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Background: Screening programmes using echocardiography offer opportunity for intervention through identification and treatment of early (latent) rheumatic heart disease (RHD). We aimed to compare two methods for classifying progression or regression of latent RHD: serial review method and blinded, side-by-side review., Methods: A four-member expert panel reviewed 799 enrolment (in 2018) and completion (in 2020) echocardiograms from the GOAL Trial of latent RHD in Uganda to make consensus determination of normal, borderline RHD or definite RHD. Serial interpretations (enrolment and completion echocardiograms read at two different time points, 2 years apart, not beside one another) were compared with blinded side-by-side comparisons (enrolment and completion echocardiograms displayed beside one another in random order on same screen) to determine outcomes according to prespecified definitions of disease progression (worsening), regression (improving) or no change. We calculated inter-rater agreement using Cohen's kappa., Results: There were 799 pairs of echocardiogram assessments included. A higher number, 54 vs 38 (6.8% vs 4.5%), were deemed as progression by serial interpretation compared with side-by-side comparison. There was good inter-rater agreement between the serial interpretation and side-by-side comparison methods (kappa 0.89). Disagreement was most often a result of the difference in classification between borderline RHD and mild definite RHD. Most discrepancies between interpretation methods (46 of 47, 98%) resulted from differences in valvular morphological evaluation, with valves judged to be morphologically similar between enrolment and final echocardiograms when compared side by side but classified differently on serial interpretation., Conclusions: There was good agreement between the methods of serial and side-by-side interpretation of echocardiograms for change over time, using the World Heart Federation criteria. Side-by-side interpretation has higher specificity for change, with fewer differences in the interpretation of valvular morphology, as compared with serial interpretation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Rheumatic heart disease affects more than 40.5 million people worldwide and results in 306,000 deaths annually. Echocardiographic screening detects rheumatic heart disease at an early, latent stage. Whether secondary antibiotic prophylaxis is effective in preventing progression of latent rheumatic heart disease is unknown., Methods: We conducted a randomized, controlled trial of secondary antibiotic prophylaxis in Ugandan children and adolescents 5 to 17 years of age with latent rheumatic heart disease. Participants were randomly assigned to receive either injections of penicillin G benzathine (also known as benzathine benzylpenicillin) every 4 weeks for 2 years or no prophylaxis. All the participants underwent echocardiography at baseline and at 2 years after randomization. Changes from baseline were adjudicated by a panel whose members were unaware of the trial-group assignments. The primary outcome was echocardiographic progression of latent rheumatic heart disease at 2 years., Results: Among 102,200 children and adolescents who had screening echocardiograms, 3327 were initially assessed as having latent rheumatic heart disease, and 926 of the 3327 subsequently received a definitive diagnosis on the basis of confirmatory echocardiography and were determined to be eligible for the trial. Consent or assent for participation was provided for 916 persons, and all underwent randomization; 818 participants were included in the modified intention-to-treat analysis, and 799 (97.7%) completed the trial. A total of 3 participants (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, as compared with 33 (8.2%) in the control group (risk difference, -7.5 percentage points; 95% confidence interval, -10.2 to -4.7; P<0.001). Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis)., Conclusions: Among children and adolescents 5 to 17 years of age with latent rheumatic heart disease, secondary antibiotic prophylaxis reduced the risk of disease progression at 2 years. Further research is needed before the implementation of population-level screening can be recommended. (Funded by the Thrasher Research Fund and others; GOAL ClinicalTrials.gov number, NCT03346525.