Corrigendum: Home-based exercise program in the indeterminate form of Chagas disease (PEDI-CHAGAS study): a study protocol for a randomized clinical trial.

[This corrects the article DOI: 10.3389/fmed.2022.1087188.].

Selenium, TGF-Beta and Infectious Endemic Cardiopathy: Lessons from Benchwork to Clinical Application in Chagas Disease.

For over 60 years, selenium (Se) has been known as an essential microelement to many biological functions, including cardiovascular homeostasis. This review presents a compilation of studies conducted in the past 20 years related to chronic Chagas disease cardiomyopathy (CCC), caused by Trypanosoma cruzi infection, a neglected disease that represents a global burden, especially in Latin America. Experimental and clinical data indicate that Se may be used as a complementary therapy to prevent heart failure and improve heart function. Starting from the main questions "Is Se deficiency related to heart inflammation and arrhythmogenesis in CCC?" and "Could Se be recommended as a therapeutic strategy for CCC?", we show evidence implicating the complex and multidetermined CCC physiopathology, discussing its possible interplays with the multifunctional cytokine TGF-ß as regulators of immune response and fibrosis. We present two new proposals to face this global public health challenge in vulnerable populations affected by this parasitic disease: fibrosis modulation mediated by TGF-ß pathways and the possible use of selenoproteins as antioxidants regulating the increased reactive oxygen stress present in CCC inflammatory environments. We assess the opportunity to consider the beneficial effects of Se in preventing heart failure as a concept to be applied for CCC patients.

Home-based exercise program in the indeterminate form of Chagas disease (PEDI-CHAGAS study): A study protocol for a randomized clinical trial.

Background: Chagas disease (CD) is a neglected endemic disease with worldwide impact due to migration. Approximately 50-70% of individuals in the chronic phase of CD present the indeterminate form, characterized by parasitological and/or serological evidence of Trypanosoma cruzi infection, but without clinical signs and symptoms. Subclinical abnormalities have been reported in indeterminate form of CD, including pro-inflammatory states and alterations in cardiac function, biomarkers and autonomic modulation. Moreover, individuals with CD are usually impacted on their personal and professional life, making social insertion difficult and impacting their mental health and quality of life (QoL). Physical exercise has been acknowledged as an important strategy to prevent and control numerous chronic-degenerative diseases, but unexplored in individuals with the indeterminate form of CD. The PEDI-CHAGAS study (which stands for "Home-Based Exercise Program in the Indeterminate Form of Chagas Disease" in Portuguese) aims to evaluate the effects of a home-based exercise program on physical and mental health outcomes in individuals with indeterminate form of CD. Methods and design: The PEDI-CHAGAS is a two-arm (exercise and control) phase 3 superiority randomized clinical trial including patients with indeterminate form of CD. The exclusion criteria are <18 years old, evidence of non-Chagasic cardiomyopathy, musculoskeletal or cognitive limitations that preclude the realization of exercise protocol, clinical contraindication for regular exercise, and regular physical exercise (≥1 × per week). Participants will be assessed at baseline, and after three and 6 months of follow-up. The primary outcome will be QoL. Secondary outcomes will include blood pressure, physical fitness components, nutritional status, fatigability, autonomic modulation, cardiac morphology and function, low back pain, depression and anxiety, stress, sleep quality, medication use and adherence, and biochemical, inflammatory and cardiac biomarkers. Participants in the intervention group will undergo a home-based exercise program whilst those in the control group will receive only general information regarding the benefits of physical activity. Both groups will receive the same general nutritional counseling consisting of general orientations about healthy diets. Conclusion: The findings from the present study may support public health intervention strategies to improve physical and mental health parameters to be implemented more effectively in this population. Clinical trial registration: [https://ensaiosclinicos.gov.br/rg/RBR-10yxgcr9/], identifier [U1111-1263-0153].

Effects of Selenium treatment on cardiac function in Chagas heart disease: Results from the STCC randomized Trial.

