Indeterminate form of Chagas disease: historical, conceptual, clinical, and prognostic aspects

Abstract Chagas disease (CD) remains a serious endemic disease in Latin America and a major public health problem. Because of globalization, the disease has spread to non-endemic areas in the northern hemisphere. In the chronic phase of the disease, most patients present with the indeterminate form (IF), characterized by positive serology for Trypanosoma cruzi, absence of clinical findings, and normal findings in electrocardiogram (ECG). IF was not recognized as a clinical entity until decades after the discovery of the disease, and only in the 1940-50s, it was categorized as a form of CD, and its conceptual definition was ratified in the 1980s. Children, adolescents, and young adults with the IF benefit from etiological treatment and tend to have less progression to heart disease in the long term than the untreated ones. IF patients have an essentially benign clinical condition, and their prognosis can be compared to that of healthy individuals with normal ECG findings. Currently, because of aging, patients with the IF have comorbidities that require attention in health services.

Use of tissue doppler imaging for the early detection of myocardial dysfunction in patients with the indeterminate form of Chagas disease

Abstract INTRODUCTION: Chagas disease is one of the most common diseases in Latin America and heart involvement is the main cause of death. This study aimed to determine differences in tissue Doppler imaging (TDI) parameters in the assessment left and right ventricular function in patients with the indeterminate form of Chagas disease compared to those in healthy controls. METHODS: We compared 194 patients with the indeterminate form of Chagas disease to 72 age-matched healthy individuals. We considered p-values <0.05 to be statistically significant. RESULTS: TDI analysis of the right ventricular (RV) showed lengthened isovolumic relaxation time (IRT) and higher RV index of myocardial performance (RIMP) and left ventricle (LV) index of myocardial performance (LIMP) in the Chagas group than in the control group, indicating RV and LV systolic and diastolic myocardial damage. TDI analysis of the myocardial velocities of the interventricular septum and the lateral wall of the LV also showed a systolic and diastolic myocardial damage. CONCLUSIONS: The study results demonstrated early LV systolic and diastolic myocardial damage in the RV and LV in patients with the indeterminate form of Chagas disease by TDI. These early findings of RV and LV dysfunction may help identify patients who will progress to heart failure during the disease course. TDI should be included in initial patient evaluations because it allows adequate follow-up and treatment.

Echocardiographic Study of the Coronary Sinus in the Indeterminate Form of Chagas Disease

Abstract INTRODUCTION: We investigated the occurrence of coronary sinus abnormalities in the indeterminate form of Chagas disease (CD). METHODS: Differences between the maximum and minimum diameters of the coronary sinus (∆%) on echocardiography were evaluated in individuals with the indeterminate form of CD (n=14) and those without (n=16) CD. The association of the difference with abnormalities detected by echocardiography and myocardial scintigraphy was assessed. RESULTS: The mean Δ% values did not differ significantly between the groups. There was no correlation of the measurements with echocardiographic and myocardial scintigraphy findings. CONCLUSIONS: The coronary sinus evaluation revealed no differences between the groups.

Insights into the clinical and functional significance of cardiac autonomic dysfunction in Chagas disease / Considerações sobre o significado clínico-funcional da disfunção autonômica cardíaca na doença de Chagas

INTRODUCTION: Exclusive or associated lesions in various structures of the autonomic nervous system occur in the chronic forms of Chagas disease. In the indeterminate form, the lesions are absent or mild, whereas in the exclusive or combined heart and digestive disease forms, they are often more pronounced. Depending on their severity these lesions can result mainly in cardiac parasympathetic dysfunction but also in sympathetic dysfunction of variable degrees. Despite the key autonomic effect on cardiovascular functioning, the pathophysiological and clinical significance of the cardiac autonomic dysfunction in Chagas disease remains unknown. METHODS: Review of data on the cardiac autonomic dysfunction in Chagas disease and their potential consequences, and considerations supporting the possible relationship between this disturbance and general or cardiovascular clinical and functional adverse outcomes. RESULTS: We hypothesise that possible consequences that cardiac dysautonomia might variably occasion or predispose in Chagas disease include: transient or sustained arrhythmias, sudden cardiac death, adverse overall and cardiovascular prognosis with enhanced morbidity and mortality, an inability of the cardiovascular system to adjust to functional demands and/or respond to internal or external stimuli by adjusting heart rate and other hemodynamic variables, and immunomodulatory and cognitive disturbances. CONCLUSIONS: Impaired cardiac autonomic modulation in Chagas disease might not be a mere epiphenomenon without significance. Indirect evidences point for a likely important role of this alteration as a primary predisposing or triggering cause or mediator favouring the development of subtle or evident secondary cardiovascular functional disturbances and clinical consequences, and influencing adverse outcomes.

