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Indeterminate form

The concept of the indeterminate form was not based on histological findings, but on the fact that visceral lesions could not be detected through clinical examination and complementary routine exams in a significant proportion of patients in the chronic phase of Chagas disease. According to a consensus of experts published in 1985, during the first meeting of applied research in Chagas disease (Araxa, Brazil), in order to be classified in the indeterminate form, the patients should meet all the following criteria: positive serological and/or parasitological tests; absence of signs and symptoms of disease; normal 12-lead ECG; and normal radiological examination of chest, esophagus, and colon. This strict definition provides a good opportunity to categorize patients in epidemiological surveys. In cross-sectional studies conducted in endemic areas, about half of the patients with chronic Chagas disease have the indeterminate form. Recognition of the indeterminate form delimits a group of patients with a favorable prognosis, low morbidity, capable of performing any type of activity, and having the same mortality as that of the general population.

A serious conceptual error frequently observed in the medical literature is to assume that Chagas disease has three phases (acute, indeterminate, and chronic), instead of considering “indeterminate” as one of the forms of the chronic phase. By definition, “chronic” is the time period that follows any acute condition, and where

patients with the indeterminate form are situated. Otherwise, we should not consider as being at the chronic phase of the disease an asymptomatic individual who has been infected with T. cruzi for a long time.

Although a variable proportion of patients with the indeterminate form present some structural and/or functional abnormalities when they are fully evaluated by more sensitive methods (usually for research purpose), such as ergometry, 24-h Holter monitoring, vectorcardiography, echocardiography, radioisotopic techniques, cardiac magnetic resonance imaging, hemodynamic study, electrophysiologic study, endomyocardial biopsies, autonomic tests, and esophageal and colonic manometric studies, these abnormalities are often subtle and frequently isolated. Moreover, they can occasionally be found also in healthy individuals, and are not related to a decrease in life expectancy. Of note, most studies that have assessed tests of higher sensitivity in patients with chronic Chagas disease did not include the use of contrast media in the examination of the esophagus and colon because of the difficulty of carrying out such tests in asymptomatic individuals. So, it is quite possible that some of these patients had the digestive and not the indeterminate form of the disease.

Some of us studied 103 patients with the indeterminate form, who performed an exercise testing, an echocardiogram, and a 24-h Holter monitoring and had their results compared with that of 20 healthy controls.15 All chagasic patients fulfilled the rigid definition of the indeterminate form and had a normal barium swallow and enema done. The 2D echocardiogram—only left ventricular systolic function was analyzed—was normal in all patients of both groups. The ambulatory Holter monitoring showed frequent or complex ventricular arrhythmias in 20% of chagasics versus 25% of controls. In the exercise testing, the prevalence of ventricular arrhythmias or an abnormal inotropic or chronotropic response was 16% in the cha- gasics versus 10% in normal individuals. This controlled study suggests that chaga- sic patients with the indeterminate form have similar performance when compared with normal population. Discrepancies in the results of studies investigating the role of highly sensitive tests in patients with the indeterminate form may reflect variations in sample size, lack of a normal control group, differences in the definition of abnormal responses, lack of radiological study of esophagus and/or colon, and use of plain abdominal X-ray in substitution of a barium enema.

Although patients with the indeterminate form (inclusive of those with any abnormality on more sensitive tests) have good prognosis, epidemiological studies in endemic areas have shown that 1—3% of them evolve each year from the indeterminate to a clinical (determinate) form of the disease.16,17 Whether these abnormalities are a reliable early marker of disease progression or an innocent bystander remains to be determined. The subsequent follow-up of patients with the indeterminate form should rely on annual history, physical examination, and 12-lead ECG tracing.

An individual chronically infected with T. cruzi remains in the indeterminate form, generally for a period of 10—30 years. Nevertheless, the finding of older people (far from endemic regions for decades) with antibodies against T. cruzi and no evidence of visceral involvement indicates that a proportion of the infected people (50—60%) remain in this form for longer periods of time, or even for life.

There have been few pathological studies focusing on individuals with the indeterminate form. Necropsy studies of patients who died from accidental causes revealed mild myocarditis with scattered small foci of interstitial infiltration by lymphocytes, macrophages, and plasma cells, together with a limited reduction in the number of cardiac neurons and myenteric plexuses that are insufficient to produce clinical manifestations.4 Intact parasites are rarely seen, but T. cruzi DNA can be demonstrated in the samples of myocardium, by PCR18 or other techniques, even in the absence of local inflammation. Whether these lesions represent sequelae of the acute phase, a parasite—host state of equilibrium, or are cumulative, progressing to diffuse myocardial damage remain elusive.

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