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: In 2012, the World Heart Federation (WHF) published guidelines for the echocardiographic diagnosis of rheumatic heart disease (RHD). This study assesses individual reviewer performance and inter-rater agreement and reliability on the presence of any RHD, as well classification of RHD based on the 2012 WHF criteria., Methods: Four cardiologists individually reviewed echocardiograms in the context of a randomized clinical trial (ClinicalTrials.gov:NCT03346525) and participated in a blinded adjudication panel. Panel decision was the reference standard for diagnosis. Performance of individual reviewers to panel adjudication was compared through sensitivity and specificity analyses and inter-rater reliability was assessed between individual panelists using Fleiss free marginal multirater kappa., Results: Echocardiograms from 784 children had two independent reports and panel adjudication. The accuracy of independent reviewers for any RHD had high sensitivity (94%, 95% CI 93-95%) and moderate specificity (62%, 95% CI 53-70%). Sensitivity and specificity for definite RHD was 61.3 (95% CI, 55.3-67.1) and 93.1 (95% CI, 91.6-94.4), with 86.8 (84.7-88.7) and 65.8 (61.0-70.4) for borderline RHD. There was moderate inter-rater agreement (κ = 0.66) on the presence of any RHD while agreement for specific 2012 WHF classification was only fair (κ = 0.51)., Conclusions: The 2012 WHF guidelines are moderately reproducible when used by expert cardiologists. More cases of RHD were diagnosed by an consensus panel than by individual reviewers. A revision to the criteria is now warranted to further increase the reliability of the WHF criteria., Competing Interests: Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rheumatic heart disease (RHD) remains a high prevalence condition in low- and middle-income countries. Most individuals with RHD present late, missing the opportunity to benefit from secondary antibiotic prophylaxis. Echocardiographic screening can detect latent RHD, but the impact of secondary prophylaxis in screen-detected individuals is not known., Methods/design: This trial aims to determine if secondary prophylaxis with every-4-week injectable Benzathine penicillin G (BPG) improves outcomes for children diagnosed with latent RHD. This is a randomized controlled trial in consenting children, aged 5 to 17 years in Northern Uganda, confirmed to have borderline RHD or mild definite RHD on echocardiography, according to the 2012 World Heart Federation criteria. Qualifying children will be randomized to every-4-week injectable intramuscular BPG or no medical intervention and followed for a period of 2 years. Ongoing intervention adherence and retention in the trial will be supported through the establishment of peer support groups for participants in the intervention and control arms. A blinded echocardiography adjudication panel consisting of four independent experts will determine the echocardiographic classification at enrollment and trajectory through consensus review. The primary outcome is the proportion of children in the BPG-arm who demonstrate echocardiographic progression of latent RHD compared to those in the control arm. The secondary outcome is the proportion of children in the BPG-arm who demonstrate echocardiographic regression of latent RHD compared to those in the control arm. A sample size of 916 participants will provide 90% power to detect a 50% relative risk reduction assuming a 15% progression in the control group. The planned study duration is from 2018-2021., Discussion: Policy decisions on the role of echocardiographic screening for RHD have stalled because of the lack of evidence of the benefit of secondary prophylaxis. The results of our study will immediately inform the standard of care for children diagnosed with latent RHD and will shape, over 2-3 years, practical and scalable programs that could substantially decrease the burden of RHD in our lifetime., Trial Registration: ClinicalTrials.gov: NCT03346525. Date Registered: November 17, 2017., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Estimates of the prevalence of rheumatic heart disease (RHD) in many endemic countries are limited to samples of children attending schools, which generate an incomplete picture of disease burden in communities. The present study conducted household-based RHD screening in a representative community in Gulu district, Uganda., Methods: Members of households identified through a two-stage cluster-sampling approach between the ages of 5 years and 50 years were invited to undergo limited cardiac testing with a handheld echocardiogram to assess for the presence of RHD. Suspicious cases underwent confirmatory echocardiogram with a fully functional machine., Results: Of the 2453 community members screened, 2.45% (95% CI 1.87% to 3.14%) showed echocardiographic evidence of RHD with 1.26% (95% CI 0.860% to 1.79%) having