Introduction
Chagas disease is an infection caused by a blood parasite, Trypanosoma cruzi. The disease has two phases: acute and chronic. The chronic phase is distinguished by two well-defined forms of disease: indeterminate (asymptomatic, latent or preclinical) and determinate (clinical), which is subdivided into cardiac, digestive and cardiodigestive forms. The chronic cardiac form, which manifests as dilated cardiomyopathy, heart failure, sudden death and/or systemic or pulmonary thromboembolism, is the leading cause of morbidity in this population. Factors contributing to progression from the acute or indeterminate form to the clinical form of this disease are not clear. Early studies have estimated the latency period (i.e. duration of time for indeterminate form to progress to the determinate form) to last approximately 10-30 years. However, new findings may indicate that this latency is shorter and depends on the presence of clinical factors. The revision of this latency period would have clear implications, including accelerated prevention and treatment strategies for patients with chronic infection who are at an increased risk of progression to cardiac manifestations of the disease.
Chagas disease carries a high burden of morbidity and mortality in Latin America and among those emigrating from endemic areas to countries in which Chagas disease is non-endemic. Millions of people are at risk of contracting the disease, and approximately 30% of those with chronic infection will develop cardiomyopathy.1 The Pan American Health Organization estimates that 8 million people are infected in this part of the world.2 In the United States, which has high rates of Hispanic immigration, about 300,000 people are infected.3,4 Chagas disease transmission occurs primarily through contact with a triatomine insect, also known as the "kissing bug", which carries the parasite, T. cruzi.5 Transmission also occurs orally through food contamination with vector's feces, vertically (perinatal), organ donation or blood transfusion.6 Cardiac changes can vary from absent symptoms and normal electrocardiography (ECG) results (also known as the indeterminate form) to severe terminal congestive heart failure and marked arrhythmias (cardiac form).
Latency in Chagas disease is defined as a period of asymptomatic or subclinical infection. Most commonly, researchers have called this stage the indeterminate form. The criteria for the indeterminate form are two separate serologic positive test results for Chagas disease and the absence of structural cardiomyopathy with no heart failure symptoms and normal ECG results.7 A longitudinal study in Brazil conducted from 1974 to1984 found a progression rate of 32% and 38% from the indeterminate form to Chagas cardiomyopathy in six and 10-year periods, respectively.8 A more recent cohort study in Argentina conducted in 2000 found a rapid progression rate of 21% in less than a year by polymerase chain reaction (PCR) detection.5 Oral disease transmission has been linked to faster disease progression.9
The process of cardiac injury is multifactorial. A few factors have been identified to possibly play a role in latency duration and progression of cardiomyopathy. The type of Trypanosoma genotype has been linked to varying cardiac outcomes.10 Likewise, persistent vector exposure, detection of parasitemia by PCR, oral exposure with higher inoculums and recurrent infections have been linked to cardiomyopathy severity.11-15 These findings indicate a possible persistent antigen or parasite-mediated cardiac injury. Removal of disease exposure through vector control may prove to be an effective measure in delaying cardiomyopathy progression. However, in many rural areas, fumigation campaigns, although very effective,16 are scarce or uncompleted. The low-level of education and access to care also impairs vector recognition and prioritization of its elimination.
In addition to vector control, anti-parasitic therapy has been shown to delay the progression of cardiac changes,17 although the benefit of anti-parasitic therapy has been questioned in a recent randomized trial.18 It is unclear whether the uncontrolled vector exposure could account for unseen results of the trial. Researchers estimated a negative conversion PCR rate of approximately 60% at one to two years after anti-trypanosomal treatment in areas of endemicity,18 in contrast to 93% at one-year in non-endemic countries.19 The rate of negative PCR conversion is higher after removal of the exposure. These findings highlight the need for strict vector control, in addition to anti-trypanosomal treatment, which could lead to better long-term cardiac outcomes.
