Peter Lwabi

Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study)

AIMS Rheumatic heart disease (RHD) accounts for over a million premature deaths annually; however, there is little contemporary information on presentation, complications, and treatment. METHODS AND RESULTS This prospective registry enrolled 3343 patients (median age 28 years, 66.2% female) presenting with RHD at 25 hospitals in 12 African countries, India, and Yemen between January 2010 and November 2012. The majority (63.9%) had moderate-to-severe multivalvular disease complicated by congestive heart failure (33.4%), pulmonary hypertension (28.8%), atrial fibrillation (AF) (21.8%), stroke (7.1%), infective endocarditis (4%), and major bleeding (2.7%). One-quarter of adults and 5.3% of children had decreased left ventricular (LV) systolic function; 23% of adults and 14.1% of children had dilated LVs. Fifty-five percent (n = 1761) of patients were on secondary antibiotic prophylaxis. Oral anti-coagulants were prescribed in 69.5% (n = 946) of patients with mechanical valves (n = 501), AF (n = 397), and high-risk mitral stenosis in sinus rhythm (n = 48). However, only 28.3% (n = 269) had a therapeutic international normalized ratio. Among 1825 women of childbearing age (12-51 years), only 3.6% (n = 65) were on contraception. The utilization of valvuloplasty and valve surgery was higher in upper-middle compared with lower-income countries. CONCLUSION Rheumatic heart disease patients were young, predominantly female, and had high prevalence of major cardiovascular complications. There is suboptimal utilization of secondary antibiotic prophylaxis, oral anti-coagulation, and contraception, and variations in the use of percutaneous and surgical interventions by country income level.

The utility of handheld echocardiography for early rheumatic heart disease diagnosis: A field study

AIMS The World Heart Federation (WHF) guidelines for rheumatic heart disease (RHD) are designed for a standard portable echocardiography (STAND) machine. A recent study in a tertiary care centre demonstrated that they also had good sensitivity and specificity when modified for use with handheld echocardiography (HAND). Our study aimed to evaluate the performance of HAND for early RHD diagnosis in the setting of a large-scale field screening. METHODS AND RESULTS STAND was performed in 4773 children in Gulu, Uganda, with 10% randomly assigned to also undergo HAND. Additionally, any child with mitral or aortic regurgitation also underwent HAND. Studies were performed by experienced echocardiographers and blindly reviewed by cardiologists using 2012 WHF criteria, which were modified slightly for HAND--due to the lack of spectral Doppler capability. Paired echocardiograms were performed in 1420 children (mean age 10.8 and 53% female), resulting in 1234 children who were normal, 133 who met criteria for borderline RHD, 47 who met criteria for definite RHD, and 6 who had other diagnoses. HAND had good sensitivity and specificity for RHD detection (78.9 and 87.2%, respectively), but was most sensitive for definite RHD (97.9%). Inter- and intra-reviewer agreement ranged between 66-83 and 71.4-94.1%, respectively. CONCLUSIONS HAND has good sensitivity and specificity for diagnosis of early RHD, performing best for definite RHD. Protocols for RHD detection utilizing HAND will need to include confirmation by STAND to avoid over-diagnosis. Strategies that evaluate simplified screening protocols and training of non-physicians hold promise for more wide spread deployment of HAND-based protocols.

Clinical Outcomes in 3343 Children and Adults with Rheumatic Heart Disease from 14 Low and Middle Income Countries: 2-Year Follow-up of the Global Rheumatic Heart Disease Registry (the REMEDY study)

Background: There are few contemporary data on the mortality and morbidity associated with rheumatic heart disease or information on their predictors. We report the 2-year follow-up of individuals with rheumatic heart disease from 14 low- and middle-income countries in Africa and Asia. Methods: Between January 2010 and November 2012, we enrolled 3343 patients from 25 centers in 14 countries and followed them for 2 years to assess mortality, congestive heart failure, stroke or transient ischemic attack, recurrent acute rheumatic fever, and infective endocarditis. Results: Vital status at 24 months was known for 2960 (88.5%) patients. Two-thirds were female. Although patients were young (median age, 28 years; interquartile range, 18–40), the 2-year case fatality rate was high (500 deaths, 16.9%). Mortality rate was 116.3/1000 patient-years in the first year and 65.4/1000 patient-years in the second year. Median age at death was 28.7 years. Independent predictors of death were severe valve disease (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.80–3.11), congestive heart failure (HR, 2.16; 95% CI, 1.70–2.72), New York Heart Association functional class III/IV (HR, 1.67; 95% CI, 1.32–2.10), atrial fibrillation (HR, 1.40; 95% CI, 1.10–1.78), and older age (HR, 1.02; 95% CI, 1.01–1.02 per year increase) at enrollment. Postprimary education (HR, 0.67; 95% CI, 0.54–0.85) and female sex (HR, 0.65; 95% CI, 0.52–0.80) were associated with lower risk of death. Two hundred and four (6.9%) patients had new congestive heart failure (incidence, 38.42/1000 patient-years), 46 (1.6%) had a stroke or transient ischemic attack (8.45/1000 patient-years), 19 (0.6%) had recurrent acute rheumatic fever (3.49/1000 patient-years), and 20 (0.7%) had infective endocarditis (3.65/1000 patient-years). Previous stroke and older age were independent predictors of stroke/transient ischemic attack or systemic embolism. Patients from low- and lower-middle–income countries had significantly higher age- and sex-adjusted mortality than patients from upper-middle–income countries. Valve surgery was significantly more common in upper-middle–income than in lower-middle– or low-income countries. Conclusions: Patients with clinical rheumatic heart disease have high mortality and morbidity despite being young; those from low- and lower-middle–income countries had a poorer prognosis associated with advanced disease and low education. Programs focused on early detection and the treatment of clinical rheumatic heart disease are required to improve outcomes.

Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communiqué.

Abstract Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain major causes of heart failure, stroke and death among African women and children, despite being preventable and imminently treatable. From 21 to 22 February 2015, the Social Cluster of the Africa Union Commission (AUC) hosted a consultation with RHD experts convened by the Pan-African Society of Cardiology (PASCAR) in Addis Ababa, Ethiopia, to develop a ‘roadmap’ of key actions that need to be taken by governments to eliminate ARF and eradicate RHD in Africa. Seven priority areas for action were adopted: (1) create prospective disease registers at sentinel sites in affected countries to measure disease burden and track progress towards the reduction of mortality by 25% by the year 2025, (2) ensure an adequate supply of high-quality benzathine penicillin for the primary and secondary prevention of ARF/RHD, (3) improve access to reproductive health services for women with RHD and other non-communicable diseases (NCD), (4) decentralise technical expertise and technology for diagnosing and managing ARF and RHD (including ultrasound of the heart), (5) establish national and regional centres of excellence for essential cardiac surgery for the treatment of affected patients and training of cardiovascular practitioners of the future, (6) initiate national multi-sectoral RHD programmes within NCD control programmes of affected countries, and (7) foster international partnerships with multinational organsations for resource mobilisation, monitoring and evaluation of the programme to end RHD in Africa. This Addis Ababa communiqué has since been endorsed by African Union heads of state, and plans are underway to implement the roadmap in order to end ARF and RHD in Africa in our lifetime.

Handheld echocardiographic screening for rheumatic heart disease by non-experts

Objectives Handheld echocardiography (HAND) has good sensitivity and specificity for rheumatic heart disease (RHD) when performed by cardiologists. However, physician shortages in RHD-endemic areas demand less-skilled users to make RHD screening practical. We examine nurse performance and interpretation of HAND using a simplified approach for RHD screening. Methods Two nurses received training on HAND and a simplified screening approach. Consented students at two schools in Uganda were eligible for participation. A simplified approach (HAND performed and interpreted by a non-expert) was compared with the reference standard (standard portable echocardiography, performed and interpreted by experts according to the 2012 World Heart Federation guidelines). Reasons for false-positive and false-negative HAND studies were identified. Results A total of 1002 children were consented, with 956 (11.1 years, 41.8% male) having complete data for review. Diagnoses included: 913 (95.5%) children were classified normal, 32 (3.3%) borderline RHD and 11 (1.2%) definite RHD. The simplified approach had a sensitivity of 74.4% (58.8% to 86.5%) and a specificity of 78.8% (76.0% to 81.4%) for any RHD (borderline and definite). Sensitivity improved to 90.9% (58.7% to 98.5%) for definite RHD. Identification and measurement of erroneous colour jets was the most common reason for false-positive studies (n=164/194), while missed mitral regurgitation and shorter regurgitant jet lengths with HAND were the most common reasons for false-negative studies (n=10/11). Conclusions Non-expert-led HAND screening programmes offer a potential solution to financial and workforce barriers that limit widespread RHD screening. Nurses trained on HAND using a simplified approach had reasonable sensitivity and specificity for RHD screening. Information on reasons for false-negative and false-positive screening studies should be used to inform future training protocols, which could lead to improved screening performance.