definite RHD. The overall prevalence of RHD among participants <20 years was 2.52% (95% CI 1.78% to 3.45%), with a borderline prevalence of 1.97% (95% CI 1.33% to 2.82%) and a definite prevalence of 0.544% (95% CI 0.235% to 1.07%). Prevalence rates among youth increased with age and peaked in the age group of 16-20 years. The overall adult prevalence (>20 years) of RHD was 2.34% (95% CI 1.49% to 3.49%). The majority of definite cases were mild (81%) and marked by mitral regurgitation and associated morphological valve changes (71%)., Conclusion: Our data reveal a high prevalence of undiagnosed RHD within an endemic community and fill a critical gap in RHD epidemiology in African adults., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the impact of a peer-support group on knowledge, quality of life, and social support for children with rheumatic heart disease (RHD)., Methods: Children diagnosed with RHD and receiving 4-weekly injectable penicillin were invited to participate in a monthly support group for 6 months. Pre- and post-intervention assessments included a baseline RHD knowledge assessment, a measure of health related quality of life (HRQOL) (PedsQL TM 4.0), and a measure of social support (Hawthorne Friendship Scale). Groups incorporated elements of cooperative play and team building, RHD education, and emotional support., Results: 42 participants attended ≥3 groups and were included in the analyses. Attending support groups resulted in increased total HRQOL scores (60.3v 70.2, p<0.001), as well as the following HRQOL sub-scores (physical functioning 55.3v 68.6 (p<0.001), social functioning 64.2v 75.8 (p<0.001) and school functioning 59.2v 69.1 (p=0.001)). Significant increases in Friendship Scale scores (15.4v 19.7, p<0.001) and RHD Knowledge scores were observed (3.6v 6.4, p<0.001)., Conclusions: Peer-support groups may be effective at normalizing decreased HRQOL scores and increasing RHD disease knowledge and social support., Practical Implications: Peer-support groups implemented in conjunction with RHD screening can minimize the negative psychosocial effects associated with early RHD detection., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Screening echocardiography has emerged as a potentially powerful tool for early diagnosis of rheumatic heart disease (RHD). The utility of screening echocardiography hinges on the rate of RHD progression and the ability of penicillin prophylaxis to improve outcome. We report the longitudinal outcomes of a cohort of children with latent RHD and identify risk factors for unfavorable outcomes., Methods: This was a prospective natural history study conducted under the Ugandan RHD registry. Children with latent RHD and ≥1 year of follow-up were included. All echocardiograms were re-reviewed by experts (2012 World Heart Federation criteria) for inclusion and evidence of change. Bi- and multivariable logistic regression, Kaplan-Meier analysis, and Cox proportional hazards models, as well, were developed to search for risk factors for unfavorable outcome and compare progression-free survival between those treated and not treated with penicillin. Propensity and other matching methods with sensitivity analysis were implemented for the evaluation of the penicillin effect., Results: Blinded review confirmed 227 cases of latent RHD: 164 borderline and 63 definite (42 mild, 21 moderate/severe). Median age at diagnosis was 12 years and median follow-up was 2.3 years (interquartile range, 2.0-2.9). Penicillin prophylaxis was prescribed in 49.3% with overall adherence of 84.7%. Of children with moderate-to-severe definite RHD, 47.6% had echocardiographic progression (including 2 deaths), and 9.5% had echocardiographic regression. Children with mild definite and borderline RHD showed 26% and 9.8% echocardiographic progression and 45.2% and 46.3% echocardiographic improvement, respectively. Of those with mild definite RHD or borderline RHD, more advanced disease category, younger age, and morphological mitral valve features were risk factors for an unfavorable outcome., Conclusions: Latent RHD is a heterogeneous diagnosis with variable disease outcomes. Children with moderate to severe latent RHD have poor outcomes. Children with both borderline and mild definite RHD are at substantial risk of progression. Although long-term outcome remains unclear, the initial change in latent RHD may be evident during the first 1 to 2 years following diagnosis. Natural history data are inherently limited, and a randomized clinical trial is needed to definitively determine the impact of penicillin prophylaxis on the trajectory of latent RHD., (© 2017 American Heart Association, Inc.)