INTRODUÇÃO: Lesões isoladas ou combinadas de várias estruturas do sistema nervoso autônomo ocorrem nas formas crônicas da doença de Chagas. Na forma indeterminada, as lesões são discretas e podem estar até ausentes, enquanto nas formas cardíaca e digestória exclusivas ou combinadas elas são comumente mais pronunciadas. Na dependência da sua maior ou menor severidade, estas lesões podem resultar em variáveis graus de disfunção parassimpática e/ou simpática, principalmente a primeira. Apesar da crítica influência autonômica sobre o funcionamento cardiovascular, o significado fisiopatológico e clínico, notadamente em longo prazo, da disfunção autonômica cardíaca permanece desconhecido na doença de Chagas. MÉTODOS: Revisão sobre a disfunção autonômica cardíaca na doença de Chagas e suas potenciais consequências, como base para considerações acerca da possível relação entre este distúrbio e desfechos clínicos e funcionais globais e cardiovasculares desfavoráveis. RESULTADOS: Os potenciais desfechos que a disautonomia cardíaca pode variavelmente determinar ou predispor na doença de Chagas incluem: arritmias transitórias ou sustentadas, morte súbita, mal prognóstico global e cardiovascular, morbi-mortalidade aumentada, deficiente adaptação cardiovascular a demandas funcionais e/ou em resposta a estímulos internos e externos por meio de ajustes da frequência cardíaca e outras variáveis hemodinâmicas, e distúrbios imunomoduladores e psico-funcionais. CONCLUSÕES: A alteração da modulação autonômica cardíaca na doença de Chagas pode não representar mero epifenômeno sem significado. Evidências indiretas sugerem papel importante desta alteração como fator predisponente ou determinante primário para o desenvolvimento secundário de distúrbios funcionais manifestos ou não e consequências clínicas cardiovasculares, e para a ocorrência de desfechos desfavoráveis.

Treatment and seroconversion in a cohort of children suffering from recent chronic Chagas infection in Yoro, Honduras

Between 1999-2002, Médécins Sans Frontières-Spain implemented a project seeking to determine the efficacy and safety of benznidazole in the treatment of recent chronic Chagas disease in a cohort of seropositive children in the Yoro Department, Honduras. A total of 24,471 children were screened for Trypanosoma cruzi IgG antibodies through conventional enzyme-linked immunosorbent assays (ELISA) on filter paper. Recombinant ELISA (0.93 percent seroprevalence) showed 256 initially reactive cases, including 232 confirmed positive cases. Of these, 231 individuals were treated with benznidazole (7.5 mg/kg/day) for 60 days and were followed with a strict weekly medical control and follow-up protocol. At the end of the project, 229 patients were examined by the Honduras Secretariat of Health for post-treatment serological assessments; 88.2 percent seroconverted after 18 months and 93.9 percent seroconverted after three years. No differences were found in the seroconversion rates according to age or sex. Most of the side effects of the treatment were minor. These results support the argument that in areas where T. cruzi I is predominant and in areas affected by T. cruzi II, when vector transmission has been interrupted, Chagas disease diagnosis and treatment are feasible, necessary and ethically indisputable.

Apresentação clínica da doença de Chagas crônica em indivíduos idosos / Clinical presentation of chronic Chagas disease in elderly individuals

Com o objetivo de avaliar a apresentação clínica da doença de Chagas em idosos foi realizado estudo retrospectivo utilizando-se os prontuários de doentes atendidos em ambulatório de referência. A casuística foi dividida em idosos (> 60 anos) e não idosos. Avaliou-se: sexo, co-morbidades, forma clínica, eletrocardiograma e títulos das sorologias. Idosos (61 casos): média de idade de 66,0 ± 5 anos, 67,2 por cento do sexo feminino; comorbidades em 59 por cento, mais freqüente a hipertensão arterial sistêmica (HAS)= 39,3 por cento; forma indeterminada= 1,6 por cento, forma cardíaca= 88,5 por cento, forma digestiva= 36,1 por cento; alterações freqüentes no eletrocardiograma: bloqueio divisional ântero-superior esquerdo (BDASE)= 41 por cento, bloqueio completo de ramo direito (BCRD)= 32,8 por cento, extra-sístole ventricular (EV)=22,9 por cento. Não idosos (61 casos): média de idade: 39,30±8,36 anos, 54,1 por cento do sexo feminino; comorbidades em 50,8 por cento, mais freqüente a HAS (26,2 por cento); forma indeterminada= 18 por cento (p<0,05), forma cardíaca= 78,7 por cento, forma digestiva= 32,8 por cento; alterações freqüentes no eletrocardiograma: BDASE= 24,6 por cento, BCRD= 21,3 por cento, EV =18 por cento. Concluindo, não houve diferenças clínicas entre indivíduos idosos e não idosos e a forma indeterminada predominou nos indivíduos abaixo dos 60 anos.

