How do we classify organ involvement in Chagas disease? A systematic review of organ involvement since 1909, Highlighting the urgent need for a universal classification system in Chronic Chagas disease.

Chagas disease (CD) is recognized as one of the 20 neglected tropical diseases by the World Health Organization (WHO), posing a significant global health challenge. The objective of this work was to conduct a systematic methodology review to explore the different classifications used to describe the presence and degree of organ involvement in patients with CD since the disease's description in 1909. We searched relevant electronic medical databases from their inception dates to July 2023. We also delved into historical variations and revisions of each classification, the necessary diagnostic methods, their prognostic value, and their uptake. Our study underscores the conspicuous absence of a universally accepted CD classification system for cardiac and digestive involvement, both in the context of clinical trials and within current clinical guidelines. This endeavour will facilitate cross-population comparisons if clinical manifestations and complementary test results are available for each patient, constituting a pivotal stride toward identifying precise prognoses and establishing a minimum data set requisite for a fitting CD classification, tailored to the test availability in both endemic and non-endemic regions.

A standardized clinical database for research in Chagas disease: The NHEPACHA network.

The NHEPACHA Iberoamerican Network, founded on the initiative of a group of researchers from Latin American countries and Spain, aims to establish a research framework for Chagas disease that encompasses diagnosis and treatment. For this purpose, the network has created a questionnaire to gather relevant data on epidemiological, clinical, diagnostic, and therapeutic aspects of the disease. This questionnaire was developed based on a consensus of expert members of the network, with the intention of collecting high-quality standardized data, which can be used interchangeably by the different research centers that make up the NHEPACHA network. Furthermore, the network intends to offer a clinical protocol that can be embraced by other researchers, facilitating comparability among published studies, as well as the development of therapeutic response and progression markers.

A guide for the generation of repositories of clinical samples for research on Chagas disease.

Chagas disease, caused by the parasite Trypanosoma cruzi, affects over 6 million people, mainly in Latin America. Two different clinical phases, acute and chronic, are recognised. Currently, 2 anti-parasitic drugs are available to treat the disease (nifurtimox and benznidazole), but diagnostic methods require of a relatively complex infrastructure and trained personnel, limiting its widespread use in endemic areas, and the access of patients to treatment. New diagnostic methods, such as rapid tests (RDTs) to diagnose chronic Chagas disease, or loop-mediated isothermal amplification (LAMP), to detect acute infections, represent valuable alternatives, but the parasite's remarkable genetic diversity might make its implementation difficult. Furthermore, determining the efficacy of Chagas disease treatment is complicated, given the slow reversion of serological anti-T. cruzi antibody reactivity, which may even take decades to occur. New biomarkers to evaluate early therapeutic efficacy, as well as diagnostic tests able to detect the wide variety of circulating genotypes, are therefore, urgently required. To carry out studies that address these needs, high-quality and traceable samples from T. cruzi-infected individuals with different geographical backgrounds, along with associated clinical and epidemiological data, are necessary. This work describes the framework for the creation of such repositories, following standardised and uniform protocols, and considering the ethical, technical, and logistic aspects of the process. The manual can be adapted according to the resources of each laboratory, to guarantee that samples are obtained in a reproducible way, favouring the exchange of data among different work groups, and their generalizable evaluation and analysis. The main objective of this is to accelerate the development of new diagnostic methods and the identification of biomarkers for Chagas disease.

Physical activity levels during COVID-19 pandemic and its associated factors in patients with Chagas disease.