BACKGROUND: Chagas disease (caused by Trypanosoma cruzi infection) evolves to chronic chagasic cardiomyopathy (CCC) affecting 1.8 million people worldwide. This is the first randomized, placebo-controlled, double-blinded, clinical trial designed to estimate efficacy and safety of selenium (Se) treatment in CCC. METHODS: 66 patients with CCC stages B1 (left ventricular ejection fraction [LVEF] > 45% and no heart failure; n = 54) or B2 (LVEF < 45% and no heart failure; n = 12) were randomly assigned to receive 100 mcg/day sodium selenite (Se, n = 32) or placebo (Pla, n = 34) for one year (study period: May 2014-September 2018). LVEF changes over time and adverse effects were investigated. Trial registration number: NCT00875173 (clinicaltrials.gov). FINDINGS: No significant differences between the two groups were observed for the primary outcome: mean LVEF after 6 (ß= +1.1 p = 0.51 for Se vs Pla) and 12 months (ß= +2.1; p = 0.23). In a subgroup analysis, statistically significant longitudinal changes were observed for mean LVEF in the stage B2 subgroup (ß= +10.1; p = 0.02 for Se [n = 4] vs Pla [n = 8]). Se treatment was safe for CCC patients, and the few adverse effects observed were similarly distributed across the two groups. INTERPRETATION: Se treatment did not improve cardiac function (evaluated from LVEF) in CCC. However, in the subgroup of patients at B2 stage, a potential beneficial influence of Se was observed. Complementary studies are necessary to explore diverse Se dose and/or associations in different CCC stages (B2 and C), as well as in A and B1 stages with longer follow-up. FUNDING: Brazilian Ministry of Health, Fiocruz, CNPq, FAPERJ.

Benznidazole decreases the risk of chronic Chagas disease progression and cardiovascular events: A long-term follow up study.

BACKGROUND: Chagas disease (CD) remains an important endemic disease in Latin America. However, CD became globalized in recent decades. The majority of the chronically infected individuals did not receive etiologic treatment for several reasons, among them the most conspicuous is the lack of access to diagnosis. The impact of trypanocidal treatment on CD chronic phase, without cardiac involvement (indeterminate form ICF), is yet to be determined. We aimed to evaluate the effect of trypanocidal treatment with benznidazole (BZN) on the rate of progression to Chagas heart disease in patients with ICF. METHODS: This is a retrospective cohort observational study including patients with ICF treated with BZN and compared to a group of non-treated patients matched for age, sex, region of origin, and the year of cohort entry. We reviewed the medical charts of all patients followed from May 1987 to June 2020 at the outpatient center of the Evandro Chagas National Institute of Infectious Diseases (INI) of the Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil. Patients' follow-up included at least one annual medical visit and one annual electrocardiogram (ECG). Echocardiographic exams were performed at baseline and during the follow-up. Disease progression from ICF to cardiac form was defined by changes in baseline ECG. Cumulative incidence and the incidence rate were described in the incidence analysis. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the association between BZN and CD progression, cardiovascular events or death. FINDINGS: One hundred and fourteen treated patients met the study inclusion criteria. A comparison group of 114 non-treated patients matched for age, sex, region of origin, and the year of cohort entry was also included, totalizing 228 patients. Most patients included in the study were male (70.2%), and their mean age was 31.3 (+7.4) years. Over a median follow-up of 15.1 years (ranging from 1.0 to 32.4), the cumulative CD progression incidence in treated patients was 7.9% vs. 21.1% in the non-treated group (p = 0.04) and the CD progression rate was 0.49 per 1.000 patients/year in treated patients vs. 1.10 per 1.000 patients/year for non-treated patients (p = 0.02). BZN treatment was associated with a decreased risk of CD progression in both unadjusted (HR 0.46; 95%CI 0.21 to 0.98) and adjusted (HR 0.43; 95%CI 0.19 to 0.96) models and with a decreased risk of occurrence of the composite of cardiovascular events only in the adjusted (HR 0.15; 95%CI 0.03 to 0.80) model. No association was observed between BZN treatment and mortality. INTERPRETATION: In a long-term follow-up, BZN treatment was associated with a decreased incidence of CD progression from ICF to the cardiac form and also with a decreased risk of cardiovascular events. Therefore, our results indicate that BZN treatment for CD patients with ICF should be implemented into clinical practice.