Background: Rheumatic heart disease (RHD) is a leading cause of premature death and disability in low-income countries; however, few receive optimal benzathine penicillin G (BPG) therapy to prevent disease progression. We aimed to comprehensively describe the treatment cascade for RHD in Uganda to identify appropriate targets for intervention., Methods and Results: Using data from the Uganda RHD Registry (n=1504), we identified the proportion of patients in the following care categories: (1) diagnosed and alive as of June 1, 2016; (2) retained in care; (3) appropriately prescribed BPG; and (4) optimally adherent to BPG (>80% of prescribed doses). We used logistic regression to investigate factors associated with retention and optimal adherence. Overall, median (interquartile range) age was 23 (15-38) years, 69% were women, and 82% had clinical RHD. Median follow-up time was 2.4 (0.9-4.0) years. Retention in care was the most significant barrier to achieving optimal BPG adherence with only 56.9% (95% confidence interval, 54.1%-59.7%) of living subjects having attended clinic in the prior 56 weeks. Among those retained in care, however, we observed high rates of BPG prescription (91.6%; 95% confidence interval, 89.1%-93.5%) and optimal adherence (91.4%; 95% confidence interval, 88.7-93.5). Younger age, latent disease status, and access to care at a regional center were the strongest independent predictors of retention and optimal adherence., Conclusions: Our study suggests that improving retention in care-possibly by decentralizing RHD services-would have the greatest impact on uptake of antibiotic prophylaxis among patients with RHD in Uganda., (© 2017 American Heart Association, Inc.)

Background: Echocardiographic screening for detection of latent RHD has shown potential as a strategy to decrease the burden of disease. However, further research is needed to determine optimal implementation strategies. RHD results from a complex interplay between environment and host susceptibility. Family members share both and relatives of children with latent RHD may represent a high-risk group. The objective of this study was to use echocardiographic family screening to determine the relative risk of RHD among first-degree relatives of children with latent RHD compared to the risk in first-degree relatives of healthy peers., Methodology/principal Findings: Previous school-based screening data were used to identify RHD positive children and RHD negative peers. All first-degree relatives ≥ 5 years were invited for echocardiography screening (2012 World Heart Federation Criteria). Sixty RHD positive cases (30 borderline/30 definite RHD) and 67 RHD negative cases were recruited. A total of 455/667 (68%) family members were screened. Definite RHD was more common in childhood siblings of RHD positive compared to RHD negative (p = 0.05). Children with any RHD were 4.5 times as likely to have a sibling with definite RHD, a risk that increased to 5.6 times when considering only cases with definite RHD. Mothers of RHD positive and RHD negative cases had an unexpectedly high rate of latent RHD (9.3%)., Conclusions/significance: Siblings of RHD positive cases with RHD are more likely to have definite RHD and the relative risk is highest if the index case has definite RHD. Future screening programs should consider implementation of sibling screening following detection of an RHD positive child. Larger screening studies of adults are needed, as data on prevalence of latent RHD outside of childhood are sparse. Future studies should prioritize implementation research to answer questions of how RHD screening can best be integrated into existing healthcare structures, ensuring practical and sustainable screening programs.

Acute rheumatic fever (ARF) is a multiorgan inflammatory disorder that results from the body's autoimmune response to pharyngitis or a skin infection caused by Streptococcus pyogenes (Strep A). Acute rheumatic fever mainly affects those in low- and middle-income nations, as well as in indigenous populations in wealthy nations, where initial Strep A infections may go undetected. A single episode of ARF puts a person at increased risk of developing long-term cardiac damage known as rheumatic heart disease. We present case definitions for both definite and possible ARF, including initial and recurrent episodes, according to the 2015 Jones Criteria, and we discuss current tests available to aid in the diagnosis. We outline the considerations specific to ARF surveillance methodology, including discussion on where and how to conduct active or passive surveillance (eg, early childhood centers/schools, households, primary healthcare, administrative database review), participant eligibility, and the surveillance population. Additional considerations for ARF surveillance, including implications for secondary prophylaxis and follow-up, ARF registers, community engagement, and the impact of surveillance, are addressed. Finally, the core elements of case report forms for ARF, monitoring and audit requirements, quality control and assurance, and the ethics of conducting surveillance are discussed. [ABSTRACT FROM AUTHOR]

