Risk Factors for Progression to Chronic Chagas Cardiomyopathy: A Systematic Review and Meta-Analysis

Melissa K Cutshaw; Michael Sciaudone; Natalie M Bowman

doi:10.4269/ajtmh.22-0630

. 2023 Feb 27;108(4):791–800. doi: 10.4269/ajtmh.22-0630

Risk Factors for Progression to Chronic Chagas Cardiomyopathy: A Systematic Review and Meta-Analysis

Melissa K Cutshaw ^1,^*, Michael Sciaudone ², Natalie M Bowman ³

PMCID: PMC10076993 PMID: 36848894

ABSTRACT.

Approximately one-third of people with chronic Trypanosoma cruzi infection develop Chagas cardiomyopathy, which carries a poor prognosis. Accurate prediction of which individuals will go on to develop Chagas cardiomyopathy remains elusive. We performed a systematic review of literature comparing characteristics of individuals with chronic Chagas disease with or without evidence of cardiomyopathy. Studies were not excluded on the basis of language or publication date. Our review yielded a total of 311 relevant publications. We further examined the subset of 170 studies with data regarding individual age, sex, or parasite load. A meta-analysis of 106 eligible studies indicated that male sex was associated with having Chagas cardiomyopathy (Hedge’s g: 1.56, 95% CI: 1.07–2.04), and a meta-analysis of 91 eligible studies indicated that older age was associated with having Chagas cardiomyopathy (Hedge’s g: 0.66, 95% CI: 0.41–0.91). A meta-analysis of four eligible studies did not find an association between parasite load and disease state. This study provides the first systematic review to assess whether age, sex, and parasite load are associated with Chagas cardiomyopathy. Our findings suggest that older and male patients with Chagas disease are more likely to have cardiomyopathy, although we are unable to identify causal relationships due to the high heterogeneity and predominantly retrospective study designs in the current literature. Prospective, multidecade studies are needed to better characterize the clinical course of Chagas disease and identify risk factors for progression to Chagas cardiomyopathy.

INTRODUCTION

Almost 6 million people worldwide are estimated to have Chagas disease, caused by the protozoan parasite Trypanosoma cruzi.¹ Considered a neglected tropical disease, Chagas disease is endemic to 21 countries in Latin America and is a major source of morbidity and mortality in this region.² Globally, Chagas disease is associated with an annual burden of more than 800,000 disability-adjusted life years and $600 million (USD) in healthcare costs.³ Converted into lost productivity, the annual burden of Chagas disease is estimated at $7.2 billion, higher than that of other costly diseases, such as cervical cancer ($4.7 billion) or cholera ($5.4 billion).

The natural history of chronic Chagas disease comprises two stages: the indeterminate stage, characterized by positive serology but no clinical signs or symptoms, and a symptomatic stage, characterized by well-defined clinical syndromes. Although the majority of individuals remain in the indeterminate stage throughout their lifetime, approximately 30% of individuals develop clinical disease, characterized by cardiac, gastrointestinal, or mixed sequelae.⁴ The most common and severe complication is chronic Chagas cardiomyopathy, which results in the majority of mortality and morbidity from Chagas disease.⁵ Among individuals with indeterminate Chagas disease, the annual risk of developing cardiomyopathy is approximately 1.9%.⁶ Often initially asymptomatic, patients with Chagas cardiomyopathy may develop dilated cardiomyopathy, congestive heart failure, arrhythmias, thromboembolism, or sudden death.⁷ Although antitrypanosomal therapy can be used to successfully treat acute or indeterminate Chagas disease, these medications do not provide a mortality benefit or slow disease progression once cardiomyopathy has developed.⁸

Currently, no methodology exists to predict which patients with indeterminate Chagas disease will develop cardiomyopathy. Antitrypanosomal therapy frequently causes moderate to severe adverse reactions, including dermatologic manifestations, gastrointestinal upset, and neuropathy. Therefore, better prediction of high-risk patients could improve targeted efforts to provide antitrypanosomal therapy to patients who would benefit the most and to reduce the morbidity and mortality of Chagas disease. In this systematic review, we aim to identify risk factors for progression from the indeterminate form of Chagas disease to Chagas cardiomyopathy.

