Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease.

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.).

Establishment of a cardiac telehealth program to support cardiovascular diagnosis and care in a remote, resource-poor setting in Uganda.

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.

Rheumatic Heart Disease in the United States: Forgotten But Not Gone: Results of a 10 Year Multicenter Review.

Background Recent evaluation of rheumatic heart disease (RHD) mortality demonstrates disproportionate disease burden within the United States. However, there are few contemporary data on US children living with acute rheumatic fever (ARF) and RHD. Methods and Results Twenty-two US pediatric institutions participated in a 10-year review (2008-2018) of electronic medical records and echocardiographic databases of children 4 to 17 years diagnosed with ARF/RHD to determine demographics, diagnosis, and management. Geocoding was used to determine a census tract-based socioeconomic deprivation index. Descriptive statistics of patient characteristics and regression analysis of RHD classification, disease severity, and initial antibiotic prescription according to community deprivation were obtained. Data for 947 cases showed median age at diagnosis of 9 years; 51% and 56% identified as male and non-White, respectively. Most (89%) had health insurance and were first diagnosed in the United States (82%). Only 13% reported travel to an endemic region before diagnosis. Although 96% of patients were prescribed secondary prophylaxis, only 58% were prescribed intramuscular benzathine penicillin G. Higher deprivation was associated with increasing disease severity (odds ratio, 1.25; 95% CI, 1.08-1.46). Conclusions The majority of recent US cases of ARF and RHD are endemic rather than the result of foreign exposure. Children who live in more deprived communities are at risk for more severe disease. This study demonstrates a need to improve guideline-based treatment for ARF/RHD with respect to secondary prophylaxis and to increase research efforts to better understand ARF and RHD in the United States.

Incidence of acute rheumatic fever in northern and western Uganda: a prospective, population-based study.

BACKGROUND: Acute rheumatic fever is infrequently diagnosed in sub-Saharan African countries despite the high prevalence of rheumatic heart disease. We aimed to determine the incidence of acute rheumatic fever in northern and western Uganda. METHODS: For our prospective epidemiological study, we established acute rheumatic fever clinics at two regional hospitals in the north (Lira district) and west (Mbarara district) of Uganda and instituted a comprehensive acute rheumatic fever health messaging campaign. Communities and health-care workers were encouraged to refer children aged 3-17 years, with suspected acute rheumatic fever, for a definitive diagnosis using the Jones Criteria. Children were referred if they presented with any of the following: (1) history of fever within the past 48 h in combination with any joint complaint, (2) suspicion of acute rheumatic carditis, or (3) suspicion of chorea. We excluded children with a confirmed alternative diagnosis. We estimated incidence rates among children aged 5-14 years and characterised clinical features of definite and possible acute rheumatic fever cases. FINDINGS: Data were collected between Jan 17, 2018, and Dec 30, 2018, in Lira district and between June 5, 2019, and Feb 28, 2020, in Mbarara district. Of 1075 children referred for evaluation, 410 (38%) met the inclusion criteria; of these, 90 (22%) had definite acute rheumatic fever, 82 (20·0%) had possible acute rheumatic fever, and 24 (6%) had rheumatic heart disease without evidence of acute rheumatic fever. Additionally, 108 (26%) children had confirmed alternative diagnoses and 106 (26%) had an unknown alternative diagnosis. We estimated the incidence of definite acute rheumatic fever among children aged 5-14 years as 25 cases (95% CI 13·7-30·3) per 100 000 person-years in Lira district (north) and 13 cases (7·1-21·0) per 100 000 person-years in Mbarara district (west). INTERPRETATION: To the best of our knowledge, this is the first population-based study to estimate the incidence of acute rheumatic fever in sub-Saharan Africa. Given the known rheumatic heart disease burden, it is likely that only a proportion of children with acute rheumatic fever were diagnosed. These data dispel the long-held hypothesis that the condition does not exist in sub-Saharan Africa and compel investment in improving prevention, recognition, and diagnosis of acute rheumatic fever. FUNDING: American Heart Association Children's Strategically Focused Research Network Grant, THRiVE-2, General Electric, and Cincinnati Children's Heart Institute Research Core.

The personal and clinical impact of screen-detected maternal rheumatic heart disease in Uganda: a prospective follow up study.