Rheumatic heart disease (RHD) is a long-term sequela of acute rheumatic fever (ARF), which classically begins after an untreated or undertreated infection caused by Streptococcus pyogenes (Strep A). RHD develops after the heart valves are permanently damaged due to ARF. RHD remains a leading cause of morbidity and mortality in young adults in resource-limited and low- and middle-income countries. This article presents case definitions for latent, suspected, and clinical RHD for persons with and without a history of ARF, and details case classifications, including differentiating between definite or borderline according to the 2012 World Heart Federation echocardiographic diagnostic criteria. This article also covers considerations specific to RHD surveillance methodology, including discussions on echocardiographic screening, where and how to conduct active or passive surveillance (eg, early childhood centers/schools, households, primary healthcare), participant eligibility, and the surveillance population. Additional considerations for RHD surveillance, including implications for secondary prophylaxis and follow-up, RHD registers, community engagement, and the negative impact of surveillance, are addressed. Finally, the core elements of case report forms for RHD, monitoring and audit requirements, quality control and assurance, and the ethics of conducting surveillance are discussed. [ABSTRACT FROM AUTHOR]

Introduction: To address workforce shortages and expand access to care, we developed a telemedicine program incorporating existing infrastructure for delivery of cardiovascular care in Gulu, Northern Uganda. Our study had three objectives: 1) assess feasibility and clinical impact 2) evaluate patient/parent satisfaction and 3) estimate costs. Methods: All cardiology clinic visits during a two-year study period were included. All patients received an electrocardiogram and echocardiogram performed by a local nurse in Gulu which were stored and transmitted to the Uganda Heart Institute in the capital of Kampala for remote consultation by a cardiologist. Results were relayed to patients/families following cardiologist interpretation. The following telemedicine process was utilized: 1) clinical intake by nurse in Gulu; 2) ECG and echocardiography acquisition in Gulu; 3) echocardiography transmission to the Uganda Heart Institute in Kampala, Uganda; 4) remote telemedicine consultation by cardiologists in Kampala; and 5) communication of results to patients/families in Gulu. Clinical care and technical aspects were tracked. Diagnoses and recommendations were analyzed by age groups (0–5 years, 6–21 years, 22–50 years and > 50 years). A mixed methods approach involving interviews and surveys was used to assess patient satisfaction. Healthcare sector costs of telemedicine-based cardiovascular care were estimated using time-driven activity-based costing. Results: Normal studies made up 47%, 55%, 76% and 45% of 1,324 patients in the four age groups from youngest to oldest. Valvular heart disease (predominantly rheumatic heart disease) was the most common diagnosis in the older three age groups. Medications were prescribed to 31%, 31%, 24%, and 48% of patients in the four age groups. The median time for consultation was 7 days. A thematic analysis of focus group transcripts displayed an overall acceptance and appreciation for telemedicine, citing cost- and time-saving benefits. The cost of telemedicine was $29.48/visit. Conclusions: Our data show that transmission and interpretation of echocardiograms from a remote clinic in northern Uganda is feasible, serves a population with a high burden of heart disease, has a significant impact on patient care, is favorably received by patients, and can be delivered at low cost. Further study is needed to better assess the impact relative to existing standards of care and cost effectiveness. [ABSTRACT FROM AUTHOR]

