Electrocardiographic abnormalities in Chagas disease in the general population: A systematic review and meta-analysis
[['Chagas disease ( CD ) , is caused by the protozoan Trypanosoma cruzi[1] .', 'It affects individuals from more than 21 countries , being a major public health concern in Latin Americas and a potentially serious emerging threat to a number of non-endemic countries[2] .', 'In Latin American countries , there are currently 8-10 million people having CD , with an additional 300 , 000 individuals in the United States and 45 , 000-67 , 000 in Europe[3–6] .', 'Infection with T . cruzi has two phases: acute and chronic , separated by an indeterminate period , in which the patient is relatively asymptomatic[7 , 8] .', 'Chronically infected patients ultimately develop cardiomyopathy , which is the most important and severe manifestation of CD , and is characterized by left ventricular systolic dysfunction , wall motion abnormalities , brady and tachyarrhythmia , heart failure and sudden cardiac death[9–18] .', 'CD alterations are classified in four stages A , B , C , and D . Stage A corresponds to asymptomatic patients with normal ECG , whereas presence of electrocardiographic abnormalities implies progression towards stage B and deterioration of systolic function is observed in stages C/D , associated with heart failure symptoms .', 'Of note , sudden cardiac death may occur at any moment , including early phases[10 , 16] .', 'The association between CD and cardiac abnormalities ( stages B or more ) is widely reported , however , the information is challenged by the diverse design , sample size and quality of the studies[19–24] .', 'This information is largely based on outdated individual studies , and reports vary substantially among the population based studies making the scientific interpretation challenging[8 , 20 , 25–28] .', 'Furthermore , it is known that the prevalence of different types of ECG abnormalities such as intraventricular conduction abnormalities , atrioventricular block , and arrhythmias , is higher in subjects with CD as compared to non-CD subjects , calling for its update and synthesis , which would be very useful and relevant for physicians in non-endemic countries where health care implications of CD are real and neglected[29] .', 'Given the spread of CD , a need exists for an adequate , comprehensive assessment of CD in association with ECG abnormalities[6 , 29 , 30] .', 'We conducted a systematic review and meta-analysis to', '( i ) determine the overall prevalence of ECG abnormalities in seropositive and seronegative CD individuals in the general population;', '( ii ) quantify the prevalence of subtypes of ECG abnormalities in this population; and', '( iii ) characterize these estimates by age , sex and region of origin , and', '( iv ) evaluate the discriminatory capacity of ECG abnormalities , both general and specific to classify patients as either CD or non-CD .'], ['This review was conducted in accordance with MOOSE guideline[31] and , we followed the protocol strictly without deviation from it .', 'An extensive literature search of articles published up to March 2017 was conducted with the assistance of a medical librarian in six electronic databases ( EMBASE , Ovid Medline , Web of Science , Cochrane Central , Google Scholar and Lilacs ) without any language restriction .', 'Search combined terms related to CD ( Chagas Disease , Trypanosoma cruzi ) , with terms related to seroepidemiology ( Seroepidemiologic Studies , Seroprevalence , Seroepidemiology ) ( S1 Appendix ) .', 'Reference lists of selected studies and reviews identified on the topic were searched to identify additional publications .', 'Studies were eligible if they:', '( i ) selected cases and controls from the general population ( surveys and blood donors ) ;', '( ii ) were cross-sectional , case-control and cohort studies;', '( iii ) reported CD status based on any techniques for the detection of antibodies; and', '( iv ) reported the prevalence of ECG abnormalities in CD participants and non-CD participants , based on electrocardiographic diagnosis .', 'To avoid overestimation of the effect estimates , we did not include studies using cases and controls from a clinical setting .', 'Two independent reviewers screened the titles and abstracts of all initially identified studies according to the selection criteria .', 'Full texts were retrieved from studies that fulfilled all selection criteria .', 'Any disagreements were resolved through consensus or consultation with a third independent reviewer .', 'The data collection form included questions on qualitative aspects of the studies ( such as author , date of publication , country , design , period , setting , area and sample size ) , participant characteristics ( such as age , sex and serological test of CD ) and information on the reported exposure/outcome ( such as measure definition of ECG abnormalities , number of patients seropositive/seronegative CD , number of patients with general and specific ECG abnormalities and confounders adjustment ) .', 'For cohort studies , only the information from the baseline assessment was extracted .', 'Study quality was assessed by two independent reviewers based on the nine-star Newcastle-Ottawa Scale ( NOS ) using three predefined domains , namely: selection of participants ( population representativeness ) , comparability ( adjustment for confounders ) and ascertainment of outcomes of interests[32] .', 'The NOS assigns a maximum of four or five points for selection , one or two points for comparability and three points for outcome , depending on study design ( cross-sectional or cohort ) .', 'We used the NOS scale adapted for cross-sectional studies and the NOS for case-control studies while for cohort studies we used the NOS for a cross-sectional design ( S2 Appendix ) .', 'Studies that received a score of nine to seven stars were judged to be at low risk of bias; studies that scored five or six stars were considered at medium risk , and those that scored four or less were considered at high risk of bias .', 'Narrative synthesis and construction of descriptive summary tables were performed for the studies included .', 'For this meta-analysis , we used odds ratios ( ORs ) and 95% confidence intervals ( CIs ) , to assess the association between presence of CD , and overall and specific ECG abnormalities .', 'Also , we calculated the pooled prevalence ( P ) of ECG abnormalities for CD and non-CD participants .', 'The inverse variance weighted method was used to combine summary measures using random-effects models to minimize the effect of between-study heterogeneity[33] .', 'Heterogeneity was assessed using the Cochrane χ2 statistic and the I2 statistic and was categorized as low ( I2 ≤25% ) , moderate ( I2 >25% and <75% ) , or high ( I2 ≥75% ) [34] .', 'Sensitivity analyses were performed to assess the influence of study-level characteristics including publication year , geographical location ( according to the number of study in each country and by the prevalence of Trypanosoma cruzi genotype ) , design , area , number and age of participants , sex , definition of ECG abnormalities , test for CD diagnoses , level of adjustment and risk of bias , which were pre-specified as characteristics for assessment of heterogeneity and were evaluated using stratified analysis and random-effects meta-regression[35] .', 'Publication bias was evaluated through funnel plots and Egger’s regression symmetry tests[36] .', 'All tests were 2-tailed; p-value ≤0 . 