Background: A better understanding of the consequences of the Coronavirus Disease 2019 (COVID-19) pandemic on lifestyle of patients with Chagas disease (ChD) is of paramount importance to facilitate the implementation of intervention strategies tailored to this specific population. Objective: The present study aimed to evaluate the level of physical activity (PA) in Chagas disease (ChD) patients during the Coronavirus Disease 2019 (COVID-19) pandemic and its main associated factors. Methods: This is a cross-sectional study with 187 patients of both sexes, aged ≥18 years, followed in a national infectious disease center (Rio de Janeiro, Brazil). The level of PA was determined by the International Physical Activity Questionnaire short version and expressed in terms of total volume of physical activity (PA) (MET-minutes per week). Individuals were classified as physically active following the 2020 World Health Organization PA guideline. The exposure variables were age, sex, race, marital status, schooling, income per capita, number of rooms per domicile, number of residents per domicile, body mass index, clinical form of ChD, COVID-19 antibodies, comorbidities, self-reported anxiety, self-reported depression, self-reported fear, and self-reported sadness. The association between the exposure variables with total PA (as a continuous variable) was determined using univariate and multivariate linear regression models. Results: Mean age was 61.1 ± 11.6 years. Most (62%) were women and self-declared their race as mixed (50.8%). The percentage of physically active individuals according to was 52%. The variables independently associated with total PA levels were non-white race (Exp ß = 1.39; 95% CI 1.02 to 1.90), dyslipidemia (Exp ß = 0.73; 95% CI 0.56 to 0.95) and self-reported depression during quarantine (Exp ß = 0.71; 95% CI 0.52 to 0.96). Conclusion: Non-white race was positively associated with total levels of PA, while dyslipidemia, and self-reported depression during quarantine were negatively associated with total levels of PA. The identification of associated factors can facilitate the development of tailored strategies to increase PA levels ChD patients.

Effect of an exercise-based cardiac rehabilitation program on quality of life of patients with chronic Chagas cardiomyopathy: results from the PEACH randomized clinical trial.

To investigate the effect of an exercise-based cardiac rehabilitation program on the quality of life (QoL) of patients with chronic Chagas cardiomyopathy (CCC). PEACH study was a single-center, superiority randomized clinical trial of exercise training versus no exercise (control). The sample comprised Chagas disease patients with CCC, left ventricular ejection fraction < 45%, without or with HF symptoms (CCC stages B2 or C, respectively). QoL was assessed at baseline, after three months, and at the end of six months of follow-up using the SF-36 questionnaire. Patients randomized for the exercise group (n = 15) performed exercise training (aerobic, strength and stretching exercises) for 60 min, three times a week, during six months. Patients in the control group (n = 15) were not provided with a formal exercise prescription. Both groups received identical nutritional and pharmaceutical counseling during the study. Longitudinal analysis of the effects of exercise training on QoL, considering the interaction term (group × time) to estimate the rate of changes between groups in the outcomes (represented as beta coefficient), was performed using linear mixed models. Models were fitted adjusting for each respective baseline QoL value. There were significant improvements in physical functioning (ß = + 10.7; p = 0.02), role limitations due to physical problems (ß = + 25.0; p = 0.01), and social functioning (ß = + 19.2; p < 0.01) scales during the first three months in the exercise compared to the control group. No significant differences were observed between groups after six months. Exercise-based cardiac rehabilitation provided short-term improvements in the physical and mental aspects of QoL of patients with CCC.Trial registration: ClinicalTrials.gov Identifier: NCT02517632; August 7, 2015.

Chagas heart disease is associated with decreased physical activity levels: A cross-sectional analysis.

Background: Studies evaluating physical activity (PA) levels in individuals with Chagas disease (CD) are still scarce. The present study aimed to evaluate PA levels in CD individuals and examine their association with Chagas heart disease (ChHD). Methods: We included patients with CD regularly followed in a reference center for treatment of infectious diseases. PA levels were assessed using the short version of the International Physical Activity Questionnaire (IPAQ). ChHD was determined following the Brazilian Consensus on Chagas Disease. The association between ChHD and levels of PA (total, walking, moderate, and vigorous) as a continuous variable was fitted using generalized linear models. Logistic regression models were fitted to evaluate the association between ChHD and meeting WHO's PA recommendations. Results: Among the 361 participants included in the analysis (60.7 ± 10.7 years; 56.2 % women), 58.1 % (n = 210) complied with the WHO's PA recommendations. After adjustments for potential confounders, regression analyses revealed that ChHD without heart failure was significantly associated with reduced vigorous PA (Exp ß 0.32 95 % CI 0.10 to 0.98). ChHD with heart failure had significantly lower levels of total (Exp ß 0.61 95 % CI 0.44 to 0.84) and moderate (Exp ß 0.59 95 % CI 0.39 to 0.89) PA. ChHD with heart failure had a lower odd of meeting the PA recommendation in comparison to those with no cardiac involvement (OR 0.48 95 % CI 0.24 to 0.97). Conclusions: We found low levels of PA among individuals with CD. Presence of ChHD (mainly with HF) was associated with decreased levels of PA.