METHODS

Search strategy.

Our review followed Preferred Reporting Items for Systematic review and Meta-analyses (PRISMA) guidelines and was not limited by publication date, country of origin, or language.⁹ Searches were performed for relevant literature in PubMed, LILACS, and Embase electronic databases (Supplemental Table 1). An electronic search of gray literature and clinicaltrials.gov was also performed to identify ongoing or unpublished studies. The last search was performed on March 20, 2020. There was not a registered protocol.

Study selection.

Studies from the aforementioned searches were compiled for further review in Covidence, which removed duplicate studies. Two reviewers independently screened studies by title and abstract and removed irrelevant studies; conflicts were resolved through discussion. Next, full-text articles were screened for inclusion using eligibility criteria determined a priori (Table 1). Studies of adults aged 18 and older with chronic T. cruzi infection were included. Acceptable exposures included a broad array of potential risk factors for progression to Chagas cardiomyopathy, including patient, parasite, and environmental characteristics. We included studies that compared these risk factors between chronically infected patients with Chagas cardiomyopathy to those with the indeterminate form. Individuals were considered to have the indeterminate form of Chagas disease if they had positive serology confirmed by at least two serologic assays using different methods, with no signs or symptoms of cardiomyopathy or gastrointestinal disease. Individuals with mixed disease (combined cardiac and digestive forms) were excluded from the cardiomyopathy group. Studies in which participants had received antitrypanosomal treatment were excluded to avoid confounding because treatment may mask associations between a risk factor and the development of cardiomyopathy. In addition, the association between antitrypanosomal treatment and disease progression has been reviewed elsewhere.¹⁰ We also excluded studies that only examined known sequelae of Chagas cardiomyopathy or direct measures of cardiac function (such as cardiac imaging or electrocardiogram [ECG] findings). We included empirical interventional or observational study designs including randomized controlled trials, cohort studies, case–control studies, or cross-sectional studies. Review articles, case reports, abstracts, posters, theses or dissertations, animal-only studies, letters, comments, and editorials were excluded. No studies were excluded based on language, date of publication, publication status, country of origin, or clinical setting.

Table 1.

Inclusion and exclusion criteria

PICOTSS	Inclusion criteria	Exclusion criteria
Population	Adults with Trypanosoma cruzi infection	Children under age 18
Exposure	Risk factors such as age, sex, or parasite load	Known sequelae of Chagas cardiomyopathy or direct measures of cardiac function (e.g., cardiac imaging or electrocardiogram findings); treatment with antitrypanosomal therapy; accuracy of diagnostic testing
Comparison	Patients in the indeterminate stage of disease	Nonchagasic heart disease; nonchagasic healthy controls; chagasic patients with gastrointestinal or mixed manifestations of Chagas disease
Outcomes	Presence of or progression to Chagas cardiomyopathy	Acute myocarditis after acute infection with T. cruzi
Timing	Diagnosis at any point as an adult after chronic infection with T. cruzi
Setting	Any country, medical setting, publication date, or language
Study type	Empirical interventional or observational study designs including randomized controlled trials, cohort studies, case–control studies, or cross-sectional studies	Reviews, case reports, abstracts, posters, theses/dissertations, animal-only studies, letters, comments, or editorials

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PICOTSS = patients, interventions, comparators, outcomes, timing, setting, and study design.

An initial survey of the included studies revealed a heterogeneous array of risk factors. We identified age, sex, and parasite load among the most frequently examined risk factors. These factors could also be more effectively compared between studies due to relatively consistent measurement. Studies that included any of these risk factors subsequently underwent data extraction and study assessment.

Data extraction.