Anti-parasitic treatments convey a better response rate during acute infection and a lower rate during chronic infections. The observed progression over time recorded via either persistent parasitemia detection20 or development of cardiac damage18 also shows decreased effectiveness of benznidazole therapy on chronic tissue intracellular amastigotes forms.21,22 The late detection of parasitemia may be attributed not only to reinfections, but also to the release of trypomastigotes from tissue amastigotes. Since cardiomyopathy only develops in approximately 30% of chronically infected patients, a genetic host mechanism has been postulated to drive cardiac outcomes in this setting. Unfortunately, different genetic markers have been inconclusive, and the underlying genetic mechanism of potential protection remains elusive.1 Thus, among others, at least four factors seem to be determinants on chronic infections outcomes and development of cardiomyopathy: i) trypanosome genotype, ii) sustained vector exposure, iii) anti-trypanosomal therapy and iv) host genetics.23 This is illustrated in Figure 1. Based on previous data, persistent vector exposure and host genetics may play a definitive role. However, understanding of the duration and the factors determining the latency period is limited prior to the development of Chagas cardiomyopathy.
A preliminary search of databases (i.e. MEDLINE and PROSPERO) has been undertaken, and no existing reviews on the topic were identified. This systematic review protocol aims to examine the literature on duration and factors affecting the latency period in chronic Chagas disease. More specifically, the objectives of the systematic review are to explore the duration of the latency period among asymptomatic people with chronic Chagas disease and also to expore the potential clinical determinants (etiology) of this latency period.
Review questions
What is the latency period of asymptomatic Chagas disease between infection acquisition and development of chronic cardiac manifestations?
A secondary review question is: What potential clinical factors determine this latency period?
Inclusion criteria
Participants
The review will consider studies that explore the rate of progression among asymptomatic people with chronic Chagas disease. Studies that include individuals who have been diagnosed with the indeterminate form of Chagas disease will be considered for inclusion. Indeterminate Chagas disease must be confirmed through positive serologic testing for Chagas disease and the absence of structural cardiomyopathy with no heart failure symptoms and normal ECG.7 All ages, sexes and ethnicities will be included. Studies also must include a longitudinal observation of participants with the acute acquisition of the infection or already established indeterminate (i.e. asymptomatic) form of the disease until the development of a primary or secondary outcome (i.e. cardiomyopathy manifestations).
Exposures
This review will evaluate the duration and determinants of Chagas disease latency among the selected studies. Periods and rate of progression (reported in years) from the acute infection or indeterminate form of the disease to the chronic cardiac clinical manifestations will be reviewed. Potential clinical factors influencing the Chagas latency period or rate of disease progression will also be extrapolated from the studies, such as human immunodeficiency virus infection, re-infection, anti-parasitical treatment, oral transmission, sex, various forms of immunosuppression, age, comorbidities, T. cruzi strain, host single-nucleotide polymorphisms and various forms of cardiomyopathy.
Outcomes
This review will include the following outcome measures:
Primary outcomes:
i. Development of cardiac or heart failure symptoms including shortness of breath, dyspnea on exertion, lower extremity edema, paroxysmal nocturnal dyspnea and orthopnea.
ii. Development of structural cardiomyopathy or cardiac arrhythmias as evidenced by abnormal echocardiogram and/or abnormal ECG.
iii. Presence of complications from advanced cardiomyopathy including mortality resulting from advanced heart failure, sudden death, pulmonary embolism or stroke.
Secondary outcomes (other surrogates for progression to chronic disease):
i. Hospitalization rates in number per year and length-of-stay duration in days due to congestive heart failure from Chagas cardiomyopathy.
ii. Heart transplant reception status.
iii. Need for anti-arrhythmogenic medications, ablation therapy or placement of implantable cardiac defibrillator or pacemaker.
Type of studies
This review will consider longitudinal studies, prospective and retrospective cohort studies, randomized and non-randomized clinical trials, case-control studies and time-series studies. Case reports, case series and descriptive cross-sectional studies will also be included depending on the outcome's measurements.