This study had the aim of evaluating the clinical presentation of chronic Chagas disease among the elderly. It was a retrospective analysis of clinical records at an outpatient referral service. The sample was divided into two groups: elderly (> 60 years old) and non-elderly. Sex, comorbidities, clinical form, electrocardiogram and serological titers were evaluated. In the elderly group (61 cases), the mean age was 66.03 ± 5 years; 67.2 percent were female; 59 percent presented comorbidities (most frequently systemic arterial hypertension, in 39.3 percent); 1.6 percent had the indeterminate clinical form, 88.5 percent the cardiac form and 36 percent the digestive form; and abnormalities were frequently found on electrocardiograms: 41 percent presented anterosuperior left bundle branch block (AS-LBBB), 32.8 percent presented right bundle branch block (RBBB) and 22.9 percent presented ventricular ectopic beats (VEB). In the non-elderly group (61 cases), the mean age was 39.30 ± 8.36 years; 54.1 percent were female; 50.8 percent presented comorbidities (most frequently systemic arterial hypertension, in 26.2 percent); 18 percent had the indeterminate clinical form (p<0.05), 78.7 percent the cardiac form and 32.8 percent the digestive form; and abnormalities were frequently found on electrocardiogram: 24.6 percent presented AS-LBBB, 21.3 percent RBBB and 18 percent VEB. It was concluded that there were no clinical differences between elderly and non-elderly Chagas patients. The indeterminate clinical form predominated in patients less than 60 years old.

Forma indeterminada da doença de Chagas: consideraçoes acerca do diagnóstico e do prognóstico / Indeterminate form of Chagas disease: considerations about diagnosis and prognosis

A forma indeterminada da doença de Chagas é definida pela presença de infecção pelo Trypanosoma cruzi na ausência de manifestações clínicas, radiológicas e eletrocardiográficas de acometimento cardíaco ou digestivo. Pacientes na forma indeterminada podem apresentar anormalidades cardiovasculares significativas à propedêutica mais avançada. Entretanto, a validade do conceito de forma indeterminada tem sido reafirmada, pela simplicidade diagnóstica e benignidade do prognóstico. Na prática clínica, dificuldades diagnósticas são freqüentes, relacionadas à subjetividade e ao significado incerto de achados clínicos, eletrocardiográficos e radiológicos. Adicionalmente, o prognóstico na forma indeterminada não é uniformemente bom: após cinco a 10 anos, postula-se que um terço dos pacientes evoluirão para a forma cardíaca. A morte súbita, uma complicação rara, pode ser a primeira manifestação da doença. É necessária uma reavaliação do conceito de forma indeterminada, com redefinição dos critérios diagnósticos e da conduta terapêutica. A estratificação do risco individual, através de métodos clínicos e não-invasivos, pode permitir o reconhecimento de grupos de risco aumentado, passíveis de intervenções terapêuticas. Como o tratamento etiológico pode prevenir o aparecimento da cardiopatia, seu papel no manejo da forma indeterminada deve ser reavaliado.

The indeterminate form of Chagas' disease is defined by the absence of clinical, radiological and electrocardiographic manifestations of cardiac or digestive involvement in Trypanosoma cruzi chronic infected persons. When submitted to advanced cardiovascular tests, these patients may present significant abnormalities. However, the indeterminate form concept was reaffirmed as valid, since diagnostic criteria are simple and prognosis is benignant. In clinical practice, diagnostic difficulties are frequent, related to subjectivity and uncertain meaning of clinical, electrocardiographic and radiological findings. Moreover, indeterminate form prognosis is not equally good: after five to 10 years, a third of patients will have cardiopathy. Sudden death, a rare complication, may be the first manifestation of Chagas' disease. It is necessary to reappraise indeterminate form concept, redefining diagnostic criteria and therapeutic management. Clinical and noninvasive evaluation may allow individual risk stratification; therapeutic interventions may be beneficial in high risk groups. Since etiologic treatment may prevent cardiopathy, its role in indeterminate form management must be reassessed.