05 was considered statistically significant .', 'Stata release 15 ( StataCorp ) was used for all analyses .', 'Additionally , we evaluated the discriminatory capacity of ECG abnormalities , both general and specific: sensitivity , specificity , positive predictive value ( PPV ) , negative predictive value ( NPV ) to classify patients as either CD or non-CD .'], ['The database searches identified 5 , 396 citations .', 'After screening the titles and abstracts , 252 articles were selected for detailed evaluation of full texts .', 'Of these , 49 articles met our inclusion criteria and were included in the review ( Fig 1 , S3 Appendix and S1–S3 Tables ) .', 'General characteristics of included studies are shows in S1–S3 Tables summarize the key characteristics of the included studies .', 'Of 49 included studies , 43 were cross-sectional and 6 cohort population-based studies and were published between 1964 and 2015 .', 'Studies were based on data from 10 Latin America countries .', 'The majority of studies was conducted in Brazil ( 38 . 7% ) , collected data between 2001 and 2010 ( 34 . 6% ) , and included participants from rural areas ( 44 . 9% ) .', 'In aggregate , 34 , 023 participants ( 12 , 276 CD and 21 , 747 non-CD ) were included in this review .', 'The age range of the participants was 0-97 years and 54 . 4% of participants were women ( reported by 38 articles ) .', 'The majority of studies ( 81 . 6% ) used two or more different diagnostic tests for T . cruzi infection .', 'In the meta-analysis of 34 , 023 participants and 12 , 276 CD participants , overall ECG abnormalities were significantly more prevalent in participants with CD ( Prevalence ( P ) =40 . 1%; 95%CIs=39 . 2-41 . 0 ) compared to those without CD ( P=24 . 1%; 95%CIs=23 . 5-24 . 7 ) ( OR=2 . 78; 95%CIs=2 . 37-3 . 26 ) ( Fig 2 and Table 1 ) .', 'Up to 30 studies ( range 3 to 30 ) , based on 3 , 451 ± 1 , 350 participants , examined prevalence of ventricular conduction defects in CD and non-CD participants ( Table 2 ) .', 'In the pooled analysis , prevalence of complete right bundle branch block ( RBBB ) ( OR=4 . 60; 95%CIs=2 . 97-7 . 11 ) , left anterior fascicular block ( LAFB ) ( OR=1 . 60; 95%CIs=1 . 21-2 . 13 ) and , the combination of complete RBBB and LAFB ( OR=3 . 34 , 95%CIs=1 . 76-6 . 35 ) was higher in CD participants compared to non-CD participants ( Fig 3 ) , while no difference in prevalence of incomplete RBBB ( OR=0 . 85; 95%CIs=0 . 63-1 . 16 ) , incomplete left bundle branch block ( LBBB ) ( OR=0 . 63; 95%CIs=0 . 39-1 . 01 ) , complete LBBB ( OR=0 . 99; 95%CIs=0 . 62-1 . 58 ) and left posterior fascicular block ( LPFB ) ( OR=0 . 96 , 95%CIs=0 . 35-2 . 62 ) was found between CD and non-CD individuals ( Table 2 and S1–S7 Figs ) .', 'Prevalence of AV-B in CD and non-CD participants was examined by 21 studies ( range 5 to 21 ) , including 4 , 438 ± 1 , 847 participants .', 'Pooled prevalence first degree AV-B ( OR=1 . 71; 95%CIs=1 . 25-2 . 33 ) was higher in CD participants compared to non-CD ( Fig 3 ) , while no difference in prevalence of second-degree AV-B ( OR=1 . 15; 95%CIs=0 . 33-4 . 06 ) and third-degree AV-B ( OR=2 . 10; 95% CIs=0 . 60-7 . 34 ) was found between CD and non-CD participants ( Table 2 and S8–S10 Figs ) .', 'Twenty-five studies ( range 11 to 25 studies ) , based on 4 , 848 ± 1 , 591 participants , compared prevalence of arrhythmias between CD and non-CD participants .', 'Pooled prevalence of AF or flutter ( OR=2 . 11 , 95%CIs=1 . 40-3 . 19 ) and ventricular extrasystoles ( VE ) ( OR=1 . 62; 95%CIs=1 . 14-2 . 30 ) was higher in CD participants ( Table 2 , Fig 3 and S11–S14 Figs ) .', 'In a pooled analysis of 10 studies , comprising 5 , 575 individuals , no statistically significant difference in prevalence of other ECG abnormalities ( Low voltage QRS , OR=0 . 84; 95%CIs=0 . 47-1 . 50 ) was found between CD and non-CD ( Table 2 and S15 Fig ) .', 'Regarding of study quality and assessment bias , among the 49 included studies , 10 studies were judged to be at low risk of bias , 28 were at medium risk , and 11 studies were evaluated to be at high risk of bias ( Table 1 , S2 Appendix , S3 Table and S16 Fig ) .', 'In the sensitivity analysis , of 16 meta-analyses , while five showed no heterogeneity ( I2=0 , p>0 . 