Methods
This review will use the JBI methodology for conducting reviews.24,25
Search strategy
A three-phase search strategy will be utilized. The search strategy will aim to find both published and unpublished studies. The search strategy will include a combination of controlled vocabulary terms (specific to each database) and keyword terms. Concepts including Chagas disease, latency duration and determinants of the Chagas latency period will be included in the search. An initial limited search of MEDLINE has been undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. This will inform the development of a search strategy which will be tailored for each information source. Appendix I lists a full search strategy for MEDLINE. The following electronic databases will be searched: MEDLINE (via Ovid), Embase (via Elsevier), Cochrane Library (via Wiley, including Cochrane Central Register of Controlled Trials), Web of Science Core Collection (via Thomson Reuters, including Science Citation Index Expanded and Social Sciences Citation Index), and LILACS (Latin American & Caribbean Health Sciences Literature). The reference list of all studies selected for critical appraisal will be screened for additional studies. There will be no restrictions or limits on the date of publication or age of subjects. The language will be restricted to English, Spanish or Portuguese. Filters will be used to limit results to human studies.
Study selection
After the search, all identified studies will be uploaded to EndNote VX8 (Clarivate Analytics, PA, USA) and Covidence (Covidence, Melbourne, Australia). Duplicated studies will be removed. In Covidence, "highlights" will be created for both inclusion and exclusion keywords.
Through Covidence, a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram will be generated with the number of results found, number excluded during title/abstract screening, and number excluded during full-text assessments, along with reasons for exclusion.26 The final number of included/excluded studies will be reported in the final systematic review.
Assessment of methodological quality
Two reviewers with field expertise in Chagas disease will independently revise the selected studies for methodological quality performing quality critical standard measures from JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; Joanna Briggs Institute, Adelaide, Australia). A third reviewer will be asked to reconcile disagreements between the two reviewers. Critical appraisals will be performed utilizing the JBI Reviewer's Manual checklists for cohorts, case-control, case-series, case reports and cross-sectional studies.25 All studies with greater than 60% of "yes" answers to the critical appraisal questions will be subject to data extraction and synthesis.
Data extraction
Data will be extracted using extraction tools from JBI SUMARI. Extracted data will include: type of study, country of origin, number of participants, length of follow-up, population demographic description, study methods, interventions (diagnostic and therapeutic), and outcomes of significance as delineated above (e.g. death, heart failure symptoms, presence of abnormal ECG or echocardiogram, development of sudden death, pulmonary embolism or stroke). Two independent persons will be involved in the data extraction. Any disagreements will be resolved through a discussion or with a third reviewer. All extractions forms and tools will be pilot tested.
Data synthesis
Studies will, where possible, be pooled in a statistical meta-analysis using JBI SUMARI. All data will be presented and synthesized through tables, summaries, figures and charts. Quantitative data, latency period duration indicated years, will be pooled with statistical meta-analysis. Heterogeneity will be assessed using the I-squared test. A fixed or random effect meta-analysis method, depending on studies' heterogeneity and sample size, will also be conducted. Odds ratios and mean differences will be calculated depending on the outcome variable. The meta-analysis forest plots for all performed meta-analyses will be presented, as appropriate. If used, results of a funnel plot for publication bias or risk of publication bias will be presented. If meta-analysis is not performed, a narrative summary and tabular results will be included.
Assessing certainty in the findings
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for grading the quality of evidence will be followed. A Summary of Findings (SoF) will be created using GRADEpro (McMaster University, ON, Canada). All primary outcomes will be included in the SoF. The SoF will present the following information, where appropriate: absolute risks for the case and control, estimates of relative risk, and a ranking of the quality of the evidence based on the risk of bias, directness, heterogeneity, precision and risk of publication bias of the review results. Summary results from meta-analyses will be reported as summary point estimates and interval estimates
Acknowledgment
The views expressed in this article are those of the authors and do not necessarily represent the views of the University of Colorado Denver, NRI General Hospital, Hospital Universitario de Sincelejo, Anis Rassi Hospital, or Hospital Infantil de Mexico.
Appendix I: Search strategy for MEDLINE
MEDLINE (via Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) 1946 to October 10, 2018)
Search date: 22 October 2018
References