Data extracted for each study included population; study design; definitions of Chagas cardiomyopathy and indeterminate disease categories; and age, sex, and parasite load stratified by clinical form, if applicable (Supplemental Table 2). Study data were independently extracted manually by two reviewers; conflicts were resolved through discussion.

Study assessment.

Risk of bias in individual studies was assessed using the Joanna Briggs Institute Checklist for Analytical Cross Sectional Studies (Supplemental Table 3). Studies were independently evaluated by two reviewers; conflicts were resolved through discussion.

Statistics.

Data analysis was performed in Stata 16 (StataCorp LLC, College Station, TX). Forest plots were generated using random-effects meta-analysis among studies with nonoverlapping data to examine potential risk factors for cardiomyopathy development, including age, sex, and parasite load. If means and standard deviations were not available, these were calculated from the medians and interquartile ranges using established methodology.¹¹ Hedge’s g was interpreted to signify a small (0.2 < g < 0.5), medium (0.5 ≤ g < 0.8), or high (g ≥ 0.8) effect size, respectively.

RESULTS

Search strategy.

The search identified a total of 7,917 publications (Figure 1). The publications underwent screening by title and abstract, and 7,377 were determined to be irrelevant. The remaining 540 were screened with full text review, and 229 met exclusion criteria. The final analysis included 311 publications; 170 publications were subsequently identified that included data on individual age (n = 162), sex (n = 133), and/or parasite load (n = 8), stratified by disease. Of these, six publications were available exclusively in Spanish¹²^–¹⁷ and one exclusively in Portuguese.¹⁸ For studies available in multiple languages, the English text was used.

Study characteristics and findings.

One hundred and seventy articles were identified that included information about patient age, sex, or parasite load (Supplemental Table 2). These articles were extracted for study population, study design, clinical form (indeterminate or cardiomyopathy) definitions, age by clinical form, and sex by clinical form.¹²^–¹⁸³ Patients described as having indeterminate or asymptomatic disease or those without suggestive ECG changes were considered to have indeterminate Chagas disease. Patients described as having cardiac symptoms or characteristic changes on ECG or echocardiogram were considered to have cardiomyopathy. Studies included participants in Argentina, Bolivia, Brazil, Chile, Colombia, Mexico, Spain, and Venezuela.

Risk of Chagas cardiomyopathy by age.

A total of 162 publications included age stratified by disease status. A meta-analysis was performed using 91 studies with sufficient, nonoverlapping data on patient age divided by disease stage (Supplemental Figure 1).¹²^,¹⁶^,²⁰^,²³^,²⁵^,²⁷^,²⁹^–³²^,³⁴^–³⁸^,⁴¹^,⁴⁴^–⁴⁷^,⁴⁹^,⁵⁰^,⁵²^–⁵⁴^,⁵⁷^,⁵⁸^,⁶⁰^,⁶²^,⁶⁴^–⁶⁸^,⁷⁰^–⁷⁵^,⁷⁷^–⁷⁹^,⁸¹^,⁹⁰^,⁹³^–⁹⁷^,⁹⁹^,¹⁰⁰^,¹⁰⁶^,¹⁰⁷^,¹⁰⁹^,¹¹⁰^,¹¹²^,¹¹³^,¹¹⁵^,¹¹⁷^,¹¹⁸^,¹²²^,¹²⁴^,¹²⁶^–¹²⁸^,¹³³^–¹³⁵^,¹³⁷^,¹³⁹^,¹⁴¹^,¹⁴³^,¹⁴⁵^,¹⁴⁷^–¹⁴⁹^,¹⁵¹^,¹⁵³^–¹⁵⁵^,¹⁵⁷^,¹⁵⁸^,¹⁶¹^,¹⁶⁵^,¹⁶⁸^–¹⁷⁰ In this analysis, older patient age was significantly associated with risk of Chagas cardiomyopathy, with an overall effect size (Hedge’s g) of 0.66 (95% CI: 0.41–0.91). Heterogeneity in this analysis was high (97%). A sensitivity analysis including 88 studies in which none of the patients had received antitrypanosomal therapy had similar results, with an overall effect size of 0.67 (95% CI: 0.41–0.93).¹²^,¹⁶^,²³^,²⁵^,²⁷^,³⁰^–³²^,³⁴^–³⁸^,⁴¹^,⁴⁴^–⁴⁷^,⁴⁹^,⁵⁰^,⁵²^–⁵⁴^,⁵⁷^,⁵⁸^,⁶⁰^,⁶²^,⁶⁴^–⁶⁸^,⁷⁰^–⁷⁵^,⁷⁷^–⁷⁹^,⁸¹^,⁹⁰^,⁹³^–⁹⁷^,⁹⁹^,¹⁰⁰^,¹⁰⁶^,¹⁰⁷^,¹⁰⁹^,¹¹⁰^,¹¹²^,¹¹³^,¹¹⁵^,¹¹⁷^,¹¹⁸^,¹²²^,¹²⁴^,¹²⁶^–¹²⁸^,¹³³^–¹³⁵^,¹³⁷^,¹³⁹^,¹⁴¹^,¹⁴³^,¹⁴⁵^,¹⁴⁷^–¹⁴⁹^,¹⁵¹^, ¹⁵³^,¹⁵⁵^,¹⁵⁷^,¹⁵⁸^,¹⁶¹^,¹⁶⁵^,¹⁶⁸^–¹⁷⁰