Inspiratory muscle endurance is similarly reduced in the early and late stages of chronic Chagas heart disease.

OBJECTIVE: Inspiratory muscle strength (IMS) appears to be reduced in subjects with chronic Chagas heart disease (CHD), especially in the presence of heart failure (HF). However, only one study about IMS and inspiratory muscle endurance (IME) in those with CHD without heart failure is available. This study aimed to compare IMS and IME in subjects with CHD in the presence and absence of HF. METHODS: This is a cross-sectional study in which 30 CHD adult patients were divided into CHD-CC group (initial phase of CHD, without HF; n = 15) and CHD-HF group (advanced phase of CHD, with HF; n = 15). We assessed IMS by maximum inspiratory pressure (MIP) and IME by incremental (Pthmax) and constant load (TLim) tests. Reduced IMS and IME were considered by predicted MIP values <70% and Pthmax/MIP <75%, respectively. RESULTS: Inspiratory muscle weakness (IMW) was more frequent in CHD-HF than in CHD-CC (46.7% vs. 13.3%; p = 0.05), and both groups had high frequencies of reduced IME (93.3% CHD-CC vs. 100.0% CHD-HF; p = 0.95). Age-adjusted logistic regression analysis using HF as a dependent variable showed that HF was associated with an increased chance of IMW compared with the CHD-CC group (OR = 7.47; p = 0.03; 95% CI 1.20-46.19). CONCLUSION: This study suggests that, in patients with CHD, HF is associated with IMW, and that reduction of IME is already present in the initial phase, similar to the advanced phase with HF.

Interesting case from Argentina: Kidney transplant recipient with skin lesions-A Latin American perspective.

This is a case of a kidney transplant recipient who presented with skin lesions, low-grade fevers, and pancytopenia 2 months after his transplant.

Inspiratory Muscle Strength in Chagas Cardiomyopathy: A Systematic Scoping Review.

The increase in inflammatory markers associated with persistent chronic fibrosing myocarditis, a characteristic of chronic Chagas disease, can result in a reduction in inspiratory muscle strength (IMS) in Chagas cardiomyopathy (CC). However, literature in this field is still scarce. This review aimed to map and summarize the evidence regarding IMS in patients with CC. The inclusion criteria included reports with adult participants with a CC diagnosis, with or without heart failure (HF). The core concept examined was the maximum inspiratory pressure evaluated in the untrained and trained groups in the pre-training period. The context was open, including but not limited to hospitals and health centers. Two authors independently identified eligible studies and extracted the data. Descriptive synthesis was used as the primary strategy for analyzing the results. Nine studies (five clinical trials, three cross-sectional, and one cohort) were included. The CC classification differed among the studies, with no mention of HF in five and no CC staging specification in six. IMS was assessed using a manovacuometer, and only six studies analyzed and interpreted the data concerning the predicted values. The CC population with HF appeared to have impaired IMS. All studies involved only Brazilian volunteers. In conclusion, randomized clinical trials evaluating IMS and the effects of inspiratory muscle training need to be conducted to better understand the prevalence and risk of inspiratory muscle weakness in the CC population, as well as the effects of training. Such studies should be conducted at different stages of CC in different populations and countries.

Exploring the Historical Background and Clinical Implications of Electrocardiogram in the Context of Chagas Disease Research.