The Search for Biomarkers and Treatments in Chagas Disease: Insights From TGF-Beta Studies and Immunogenetics.

The anti-inflammatory cytokine transforming growth factor beta (TGF-ß) plays an important role in Chagas disease (CD), a potentially life-threatening illness caused by Trypanosoma cruzi. In this review we revisited clinical studies in CD patients combined with in vitro and in vivo experiments, presenting three main sections: an overview of epidemiological, economic, and clinical aspects of CD and the need for new biomarkers and treatment; a brief panorama of TGF-ß roles and its intracellular signaling pathways, and an update of what is known about TGF-ß and Chagas disease. In in vitro assays, TGF-ß increases during T. cruzi infection and modulates heart cells invasion by the parasite fostering its intracellular parasite cycle. TGF-ß modulates host immune response and inflammation, increases heart fibrosis, stimulates remodeling, and slows heart conduction via gap junction modulation. TGF-ß signaling inhibitors reverts these effects opening a promising therapeutic approach in pre-clinical studies. CD patients with higher TGF-ß1 serum level show a worse clinical outcome, implicating a predictive value of serum TGF-ß as a surrogate biomarker of clinical relevance. Moreover, pre-clinical studies in chronic T. cruzi infected mice proved that inhibition of TGF-ß pathway improved several cardiac electric parameters, reversed the loss of connexin-43 enriched intercellular plaques, reduced fibrosis of the cardiac tissue, restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Finally, TGF-ß polymorphisms indicate that CD immunogenetics is at the base of this phenomenon. We searched in a Brazilian population five single-nucleotide polymorphisms (-800 G>A rs1800468, -509 C>T rs1800469, +10 T>C rs1800470, +25 G>C rs1800471, and +263 C>T rs1800472), showing that CD patients frequently express the TGF-ß1 gene genotypes CT and TT at position -509, as compared to noninfected persons; similar results were observed with genotypes TC and CC at codon +10 of the TGF-ß1 gene, leading to the conclusion that 509 C>T and +10 T>C TGF-ß1 polymorphisms are associated with Chagas disease susceptibility. Studies in genetically different populations susceptible to CD will help to gather new insights and encourage the use of TGF-ß as a CD biomarker.

Chagas heart disease: An overview of diagnosis, manifestations, treatment, and care.

Chagas heart disease (CHD) affects approximately 30% of patients chronically infected with the protozoa Trypanosoma cruzi. CHD is classified into four stages of increasing severity according to electrocardiographic, echocardiographic, and clinical criteria. CHD presents with a myriad of clinical manifestations, but its main complications are sudden cardiac death, heart failure, and stroke. Importantly, CHD has a higher incidence of sudden cardiac death and stroke than most other cardiopathies, and patients with CHD complicated by heart failure have a higher mortality than patients with heart failure caused by other etiologies. Among patients with CHD, approximately 90% of deaths can be attributed to complications of Chagas disease. Sudden cardiac death is the most common cause of death (55%-60%), followed by heart failure (25%-30%) and stroke (10%-15%). The high morbimortality and the unique characteristics of CHD demand an individualized approach according to the stage of the disease and associated complications the patient presents with. Therefore, the management of CHD is challenging, and in this review, we present the most updated available data to help clinicians and cardiologists in the care of these patients. We describe the clinical manifestations, diagnosis and classification criteria, risk stratification, and approach to the different clinical aspects of CHD using diagnostic tools and pharmacological and non-pharmacological treatments.

Quality of life and associated factors in patients with chronic Chagas disease.