Risk of Chagas cardiomyopathy by sex.

A total of 133 publications included sex stratified by disease status. A meta-analysis was performed using 106 studies with sufficient, nonoverlapping data on patient sex divided by disease stage (Supplemental Figure 2).¹¹^,¹²^,¹⁶^,¹⁸^,¹⁹^,²¹^,²²^,²⁴^,²⁸^,³⁰^,³¹^,³⁴^–³⁷^,⁴⁰^–⁴⁷^,⁵³^, ⁵⁶^,⁵⁷^,⁶¹^–⁷¹^,⁷³^,⁷⁵^–⁸⁰^,⁸⁷^,⁸⁹^,⁹⁰^,⁹²^,⁹³^,⁹⁶^,⁹⁸^,⁹⁹^,¹⁰¹^–¹⁰⁶^,¹⁰⁸^,¹⁰⁹^,¹¹²^,¹¹³^,¹¹⁶^,¹¹⁷^, ¹²¹^–¹²⁸^,¹³⁰^–¹³⁶^,¹⁴⁰^–¹⁴⁴^,¹⁴⁶^,¹⁴⁸^–¹⁵⁰^,¹⁵²^–¹⁵⁸^,¹⁶⁰^,¹⁶⁴^–¹⁶⁹^,¹⁷³^,¹⁷⁵^,¹⁷⁷^,¹⁷⁹^, ¹⁸¹ In this analysis, male sex was significantly associated with risk of Chagas cardiomyopathy, with an overall effect size (Hedge’s g) of 1.56 (95% CI: 1.07–2.04). Heterogeneity in this analysis was high (99%). A sensitivity analysis including 103 studies in which none of the patients had received antitrypanosomal therapy had similar results, with an overall effect size of 1.57 (95% CI: 1.07–2.07).¹²^,¹³^,¹⁷^,¹⁹^,²²^,²³^,²⁵^,²⁹^,³¹^, ³²^,³⁵^–³⁸^,⁴¹^–⁴⁸^,⁵⁴^,⁵⁷^,⁵⁸^,⁶²^–⁷²^,⁷⁴^,⁷⁶^–⁸¹^,⁸⁸^,⁹⁰^,⁹¹^,⁹³^,⁹⁴^,⁹⁷^,⁹⁹^,¹⁰⁰^,¹⁰²^–¹⁰⁷^, ¹⁰⁹^,¹¹⁰^,¹¹³^,¹¹⁴^,¹¹⁷^,¹¹⁸^,¹²²^–¹²⁹^,¹³¹^–¹³⁷^,¹⁴¹^–¹⁴⁵^,¹⁴⁷^,¹⁴⁹^–¹⁵¹^,¹⁵³^,¹⁵⁴^, ¹⁵⁷^–¹⁵⁹^,¹⁶¹^,¹⁶⁵^–¹⁷⁰^,¹⁷⁴^,¹⁷⁶^,¹⁷⁸^,¹⁸⁰^,¹⁸¹

Risk of Chagas cardiomyopathy by parasite load.