05 for the Cochrane χ2 statistic ) , four showed low ( I2=<25% ) , six moderate and one high between-study heterogeneity , four of which with an I2 estimate exceeding 50% ( overall ECG abnormalities , complete RBBB , LAFB and VE ) ( Fig 2 , Tables 1 and 2 and S4–S6 Tables ) .', 'No study characteristics could explain the heterogeneity observed in overall ECG abnormalities ( p-value of meta-regression ≥0 . 05 ) ( Table 1 and S17–S27 Figs ) .', 'Additionally , S28 Fig shows meta-analyses estimates of overall ECG abnormalities excluding single studies one by one , with no evidence of change in the pooled .', 'Similarly , the stratified analysis by sex and age , although showed higher magnitudes of the association in children and men , the effects were not significantly different between sex and age strata: higher OR was observed in children ( OR=3 . 88; 95%CIs=1 . 69-8 . 88; I2=63 . 9% ) compared with all ages or ≥10 years categories; however , when a small-sample study was omitted , the OR of children was similar to that of the other categories ( OR=2 . 83; 95%CIs=2 . 26-3 . 53; I2=0 . 0% ) without being statistically significant in the meta-regression analysis ( p-value of meta-regression=0 . 704 ) , and comparison of overall ECG abnormalities by sex , could be quantified only in a limited number of studies ( 12 . 2% ) ( Table 1 , S25 , S26 and S29 Figs ) .', 'For the studies on the association between CD , complete RBBB , LAFB and VE , the identified heterogeneity was largely explained by geographic location , area , number of participants , number of tests used for diagnoses of CD , level of adjustment and risk of bias ( S4–S6 Tables ) .', 'Considering a P value of 0 . 10 , rather than the conventional level of 0 . 05 , is sometimes used to determine statistical significance for heterogeneity , we investigated further the sources of heterogeneity across our meta-analyses using a p-value lower than 0 . 10 as statistical significant .', 'When setting the p-value threshold to 0 . 10 , the findings of meta-regression were similar as when setting the p-value threshold of 0 . 05 , except for the characteristics “location of the study” which on p-value of 0 . 10 , showed to contribute to heterogeneity of the meta-analysis for overall ECG abnormalities .', 'Under visual examination , funnel plots for studies assessing the general and specific prevalence of ECG abnormalities were symmetrical , providing evidence for no publication bias .', 'This was further supported by the results of Egger’s test , showing no evidence of publication bias , either graphically from the funnel plot , or quantitatively ( p≥0 . 05 for Egger’s test asymmetry ) ( S7 Table and S30 Fig ) .', 'Finally , Sensitivity , specificity , PPV and NPV of general ECG abnormalities were 40 . 09% , 75 . 89% , 48 . 42% and 69 . 18% , respectively .', 'PPV of specific ECG abnormalities for diagnosis of CD varied , ranging between 61 . 64% and 83 . 08% , with two ECG abnormalities showing values over 80%: complete RBBB ( 80 . 77%; 95%CIs=78 . 17-83 . 13 ) and the combination of complete RBBB and LAFB ( 83 . 08%; 95%CIs= 77 . 36-87 . 59 ) ( S8 Table ) .'], ['This systematic review and meta-analysis provides an update and synthesis in this field .', 'This research of observational studies indicates a significant excess in prevalence of ECG abnormalities ( 40 . 1% ) related to T . cruzi infection in the general population from Chagas endemic regions , being the most common ventricular ( RBBB and LAFB ) , and A-V B ( first-degree ) node conduction abnormalities as well as arrhythmias ( AF or flutter and VE ) .', 'Also , prevalence of ECG alterations in children was similar to that in adults and suggests earlier onset of cardiac disease .']]
