. Se utilizó la siguiente estratificación clínica: grupo I, sin cardiopatía; grupo II, con cardiopatía y sin dilatación del ventrículo izquierdo (VI); grupo III, con dilatación del VI, sin insuficiencia cardíaca. El punto final de evaluación fue la progresión hacia un grupo clínico de mayor severidad o la muerte cardiovascular. Se incluyeron las variables clínicas, electrocardiográficas y ecocardiográficas en un análisis multivariado (Cox) y se construyó una puntuación de riesgo. Resultados. La edad promedio fue de 43,7 años y el seguimiento de 8 años. La edad (hazard ratio [HR] = 1,05; intervalo de confianza [IC] del 95%, 1,02-1,07; p < 0,001), el diámetro sistólico del VI (HR = 1,06; IC del 95%, 1,04-1,09; p < 0,001), los trastornos de conducción intraventricular (HR = 1,85; IC del 95%, 1,02-3,36; p = 0,04) y la taquicardia ventricular sostenida (HR = 3,97; IC del 95%, 1,65-9,58; p = 0,002) fueron predictores de progresión de la cardiopatía. El tratamiento con benznidazol redujo el riesgo de progresión (HR = 0,40; IC del 95%, 0,23-0,72; p = 0,002). La puntuación de riesgo construido estratificó adecuadamente la probabilidad de progresión de la cardiopatía. Conclusiones. Los indicadores clínicos y la puntuación propuesta pueden establecer el pronóstico de progresión de la miocarditis chagásica crónica sin insuficiencia cardíaca (AU)

Introduction and objectives. Previous prognostic studies of Chagas' disease have focused on mortality associated with end-stage cardiopathy (i.e., heart failure). Our aim was to identify indicators of progression in early-stage Chagas' heart disease. Matherial and method. The study included 856 patients with 3 positive anti-Trypanosoma cruzi test results. Those with heart failure were excluded. Patients were divided into 3 clinical groups: those without heart disease (Group I); those with heart disease but without left ventricular enlargement (Group II); and those with left ventricular enlargement but without heart failure (Group III). The endpoint was progression to a more severe clinical stage or death due to cardiovascular disease. A Cox regression model was used to derive a clinical risk score from clinical, electrocardiographic and echocardiographic variables. Results. At study entry, the patients' mean age was 43.7 years. They were followed up for a mean of 8 years. The following were predictors of heart disease progression: age at entry (HR=1.05; 95% CI, 1.02-1.07; P<.001), left ventricular systolic diameter (HR=1.06; 95% CI, 1.04-1.09; P<.001), intraventricular conduction abnormalities (HR=1.85; 95% CI, 1.02-3.36; P=.04), and sustained ventricular tachycardia (HR=3.97; 95% CI, 1.65-9.58; P=.002). Treatment with benznidazole reduced the risk of progression (HR=0.40; 95% CI, 0.23-0.72; P=.002). The devised clinical risk score was effective in stratifying the likelihood of cardiopathy progression. Conclusions. Specific clinical indicators and a derived clinical risk score can be used to predict the progression of chronic chagasic myocarditis in patients without heart failure (AU)