OBJECTIVES: To evaluate the quality of life (QoL) of patients with Chagas disease (CD) and the association between QoL domains and several clinical, socioeconomic and lifestyle characteristics of this population. METHODS: Cross-sectional observational study conducted from March 2014 to March 2017 including a total of 361 outpatients followed at Evandro Chagas National Institute of Infectious Disease, Brazil. QoL was assessed using the Portuguese shorter version of the original WHO Quality of Life questionnaire (WHOQOL-BREF). Information about clinical CD presentation, presence of comorbidities, functional class, previous benznidazole treatment, socioeconomic profile and lifestyle was also obtained. RESULTS: Environment and physical domains presented the worst QoL scores, while the social relationship domain presented the highest score. Multivariate regression analysis demonstrated that variables independently associated with QoL were functional class, sex, clinical presentation of CD, sleep duration, schooling, physical activity level, smoking, income per capita and residents by domicile. CONCLUSIONS: The low socioeconomic status and the physical limitations imposed by the disease presented an important impact on the QoL reduction among CD patients, especially on environment and physical domains. Strategies to improve QoL among CD patients should be tailored and consider many different variables to maximise improvements not only of patients' physical but also of their mental health.

Course of serological tests in treated subjects with chronic Trypanosoma cruzi infection: A systematic review and meta-analysis of individual participant data.

OBJECTIVE: To determine the course of serological tests in subjects with chronic Trypanosoma cruzi infection treated with anti-trypanosomal drugs. METHODS: A systematic review and meta-analysis was conducted using individual participant data. Survival analysis and the Cox proportional hazards regression model with random effects to adjust for covariates were applied. The protocol was registered in the PROSPERO database (http://www.crd.york.ac.uk/PROSPERO; CRD42012002162). RESULTS: A total of 27 studies (1296 subjects) conducted in eight countries were included. The risk of bias was low for all domains in 17 studies (63.0%). Nine hundred and thirteen subjects were assessed (149 seroreversion events, 83.7% censored data) for enzyme-linked immunosorbent assay (ELISA), 670 subjects (134 events, 80.0% censored) for indirect immunofluorescence assay (IIF), and 548 subjects (99 events, 82.0% censored) for indirect hemagglutination assay (IHA). A higher probability of seroreversion was observed within a shorter time span in subjects aged 1-19 years compared to adults. The chance of seroreversion also varied according to the country where the infection might have been acquired. For instance, the pooled adjusted hazard ratio between children/adolescents and adults for the IIF test was 1.54 (95% confidence interval 0.64-3.71) for certain countries of South America (Argentina, Bolivia, Chile, and Paraguay) and 9.37 (95% confidence interval 3.44-25.50) for Brazil. CONCLUSIONS: The disappearance of anti-T. cruzi antibodies was demonstrated along the course of follow-up. An interaction between age at treatment and country setting was found.

Effects of omega-3 polyunsaturated fatty acid supplementation in patients with chronic chagasic cardiomyopathy: study protocol for a randomized controlled trial.