Correlação clínico-patológica na forma indeterminada da doença de Chagas experimental do cão / Clinico-Pathological Correlation in the Indeterminate Form of Experimental Chagas' Disease in Dogs

PURPOSE: To study the functional cardiac component of the indeterminate form of experimental Chagas' disease in dogs. METHODS: Four dogs chronically infected with Trypanosoma cruzi and eight normal controls were used. They were submitted to several invasive procedures, either in the presence of complete autonomic block or not, to test for disturbances in the origin and conduction of electric stimuli and the function of cardiac muscle. Histological examination of the heart and its conduction systems was performed in all animals. RESULTS: Mild to moderate focal myocarditis was found in infected dogs, often involving the conduction system of the heart. Sections of the heart from control dogs were histologically normal. Functional data on excitability, intra and interatrial conduction time and sinus node recovering time were essentially similar for both infected and control animals. CONCLUSION: Focal myocarditis, the hallmark of the indeterminate form of Chagas' disease, did not alter the normal parameters of cardiac function, as seen after investigation with sensitive invasive techniques. It is probable that subjects considered as belonging to the indeterminate form of Chagas' disease, but presenting mild alterations at sensitive exploratory tests, may have more severe lesions than that usually described or may be already in the early progressive cardiac form of the disease.

Forma indeterminada da doença de Chagas: uma doença polimórfica: [Editorial] / Indeterminated form of Chagas' disease. A polymorphic disease: [Editorial]

Avaliar a associaçäo entre a forma indeterminada da doença de Chagas e alteraçöes em exames cardiovasculares näo invasivos. Vinte e dois portadores da forma idndeterminada da doença de Chagas, sendo 17 do sexo feminino, com idades variando de 25 a 50 anos. Todos os pacientes foram submetidos a estudo através da vetorcardiografia, ecocardiografia, teste de esforço, eletrocardiografia dinâmica e estudo cintilográfico (ventriculografia radioisotópica e mapeamento miocárdico com pirofosfato de tecnécio), num período de dois meses após a primeira consulta. Resultaram os seguintes percentuais de exames alterados: vetorcardiograma - 68,2% (distúrbio de conduçäo - 22,7%); ecocardiograma - 15,8% (hipocinesia apical); mapeamento miocárdico - 81,8%; ventriculografia radioisotópica - 68,2%; teste de esforço - 72,7% (deltaPS diminuído - 59%; arritmia ventricular - 50%); eletrocardiografia dinâmica - 50% (arritmia ventricular). Todos apresentaram pelo menos um exame alterado e a maioria (63,6%) mais de três exames alterados. Estudo da relaçäo entre os resultados do deltaPS diminuído e arritmia ventricular com resultados concordantes em 72,7%. Parece tornar-se lícito conceituar a forma indeterminada da doença de Chagas como verdadeira forma crônica, talvez de potencial agressivo atenuado, de evoluçäo indeterminada e com exteriorizaçäo clínica polimórfica identificada somente à propedêutica armada

Purpose To evaluate the association between the indeterminate form of Chagas' disease and abnormalities in non-invasive cardiovascular propedeutics. Patients and Methods Twenty-two patients in the indeterminate form of Chagas' disease, 17 female, with ages between 25 and 50 years were submitted to studies of: vetor cardiography, echocardiography, stress test, dynamic electrocardiography and scintilographic studies (scintilographic ventriculography and cardiac mapping with pyrophosphate of tecnecium), in a period of two months after first consultation. Results The analysis shows the perceptual of altered exams: vetorcardiogram 68.2% (conduction disturbance 22.7%); echocardiogram 15.8% (apical hypocinesia); cardiac mapping 61.8%; cintilographic ventriculography68.2%; stress test 72.2% (red uced DPS50%, ventricular arrhythmia50% ); and dynamic electrocardiographic 50% (ventricular arrhythmias). We could observe also that the great majority of the patients has more than three exams altered (63.6%). The stud y of relation between methods, shows only association between reduced DPS and ventricular arrhythmia, with concordant results in 72.7%. Conclusion Indeterminate form of Chagas disease appears to be a really chronic form, may be of atenuate agressive potential, with indeterminate evolution and with polimorphical clinical exteriorization seeing only through invasive and non invasive propedeutic techniques.