• Group A β-hemolytic Streptococcus (GAS) rates seen in Uganda are higher than results pooled globally. • This has implications for primary prevention of GAS. • GAS was universally susceptible to penicillin and trimethoprim–sulfamethoxazole. • Further knowledge of the acute streptococcal pharyngitis burden is essential. Group A β-hemolytic Streptococcus (GAS), also known as Streptococcus pyogenes , is responsible for an annual 600 million cases of acute pharyngitis globally, with 92% of those infections occurring in low-resource settings. Further knowledge of the acute streptococcal pharyngitis burden in low-resource settings is essential if serious post-streptococcal complications – rheumatic fever (RF) and its long-term sequel rheumatic heart disease (RHD) – are to be prevented. Two studies were conducted in school-aged children (5–16 years): a cross-sectional study of streptococcal pharyngeal carriage followed by a prospective cohort study of streptococcal sore throat over 4 weeks from March to April 2017. The cross-sectional study revealed an overall prevalence of GAS carriage of 15.9% (79/496, 95% confidence interval 12.8–19.5%). Among 532 children enrolled in the prospective cohort study, 358 (67%) reported 528 sore throats, with 221 (41.1%) experiencing at least one GAS-positive sore throat. The overall GAS-positive rate for sore throat was 41.8% (221/528). The GAS pharyngeal carriage rates seen in Uganda (15.9%, 95% confidence interval 12.8–19.5%) are higher than the most recent pooled results globally, at 12% (range 6–28%). Additionally, pilot data suggest a substantially higher percentage of sore throat that was GAS-positive (41.8%) compared to pooled global rates when active recruitment is employed. [ABSTRACT FROM AUTHOR]

Background: The burden of pre-existing cardiovascular disease and the contribution to adverse pregnancy outcomes are not robustly quantified, particularly in low-income countries. We aimed to determine both the prevalence of maternal heart disease through active case finding and its attributable risk to adverse pregnancy outcomes.Methods: We conducted a 24-month prospective longitudinal investigation in three Ugandan health centres, using echocardiography for active case finding during antenatal care. Women with and without heart disease were followed to 6 weeks post partum to determine pregnancy outcomes. Prevalence of heart disease was calculated. Per cent attributable risk estimates were generated for maternal, fetal and neonatal mortality.Results: Screening echocardiography was performed in 3506 women. The prevalence of heart disease was 17 per 1000 women (95% CI 13 to 21); 15 per 1000 was rheumatic heart disease. Only 3.4% of women (2/58) had prior diagnosis. Cardiovascular complications occurred in 51% of women with heart disease, most commonly heart failure. Per cent attributable risk of heart disease on maternal mortality was 88.6% in the exposed population and 10.8% in the overall population. Population attributable risk of heart disease on fetal death was 1.1% and 6.0% for neonatal mortality CONCLUSIONS: Occult maternal heart disease may be responsible for a substantial proportion of adverse pregnancy outcomes in low-resource settings. Rheumatic heart disease is, by far, the most common condition, urging global prioritisation of this neglected cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background : Rheumatic heart disease (RHD) is a global cause of early heart failure. Early RHD is characterized by valvar regurgitation, leading to ventricular distention and possible elaboration of amino-terminal pro-brain natriuretic peptide (NT-proBNP). We investigated the ability of NT-proBNP to distinguish cases of latent RHD detected by echocardiographic screening from the controls. Materials and Methods : Ugandan children (N = 44, 36% males, mean age: 12 ± 2 years) with latent RHD (cases) and siblings (controls) by echocardiography were enrolled. Cases and controls were matched for age and sex, and they had normal hemoglobin (mean: 12.8 mg/dL). Children with congenital heart disease, pregnancy, left ventricular dilation or ejection fraction (EF) below 55%, or other acute or known chronic health conditions were excluded. RHD cases were defined by the World Heart Federation (WHF) 2012 consensus guideline criteria as definite. Controls had no echocardiography (echo) evidence for RHD. At the time of echo, venous blood samples were drawn and stored as serum. NT-proBNP levels were measured using sandwich immunoassay. Paired t-tests were used to compare NT-proBNP concentrations including sex-specific analyses. Results : The mean NT-proBNP concentration in the cases was 105.74 ± 67.21 pg/mL while in the controls, it was 86.63 ± 55.77 pg/mL. The cases did not differ from the controls (P = 0.3). In sex-specific analyses, male cases differed significantly from the controls (158.78 ± 68.82 versus 76 ± 42.43, P = 0.008). Female cases did not differ from the controls (75.44 ± 45.03 versus 92.30 ± 62.35 respectively, P = 0.4). Conclusion : Serum NT-proBNP did not distinguish between latent RHD cases and the controls. Sex and within-family exposures may confound this result. More investigation into biomarker-based RHD detection is warranted. [ABSTRACT FROM AUTHOR]