Chagas disease (CD) remains one of the most significant endemic diseases in Latin America. Approximately 30% of individuals with CD develop the cardiac form, the main determinant of morbidity and mortality, which is characterized by typical electrocardiogram (ECG) changes caused by chronic chagasic cardiopathy (CCC). This review accentuates to how crucial it is for research teams and reference centers that treat patients with CD to standardize ECG in CCC. This was a non-systematic review of the literature. ECG is the most widely used examination in the diagnosis and evaluation of CCC, and it is also employed in epidemiological surveys, risk stratification for cardiovascular events and death, and monitoring the clinical progression of the disease. Carlos Chagas and Eurico Villela published the first work addressing CCC in 1922. Other works followed, including the study by Evandro Chagas' which was the first to perform ECG in CD, culminating in Francisco Laranja's seminal work in 1956. Since the 1980s, standardizations and ECG reading codes for CD have been established. This standardization aimed to code complex arrhythmias and characteristic ventricular conduction disorders and standardize ECG readings for clinical and epidemiological studies in CD. Nearly all existing electrocardiographic abnormalities can be found in CD, with a predominance of abnormalities in the formation and conduction of cardiac stimuli. The complex and heterogeneous substrate of CD with varied electrocardiographic manifestations poses a significant challenge when comparing studies involving patients with CCC, emphasizing the need for ECG standardization in CD.

Predictors of Trypanosoma cruzi PCR positivity in patients with chronic Chagas disease.

BACKGROUND: A positive Trypanosoma cruzi polymerase chain reaction (PCR) is associated with a worse prognosis in patients with chronic Chagas disease (CD). OBJECTIVES: To study the association of clinical, electrocardiographic, and echocardiographic characteristics and biomarker blood levels with positive T. cruzi PCR in chronic CD. METHODS: This is a single-centre observational cross-sectional study. Positive T. cruzi PCR association with clinical, electrocardiographic, and echocardiographic characteristics, and biomarker blood levels were studied by logistic regression analysis. p values < 0.05 were considered significant. FINDINGS: Among 333 patients with chronic CD (56.4% men; 62 ± 10 years), T. cruzi PCR was positive in 41.1%. Stepwise multivariate logistic regression showed an independent association between positive T. cruzi PCR and diabetes mellitus {odds ratio (OR) 0.53 [95% confidence interval (CI) 0.30-0.93]; p = 0.03}, right bundle branch block [OR 1.78 (95% CI 1.09-2.89); p = 0.02], and history of trypanocidal treatment [OR 0.13 (95% CI 0.04-0.38); p = 0.0002]. Among patients with a history of trypanocidal treatment (n = 39), only four (10%) patients had a positive T. cruzi PCR. MAIN CONCLUSIONS: Among several studied parameters, only diabetes mellitus, right bundle branch block, and history of trypanocidal treatment showed an independent association with positive T. cruzi PCR. History of trypanocidal treatment was a strong protective factor against a positive T. cruzi PCR.

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.].

Biomarkers and Echocardiographic Predictors of Cardiovascular Outcome in Patients With Chronic Chagas Disease.

Background Chagas disease (CD) presents an ominous prognosis. The predictive value of biomarkers and new echocardiogram parameters in adjusted models have not been well studied. Methods and Results There were 361 patients with chronic CD (57.6% men, 61±11 years of age, clinical forms: indeterminate 27.1%, cardiac 56.6%, digestive 3.6%, cardiodigestive 12.7%) included in this single-center, observational, prospective longitudinal study. Echocardiographic evaluation included strain analyses of left atrial, left ventricular (LV), and right ventricular and 3-dimensional analyses of left atrial and LV volumes. Biomarkers included cardiac troponin I, brain natriuretic peptide, transforming growth factor ß1, tumor necrosis factor, matrix metalloproteinases, and Trypanosoma cruzi polymerase chain reaction. The studied end point was a composite of CD-related mortality, heart transplant, hospital admission due to worsening heart failure, or new cardiac device insertion. Event-free survival was analyzed by multivariable regression analyses adjusted for competing risks. P values <0.05 were considered significant. The composite event occurred in 79 patients after 4.9±2.0 years follow-up. LV end-diastolic volume (hazard ratio [HR], 1.01 [95% CI, 1.00-1.02]; P=0.02), peak negative global atrial strain (HR, 1.08 [95% CI, 1.00-1.17]; P=0.04), LV global circumferential strain (HR, 1.12 [95% CI, 1.04-1.21]; P=0.003), LV torsion (HR, 0.55 [95% CI, 0.35-0.81]; P=0.003), brain natriuretic peptide (HR, 2.03 [95% CI, 1.23-3.34]; P=0.005), and positive T cruzi polymerase chain reaction (HR, 1.80 [95% CI, 1.12-2.91]; P=0.01) were end point predictors independent from age, sex, 2-dimensional echocardiographic indexes, hypertension, previous cardiac device, and CD cardiac form. Conclusions Two-dimensional strain- and 3-dimensional-derived parameters, brain natriuretic peptide, and positive T cruzi polymerase chain reaction can be useful for prediction of CD cardiovascular events.