Among the eight studies that compared parasite load between individuals with indeterminate disease and cardiomyopathy, seven found no significant difference (Figure 2).²⁴^–²⁶^,⁴¹^,⁷⁵^,¹¹⁵^,¹⁸⁹^,¹⁹⁰ One study found a higher parasite load among an established cohort of Chagas cardiomyopathy patients compared with seropositive blood donors without cardiomyopathy, although no significant difference was found between seropositive blood donors with and without cardiomyopathy.¹⁹⁰

Figure 2. — Forest plot of parasite load in patients with Chagas cardiomyopathy vs. indeterminate disease. CCC = Chagas cardiomyopathy.

A meta-analysis was performed using four studies with sufficient nonoverlapping data and comparable units.²⁵^,⁴¹^,⁷⁵^,¹⁸⁹ A significant association between parasite load and disease status was not identified, with an overall effect size (Hedge’s g) of 0.13 (95% CI: −0.07 to 0.32).

Risk of bias.

The risk of bias in the included publications ranged from moderate to high, as assessed by the Joanna Briggs Institute Checklist for Analytical Cross Sectional Studies (Supplemental Table 3). The most common limitation was lack of identification of confounding factors or lack of strategies to deal with confounding factors. In addition, many studies did not provide statistical analysis comparing age and sex between clinical groups. We also noted that several studies excluded individuals of particular age ranges, such as those over age 65, which could bias results towards the null.

DISCUSSION

In this systematic review, we analyzed 311 publications that examined the role of age, sex, and parasite load in the progression from indeterminate Chagas disease to Chagas cardiomyopathy. Our findings suggest that male sex and older age are associated with Chagas cardiomyopathy.

Older age is one of the most well-established risk factors for progression to Chagas cardiomyopathy. This association is consistent with the clinical course of Chagas cardiomyopathy, which typically develops 10 to 30 years after acute infection.¹⁸³ Older individuals are also more likely to have other forms of cardiac disease, including coronary artery disease (CAD), which is likely underdiagnosed in resource-poor areas and difficult to differentiate from Chagas cardiomyopathy.

The association with male sex has been previously reported by individual studies, but our study is the first meta-analysis to assess the association between sex and Chagas cardiomyopathy. Notably, male individuals have a higher incidence of CAD, particularly at younger ages.¹⁸⁴ It is unknown whether preexisting cardiovascular disease synergistically increases the risk of developing Chagas cardiomyopathy. In addition, because CAD may be difficult to disentangle from Chagas cardiomyopathy in low-resource settings, this could lead to an overestimation of Chagas cardiomyopathy prevalence among males.

Our study did not identify a significant association between parasite load and clinical stage. Of the eight studies we identified that compared parasite load between individuals with indeterminate disease and cardiomyopathy, seven found no significant difference between groups. One large study found higher rates of polymerase chain reaction detection among an established cohort of Chagas cardiomyopathy individuals and seropositive blood donors diagnosed with Chagas cardiomyopathy compared with seropositive blood donors without cardiomyopathy. However, when the separate Chagas cardiomyopathy cohort was excluded, no significant difference was found in parasite load between individuals with and without cardiomyopathy. Our analysis was limited to a small number of studies that did not examine parasite load before evaluation of cardiac function; thus, we are unable to assess any causal effects between parasite load in early disease and development of cardiomyopathy. Additionally, peripheral parasitemia may not reflect parasite accumulation in cardiac tissue. Animal studies have demonstrated that T. cruzi tropism is influenced by a wide array of factors, including both host and parasite genetics.¹⁸⁵ The pathogenesis of Chagas disease progression is a complex process thought to involve both parasite persistence and immunological mechanisms, which may not be mediated by parasite load.¹⁸⁶