BACKGROUND: Chronic chagasic cardiomyopathy is an inflammatory disease that occurs in approximately 30% of patients infected by the protozoan Trypanosoma cruzi, and it has a profile of high morbidity and mortality. The worst prognosis and the progression of this cardiomyopathy are associated with an exacerbated immune response and the production of proinflammatory cytokines, which also occur in other cardiomyopathies. Some nutrients, including omega-3 polyunsaturated fatty acids (PUFAs), promote the inhibition and/or stimulation of cytokine production. The objective of this trial is to study the effects of omega-3 PUFA supplementation on the inflammatory response and lipid profile in patients with chronic chagasic cardiomyopathy. METHODS/DESIGN: This is a parallel, randomized, placebo-controlled, double-blind clinical trial with 40 patients that will be conducted at a reference unit for Chagas disease patients, where the patients will be selected. The study will include patients with chronic chagasic cardiomyopathy who are 18 years of age or older. The exclusion criteria are (a) ongoing diarrheal disease, (b) inflammatory bowel disease, (c) diabetes or other endocrine disease, (d) use of fibrates, niacin, or statins, (e) use of anti-inflammatory drugs, (f) pregnant and lactating women, (g) use of vitamin, mineral, or omega-3 supplementation during the previous 30 days, (h) hospital admission during the study, and (i) other associated cardiomyopathies. The intervention will be treatment with omega-3 PUFAs at a dose of 3 g/day for 8 weeks, compared to placebo (corn oil). The primary endpoints will be the concentrations of inflammatory markers (interleukin (IL)-1, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)α, interferon (IFN)γ, and transforming growth factor (TGF)ß). Secondary endpoints will be the fasting glucose, lipid, and anthropometric profiles. For statistical analysis, we plan to run either a t test or Wilcoxon test (numerical variables) and Pearson's χ2 or Fisher's exact test (categorical data), as appropriate. DISCUSSION: Evidence suggests that the anti-inflammatory action of omega-3 PUFAs may have beneficial effects on chronic chagasic cardiomyopathy, as shown for other cardiomyopathies, due to improved control of the inflammatory response. At the end of the study, we predict that patients will have lower inflammatory markers and an improved metabolic and anthropometric profile. TRIAL REGISTRATION: Current Controlled Trials NCT01863576.

Left atrial and left ventricular diastolic function in chronic Chagas disease.

BACKGROUND: Left atrial (LA) and left ventricular (LV) diastolic function analysis can yield new strategies to recognize early cardiac involvement and prognostic indicators in Chagas disease. METHODS: Patients with Chagas disease with the indeterminate (n = 69) or with the cardiac form (32 with changes limited to electrocardiography [stage A], 25 with changes in LV systolic function but no heart failure [HF; stage B], and 26 with HF) underwent evaluation of LV diastolic function (mitral inflow, pulmonary vein flow, color M-mode echocardiography, and tissue Doppler analysis), and LA function by three-dimensional echocardiography and strain analysis and were prospectively followed for the occurrence of clinical events. Echocardiograms were also obtained from 32 controls. RESULTS: LV diastolic dysfunction was gradually more prevalent and severe across groups from patients with the indeterminate form of Chagas disease to patients with HF. Tissue Doppler was the best tool to demonstrate the worsening of LV diastolic function across the groups (E' velocity: controls, 12.6 ± 2.3 cm/sec; patients with the indeterminate form, 12.1 ± 3.1 cm/sec; stage A, 10.3 ± 2.9 cm/sec; stage B, 8.3 ± 2.8 cm/sec; patients with HF, 5.6 ± 1.9; P < .0001). Although maximum LA volume was increased only in patients with HF, minimum LA volume (controls, 8 ± 2 mL/m(2); patients with the indeterminate form, 8 ± 2 mL/m(2); stage A, 9 ± 3 mL/m(2); stage B, 11 ± 4 mL/m(2); patients with HF, 27 ± 17 mL/m(2); P < .0001) and precontraction LA volume (controls, 11 ± 3 mL/m(2); patients with the indeterminate form, 12 ± 3 mL/m(2); stage A, 13 ± 4 mL/m(2); stage B, 16 ± 5 mL/m(2); patients with HF, 32 ± 19 mL/m(2); P < .0001) were increased in all cardiac form groups. LA conductive function was depressed in all cardiac form groups, while LA contractile function was depressed only in patients with HF. Cox proportional-hazards regression analysis revealed that end-systolic LV diameter (hazard ratio, 1.6; 95% confidence interval, 0.9-2.8; P = .09), E' velocity (hazard ratio, 0.5; 95% confidence interval, 0.3-0.8; P = .001), and peak negative global LA strain (hazard ratio, 1.21; 95% confidence interval, 1.02-1.4; P = .03), were independent predictors of clinical events. CONCLUSIONS: LV diastolic dysfunction was found in all forms of chronic Chagas disease, including those without LV systolic dysfunction. LV diastolic dysfunction may contribute to changes in LA volume and conductive function found in early stages of the cardiac form. Both LV diastolic function and LA contractile function were independent predictors of clinical events.