Validation of the NAT Chagas IVD Kit for the Detection and Quantification of Trypanosoma cruzi in Blood Samples of Patients with Chagas Disease.

In the absence of validated biomarkers to control the cure of Chagas disease, PCR-based diagnosis is being used as the main tool for an early indication of therapeutic failure. However, since it is considered a technique of complex reproducibility, mainly due to difficulties in establishing accurate controls to guarantee the quality of the reaction, the use of PCR for Chagas disease diagnosis is restricted to specialized centers. In an effort to disseminate the molecular diagnosis of Chagas disease and its applications, new diagnostic kits based on qPCR have been made available in the market in recent years. Here, we show the results of the validation of the NAT Chagas kit (Nucleic Acid Test for Chagas Disease) for the detection and quantification of T. cruzi in blood samples of patients suspected of Chagas disease infection. The kit, composed of a TaqMan duplex reaction targeting the T. cruzi satellite nuclear DNA and an exogenous internal amplification control, presented a reportable range from 104 to 0.5 parasite equivalents/mL and a limit of detection (LOD) of 0.16 parasite equivalents/mL of blood. In addition, the NAT Chagas kit detected T. cruzi belonging to all six discrete typing units (DTUs-TcI to TcVI), similarly to the in-house real-time PCR performed with commercial reagents, which has been selected as the best performance assay in the international consensus for the validation of qPCR for Chagas disease. In the clinical validation presented here, the kit showed 100% sensitivity and 100% specificity when compared to the consensus in-house real-time PCR assay. Thus, the NAT Chagas kit, which is produced entirely in Brazil under the international standards of good manufacturing practices (GMP), appears as an excellent alternative to enable the molecular diagnosis of Chagas disease in public and private diagnostic centers, as well as to facilitate the monitoring of patients under etiological treatment participating in clinical trials.

Correction: Clinical profile and mortality in patients with T. cruzi/HIV co-infection from the multicenter data base of the "Network for healthcare and study of Trypanosoma cruzi/HIV co-infection and other immunosuppression conditions".

[This corrects the article DOI: 10.1371/journal.pntd.0009809.].

Comparative effects of a cardiovascular rehabilitation program on functional capacity in patients with chronic chagasic cardiomyopathy with or without heart failure.

PURPOSE: The aim of the present study was to evaluate the effects of cardiovascular rehabilitation (CR) on functional capacity of patients with chronic chagasic cardiomyopathy (CCC) and to compare the responses between CCC patients without and with heart failure (HF). MATERIALS AND METHODS: A longitudinal observational retrospective study was carried out including 36 patients with CCC without HF (stage B2 [n = 7]) and with HF (stage C [n = 29]), who participated in a CR program. Functional capacity was assessed by a maximal progressive cardiopulmonary exercise test performed on a treadmill. The longitudinal effects of the CR on functional capacity were determined by linear mixed models that included an interaction term to evaluate the differential responses between patients without and with HF. RESULTS: Significant improvements in peak oxygen consumption, resting heart rate and blood pressure, and maximum pulmonary ventilation were observed for the overall study sample, with no apparent differential effects according to the presence of HF. CONCLUSIONS: CR significantly improved functional capacity of patients with CCC. The responses to CR appear to be similar among patients without and with HF, reinforcing the need for its inclusion as a standard treatment strategy of CCC.Implications for rehabilitationExercise-based cardiovascular rehabilitation (CR) is a safe strategy that improves functional capacity, cardiac function, and quality of life in patients with several cardiovascular diseases, and recent studies also suggested a potential beneficial effect of CR in chronic chagasic cardiomyopathy (CCC).In this observational study, CR seems to equally improve exercise capacity, resting heart rate, resting blood pressure, and maximum pulmonary ventilation in patients with CCC without (stage B2) and with heart failure (stage C).Cardiovascular rehabilitation should be included as a standard treatment strategy for patients with CCC, regardless the severity of cardiomyopathy.