BACKGROUND: Pre-existing maternal cardiac disease is a significant contributor to adverse maternal, fetal, and neonatal outcomes. In 2015-2017, our team conducted the first community-based study of maternal rheumatic heart disease (RHD) in sub-Saharan Africa and identified RHD in 88% of those with pre-existing heart disease. Here we conducted a follow up investigation of women previously identified with RHD, describing clinical and echocardiographic outcomes, identifying barriers to medical adherence and evaluating the personal impact of RHD. METHODS: A 2 week prospective follow up was completed at sites in Central and Eastern Uganda. Participants underwent a three-step mixed methods study comprising of 1) direct structured interview targeting clinical history and medication adherence, 2) echocardiogram to evaluate left-sided heart valves, and 3) semi-structured guideline interview to elicit personal impacts of RHD. RESULTS: The team evaluated 40 (80%) of the original 51 mothers with RHD at a median post-partum time of 2.5 years after delivery (IQR 0.5). Echocardiographic data showed improvement in nine women with the remaining 31 women showing stable echocardiographic findings. Adherence to Benzathine penicillin G (BPG) prophylaxis was poor, with 70% of patients either poorly adherent or non-adherent. Three major themes emerged from interviews: 1) social determinants of health (World Health Organization, Social determinants of health, 2019) negatively affecting healthcare, 2) RHD diagnosis negatively affecting female societal wellbeing, 3) central role of spouse in medical decision making. CONCLUSIONS: Screening echocardiography can identify women with pre-existing rheumatic heart disease during pregnancy, but long-term follow-up in Uganda reveals adherence to medical care following diagnosis, including BPG, is poor. Additionally, mothers diagnosed with RHD may experience unintended consequences such as social stigmatization. As identification of occult RHD is critical to prevent adverse pregnancy outcomes, further research is needed to determine how to best support women who face a new diagnosis of RHD, and to determine the role of screening echocardiography in high-risk settings.

Active Case Finding for Rheumatic Fever in an Endemic Country.

Background Despite the high burden of rheumatic heart disease in sub-Saharan Africa, diagnosis with acute rheumatic fever (ARF) is exceedingly rare. Here, we report the results of the first prospective epidemiologic survey to diagnose and characterize ARF at the community level in Africa. Methods and Results A cross-sectional study was conducted in Lira, Uganda, to inform the design of a broader epidemiologic survey. Key messages were distributed in the community, and children aged 3 to 17 years were included if they had either (1) fever and joint pain, (2) suspicion of carditis, or (3) suspicion of chorea, with ARF diagnoses made by the 2015 Jones Criteria. Over 6 months, 201 children met criteria for participation, with a median age of 11 years (interquartile range, 6.5) and 103 (51%) female. At final diagnosis, 51 children (25%) had definite ARF, 11 (6%) had possible ARF, 2 (1%) had rheumatic heart disease without evidence of ARF, 78 (39%) had a known alternative diagnosis (10 influenza, 62 malaria, 2 sickle cell crises, 2 typhoid fever, 2 congenital heart disease), and 59 (30%) had an unknown alternative diagnosis. Conclusions ARF persists within rheumatic heart disease-endemic communities in Africa, despite the low rates reported in the literature. Early data collection has enabled refinement of our study design to best capture the incidence of ARF and to answer important questions on community sensitization, healthcare worker and teacher education, and simplified diagnostics for low-resource areas. This study also generated data to support further exploration of the relationship between malaria and ARF diagnosis in rheumatic heart disease/malaria-endemic countries.

Cross-sectional study of population-specific streptococcal antibody titres in Uganda.

OBJECTIVE: Despite substantial variation of streptococcal antibody titres among global populations, there is no data on normal values in sub-Saharan Africa. The objective of this study was to establish normal values for antistreptolysin O (ASO) and antideoxyribonuclease B (ADB) antibodies in Uganda. DESIGN: This was an observational cross-sectional study. SETTING: This study was conducted at Mulago National Referral Hospital, which is located in the capital city, Kampala, and includes the Uganda Heart Institute. PATIENTS: Participants (aged 0-50 years) were recruited. Of 428 participants, 22 were excluded from analysis, and 183 (44.4%) of the remaining were children aged 5-15 years. MAIN OUTCOME MEASURES: ASO was measured in-country by nephelometric technique. ADB samples were sent to Australia (PathWest) for analysis by enzyme inhibition assay: 80% upper limit values were established. RESULTS: The median ASO titre in this age group was 220 IU/mL, with the 80th percentile value of 389 IU/mL. The median ADB titre in this age group was 375 IU/mL, with the 80th percentile value of 568 IU/mL. CONCLUSIONS: The estimated Ugandan paediatric population standardised 80% upper-limit-of-normal ASO and ADB titres is higher than many global populations. Appropriateness of using population-specific antibody cutoffs is yet to be determined and has important implications for the sensitivity and specificity of rheumatic fever diagnosis.