['Introduction', 'Methods', 'Results', 'Discussion']
['Chagas disease ( CD ) is a major public health concern in Latin America and a potentially serious emerging threat in non-endemic countries .', 'Although the association between CD and cardiac abnormalities is widely reported , study design diversity , sample size and quality challenge the information , calling for its update and synthesis , which would be very useful and relevant for physicians in non-endemic countries where health care implications of CD are real and neglected .', 'We performed to systematically review and meta-analyze population-based studies that compared prevalence of overall and specific ECG abnormalities between CD and non-CD participants in the general population .', 'Six databases ( EMBASE , Ovid Medline , Web of Science , Cochrane Central , Google Scholar and Lilacs ) were searched systematically .', 'Observational studies were included .', 'Odds ratios ( OR ) were computed using random-effects model .', 'Forty-nine studies were selected , including 34 , 023 ( 12 , 276 CD and 21 , 747 non-CD ) .', 'Prevalence of overall ECG abnormalities was higher in participants with CD ( 40 . 1%; 95%CIs=39 . 2-41 . 0 ) compared to non-CD ( 24 . 1%; 95%CIs=23 . 5-24 . 7 ) ( OR=2 . 78; 95%CIs=2 . 37-3 . 26 ) .', 'Among specific ECG abnormalities , prevalence of complete right bundle branch block ( RBBB ) ( OR=4 . 60; 95%CIs=2 . 97-7 . 11 ) , left anterior fascicular block ( LAFB ) ( OR=1 . 60; 95%CIs=1 . 21-2 . 13 ) , combination of complete RBBB/LAFB ( OR=3 . 34; 95%CIs=1 . 76-6 . 35 ) , first-degree atrioventricular block ( A-V B ) ( OR=1 . 71; 95%CIs=1 . 25-2 . 33 ) , atrial fibrillation ( AF ) or flutter ( OR=2 . 11; 95%CIs=1 . 40-3 . 19 ) and ventricular extrasystoles ( VE ) ( OR=1 . 62; 95%CIs=1 . 14-2 . 30 ) was higher in CD compared to non-CD participants .', 'This systematic review and meta-analysis provides an update and synthesis in this field .', 'This research of observational studies indicates a significant excess in prevalence of ECG abnormalities ( 40 . 1% ) related to T . cruzi infection in the general population from Chagas endemic regions , being the most common ventricular ( RBBB and LAFB ) , and A-V B ( first-degree ) node conduction abnormalities as well as arrhythmias ( AF or flutter and VE ) .', 'Also , prevalence of ECG alterations in children was similar to that in adults and suggests earlier onset of cardiac disease .']
['Chagas disease ( CD ) is a major public health concern in Latin America and a potentially serious emerging threat in non-endemic countries .', 'Although the association between CD and cardiac abnormalities is widely reported , study design diversity , sample size and quality challenge the information , calling for its update and synthesis , which would be very useful and relevant for physicians in non-endemic countries where health care implications of CD are real and neglected .', 'We systematically reviewed and meta-analyzed population-based studies that compared prevalence of ECG abnormalities between Chagas disease ( CD ) and non-CD participants .', 'Forty-nine studies were selected , including 34 , 023 unique participants .', 'Our meta-analysis of observational studies indicates CD presented almost a threefold increase prevalence of ECG abnormalities than non-CD participants in the general population from Chagas endemic regions , being the most common ventricular ( RBBB and LAFB ) , and A-V B ( first-degree ) node conduction abnormalities as well as arrhythmias ( AF or flutter and VE ) .']
['medicine and health sciences', 'tropical diseases', 'database searching', 'parasitic diseases', 'parasitic protozoans', 'electrocardiography', 'mathematics', 'protozoans', 'statistics (mathematics)', 'bioassays and physiological analysis', 'neglected tropical diseases', 'research and analysis methods', 'cardiology', 'public and occupational health', 'arrhythmia', 'atrial fibrillation', 'mathematical and statistical techniques', 'protozoan infections', 'electrophysiological techniques', 'research assessment', 'trypanosoma cruzi', 'trypanosoma', 'chagas disease', 'eukaryota', 'cardiac electrophysiology', 'meta-analysis', 'systematic reviews', 'database and informatics methods', 'biology and life sciences', 'physical sciences', 'statistical methods', 'organisms']