Predictive value of transforming growth factor-ß1in Chagas disease: towards a biomarker surrogate of clinical outcome.

BACKGROUND: Transforming growth factor-ß1 (TGF-ß1) may be implicated in the development of Chagas heart disease. However, the clinical value of TGF-ß1 measurement is yet to be determined. METHODS: We retrospectively analyzed the outcome of 54 Chagas disease patients without heart failure and with left ventricular (LV) ejection fraction >45% whose TGF-ß1 serum values were determined between January 1998 and December 1999. Primary end point was all-cause mortality and secondary end point was the combination of all-cause mortality or hospitalization due to worsening heart failure or cardiac arrhythmias. RESULTS: TGF-ß1 was independently associated with the occurrence of the primary and secondary end points. The optimal cutoff for TGF-ß1 to identify the primary end point was 12.9 ng/ml (area under the curve = 0.82, p = 0.004, sensitivity 100%, and specificity 57%) and to identify the secondary end point was 30.8 ng/ml (area under the curve = 0.72, p = 0.03, sensitivity 60%, and specificity 86%). LV ejection fraction and LV end-diastolic diameter were also independent predictors of the primary and secondary endpoints, respectively. CONCLUSION: The described association between TGF-ß1 and clinical outcome provides evidence towards the clinical value of TGF-ß1 in Chagas disease.

Impact of pharmaceutical care on the quality of life of patients with Chagas disease and heart failure: randomized clinical trial.

BACKGROUND: Pharmaceutical care is the direct interaction between pharmacist and patient, in order to improve therapeutic compliance, promote adequate pharmacotherapeutic follow-up, and improve quality of life. Pharmaceutical care may be effective in reducing complications and in improving the quality of life of patients with chronic diseases, like Chagas heart disease, while bringing a positive impact on health system costs. The morbidity and mortality indexes for patients with Chagas heart disease are high, especially if this heart disease is complicated by heart failure. In this setting, we hypothesize that pharmaceutical care might be an important tool for the clinical management of these patients by improving their quality of life, as a better compliance to their treatment and the avoidance and prompt correction of drug-related problems will minimize their symptoms, improve their functional class, and decrease the number of hospital admissions. Therefore, the aim of this trial is to evaluate the contribution of pharmaceutical care to clinical treatment of patients with Chagas heart disease complicated by heart failure. METHODS/DESIGN: A prospective, single-center randomized clinical trial will be conducted in patients with Chagas heart disease complicated by heart failure. A total of 88 patients will be randomly assigned into two parallel groups: an intervention group will receive standard care and pharmaceutical care, and a control group will receive only standard care. Both groups will be subjected to a follow-up period of 12 months. The primary outcome of this trial is the evaluation of quality of life, measured by the 36-item short-form and the Minnesota Living with Heart Failure Questionnaire. Secondary outcomes include drug-related problems, exercise tolerance as measured by the standard six-minute-walk test, and compliance. DISCUSSION: Patients with Chagas heart disease complicated by heart failure under pharmaceutical care are expected to improve their quality of life, present with a lower incidence of drug-related problems, improve their functional capacity, and improve in their compliance to treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01566617.

Safety of benznidazole use in the treatment of chronic Chagas' disease.