Our study has several limitations. Importantly, the existing literature that met our inclusion criteria was composed of retrospective case–control and cross-sectional studies. In addition, studies used a wide variety of definitions for Chagas cardiomyopathy and frequently did not control for confounding factors, such as other cardiac morbidities. Given the retrospective study designs and high heterogeneity among the existing literature, we are unable to identify causal relationships in our analysis. Finally, our inclusion criteria only considered studies that directly compared characteristics between individuals with cardiomyopathy and indeterminate disease. Additional literature exists that compares individuals with different stages of cardiomyopathy, compares individuals with Chagas cardiomyopathy to those with different types of cardiomyopathy, or include animal studies. A comprehensive understanding of risk factors for Chagas cardiomyopathy should consider this supportive evidence.

It is also worth noting that with the exception of one study in Mexico, almost all participants were from South America, predominantly in the Southern Cone and Bolivia. Given the geographic variation of T. cruzi genetic groups (discrete typing units [DTUs]), this potentially limits whether our results are applicable to Chagas infections in Central and North America.¹⁸⁷^,¹⁸⁸ Past literature showed mixed results of associations between DTUs and clinical forms, including cardiomyopathy.¹⁸⁸^,¹⁸⁹ The role of DTUs in clinical form, particularly in Central and North America where T. cruzi genetics and pathogenesis are less well studied, deserves future studies.

This study provided the first systematic review to assess whether age, sex, and parasite load are associated with Chagas cardiomyopathy. Our findings suggest that older and male patients with Chagas disease are more likely to have cardiomyopathy, but we cannot determine causal relationships because of the retrospective study designs and high heterogeneity in the current literature. Chagas cardiomyopathy typically develops 10 to 30 years after initial infection, and therefore prospective multidecade studies are needed to better evaluate risk factors for disease progression. In addition, given the limited benefits of antitrypanosomal therapy in patients with Chagas disease after cardiomyopathy has developed, preventive efforts are essential to reduce the morbidity and mortality associated with Chagas cardiomyopathy.

Supplemental files

Supplemental materials

tpmd220630.SD1.pdf^{(1.5MB, pdf)}

ACKNOWLEDGMENTS

We thank Sarah Towner Wright and Dr. Daniel Jonas for their assistance in the development of this systematic review strategy.

Note: Supplemental Figures 1 and 2, and Tables 1–3 appear at www.ajtmh.org.

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Risk Factors for Progression to Chronic Chagas Cardiomyopathy: A Systematic Review and Meta-Analysis

Melissa K Cutshaw

Michael Sciaudone

Natalie M Bowman

ABSTRACT.

INTRODUCTION

METHODS

Search strategy.

Study selection.

Table 1.

Data extraction.

Study assessment.

Statistics.

RESULTS

Search strategy.

Figure 1.

Study characteristics and findings.

Risk of Chagas cardiomyopathy by age.

Risk of Chagas cardiomyopathy by sex.

Risk of Chagas cardiomyopathy by parasite load.

Figure 2.

Risk of bias.

DISCUSSION

Supplemental files

ACKNOWLEDGMENTS

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Risk Factors for Progression to Chronic Chagas Cardiomyopathy: A Systematic Review and Meta-Analysis

Melissa K Cutshaw

Michael Sciaudone

Natalie M Bowman

ABSTRACT.

INTRODUCTION

METHODS

Search strategy.

Study selection.

Table 1.

Data extraction.

Study assessment.

Statistics.

RESULTS

Search strategy.

Figure 1.

Study characteristics and findings.

Risk of Chagas cardiomyopathy by age.

Risk of Chagas cardiomyopathy by sex.

Risk of Chagas cardiomyopathy by parasite load.

Figure 2.

Risk of bias.

DISCUSSION

Supplemental files

ACKNOWLEDGMENTS

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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