OBJECTIVES: To assess the safety of benznidazole use in adult patients with chronic Chagas' disease. METHODS: The Naranjo algorithm was applied to classify the causality of adverse drug reactions (ADRs). RESULTS: In total, 190 patients were treated with benznidazole over a period of 4-180 days (mean 58.90 ± 36.54 days) with a dose of 50-500 mg/day (221.33 ± 57.16 mg/day). Of the 190 patients treated, 93 had ADRs and 59 of these interrupted treatment. There was a higher incidence of ADRs among female and young adult patients. There was a higher incidence of ADRs during the first 30 days of treatment. Interruption of treatment was more frequent in women. Among the patients who interrupted treatment, 39 had mild ADRs, 19 had moderate ADRs and 1 had a severe ADR. There were no interruptions in treatment for 97 patients without ADRs. The survival curves indicated that the time until interruption of treatment in patients with moderate and severe ADRs was lower than in patients with mild or no ADRs. The most frequent disorders were in the skin (26.3%), gastrointestinal system (9.5%) and nervous system (5.3%). CONCLUSIONS: The Naranjo algorithm was a useful tool to reduce the underreporting of ADRs. Events were common, but were associated with low morbidity and were reversible upon discontinuation of drug treatment. Moreover, there were no fatal events; therefore, benznidazole treatment was considered safe.

ELISA versus PCR for diagnosis of chronic Chagas disease: systematic review and meta-analysis.

BACKGROUND: Most current guidelines recommend two serological tests to diagnose chronic Chagas disease. When serological tests are persistently inconclusive, some guidelines recommend molecular tests. The aim of this investigation was to review chronic Chagas disease diagnosis literature and to summarize results of ELISA and PCR performance. METHODS: A systematic review was conducted searching remote databases (MEDLINE, LILACS, EMBASE, SCOPUS and ISIWeb) and full texts bibliography for relevant abstracts. In addition, manufacturers of commercial tests were contacted. Original investigations were eligible if they estimated sensitivity and specificity, or reliability -or if their calculation was possible - of ELISA or PCR tests, for chronic Chagas disease. RESULTS: Heterogeneity was high within each test (ELISA and PCR) and threshold effect was detected only in a particular subgroup. Reference standard blinding partially explained heterogeneity in ELISA studies, and pooled sensitivity and specificity were 97.7% [96.7%-98.5%] and 96.3% [94.6%-97.6%] respectively. Commercial ELISA with recombinant antigens studied in phase three investigations partially explained heterogeneity, and pooled sensitivity and specificity were 99.3% [97.9%-99.9%] and 97.5% [88.5%-99.5%] respectively. ELISA's reliability was seldom studied but was considered acceptable. PCR heterogeneity was not explained, but a threshold effect was detected in three groups created by using guanidine and boiling the sample before DNA extraction. PCR sensitivity is likely to be between 50% and 90%, while its specificity is close to 100%. PCR reliability was never studied. CONCLUSIONS: Both conventional and recombinant based ELISA give useful information, however there are commercial tests without technical reports and therefore were not included in this review. Physicians need to have access to technical reports to understand if these serological tests are similar to those included in this review and therefore correctly order and interpret test results. Currently, PCR should not be used in clinical practice for chronic Chagas disease diagnosis and there is no PCR test commercially available for this purpose. Tests limitations and directions for future research are discussed.

Implication of transforming growth factor-beta1 in Chagas disease myocardiopathy.

Cardiac dysfunction with progressive fibrosis is a hallmark of Chagas disease. To evaluate the involvement of transforming growth factor (TGF)-beta1 in this disease, TGF-beta1 levels in patients were measured at 3 stages: asymptomatic indeterminate (IND), cardiac with no or slight heart dysfunction (Card 1), and cardiac with moderate or severe heart dysfunction (Card 2). All patients had significantly higher circulating levels of TGF-beta1 than did healthy persons, and 27% of patients in the Card 1 group had higher TGF-beta1 levels than did patients in the IND group. Immunohistochemical analysis of cardiac biopsy specimens showed strong fibronectin staining in the extracellular matrix and staining for phosphorylated Smad 2 (activation of the TGF-beta1 signaling pathway) in cell nuclei. The higher levels of latent TGF-beta1 observed in patients with myocardiopathy, together with intracellular activation of the TGF-beta1 pathway and tissue fibrosis, suggest that TGF-beta1 plays an important role in Chagas disease. TGF-beta1 may represent a new target for preventive and curative treatments of Chagas disease.