Handheld echocardiography versus auscultation for detection of rheumatic heart disease

BACKGROUND: Rheumatic heart disease (RHD) remains a major public health concern in developing countries, and routine screening has the potential to improve outcomes. Standard portable echocardiography (STAND) is far more sensitive than auscultation for the detection of RHD but remains cost-prohibitive in resource-limited settings. Handheld echocardiography (HAND) is a lower-cost alternative. The purpose of this study was to assess the incremental value of HAND over auscultation to identify RHD. METHODS: RHD screening was completed for schoolchildren in Gulu, Uganda, by using STAND performed by experienced echocardiographers. Any child with mitral or aortic regurgitation or stenosis plus a randomly selected group of children with normal STAND findings underwent HAND and auscultation. STAND and HAND studies were interpreted by 6 experienced cardiologists using the 2012 World Heart Federation criteria. Sensitivity and specificity of HAND and auscultation for the detection of RHD and pathologic mitral or aortic regurgitation were calculated by using STAND as the gold standard. RESULTS: Of 4773 children who underwent screening with STAND, a subgroup of 1317 children underwent HAND and auscultation. Auscultation had uniformly poor sensitivity for the detection of RHD or valve disease. Sensitivity was significantly improved by using HAND compared with auscultation for the detection of definite RHD (97.8% vs 22.2%), borderline or definite RHD (78.4% vs 16.4%), and pathologic aortic insufficiency (81.8% vs 13.6%). CONCLUSIONS: Auscultation alone is a poor screening test for RHD. HAND significantly improves detection of RHD and may be a cost-effective screening strategy for RHD in resource-limited settings.

Simplified Rheumatic Heart Disease Screening Criteria for Handheld Echocardiography

BACKGROUND Using 2012 World Heart Federation criteria, standard portable echocardiography (STAND) reveals a high burden of rheumatic heart disease (RHD) in resource-poor settings, but widespread screening is limited by cost and physician availability. Handheld echocardiography (HAND) may decrease costs, but World Heart Federation criteria are complicated for rapid field screening, particularly for nonphysician screeners. The aim of this study was to determine the best simplified screening strategy for RHD detection using HAND. METHODS In this prospective study, STAND (GE Vivid q or i or Philips CX-50) was performed in five schools in Gulu, Uganda; a random subset plus all children with detectable mitral regurgitation or aortic insufficiency also underwent HAND (GE Vscan). Borderline or definite RHD cases were defined by 2012 World Heart Federation criteria on STAND images, by two experienced readers. HAND studies were reviewed by cardiologists blinded to STAND results. Single and combined HAND parameters were evaluated to determine the simplified screening strategy that maximized sensitivity and specificity for case detection. RESULTS In 1,439 children (mean age, 10.8 ± 2.6 years; 47% male) with HAND and STAND studies, morphologic criteria and the presence of any mitral regurgitation by HAND had poor specificity. The presence of aortic insufficiency was specific but not sensitive. Combined criteria of mitral regurgitation jet length ≥ 1.5 cm or any aortic insufficiency best balanced sensitivity (73.3%) and specificity (82.4%), with excellent sensitivity for definite RHD (97.9%). With a prevalence of 4% and subsequent STAND screening of positive HAND studies, this would reduce STAND studies by 80% from a STAND-based screening strategy. CONCLUSIONS In resource-limited settings, HAND with simplified criteria can detect RHD with good sensitivity and specificity and decrease the need for standard echocardiography. Further study is needed to validate screening by local practitioners and long-term outcomes.

Socioeconomic and environmental risk factors among rheumatic heart disease patients in Uganda.

Background Although low socioeconomic status, and environmental factors are known risk factors for rheumatic heart disease in other societies, risk factors for rheumatic heart disease remain less well described in Uganda. Aims and Objective The objective of this study was to investigate the role of socio-economic and environmental factors in the pathogenesis of rheumatic heart disease in Ugandan patients. Methods This was a case control study in which rheumatic heart disease cases and normal controls aged 5–60 years were recruited and investigated for socioeconomic and environmental risk factors such as income status, employment status, distance from the nearest health centre, number of people per house and space area per person. Results 486 participants (243 cases and 243 controls) took part in the study. Average age was 32.37+/−14.6 years for cases and 35.75+/−12.6 years for controls. At univariate level, Cases tended to be more overcrowded than controls; 8.0+/−3.0 versus 6.0+/−3.0 persons per house. Controls were better spaced at 25.2 square feet versus 16.9 for cases. More controls than cases were employed; 45.3% versus 21.1%. Controls lived closer to health centers than the cases; 4.8+/−3.8 versus 3.3+/−12.9 kilometers. At multivariate level, the odds of rheumatic heart disease was 1.7 times higher for unemployment status (OR = 1.7, 95% CI = 1.05–8.19) and 1.3 times higher for overcrowding (OR = 1.35, 95% CI = 1.1–1.56). There was interaction between overcrowding and longer distance from the nearest health centre (OR = 1.20, 95% CI = 1.05–1.42). Conclusion The major findings of this study were that there was a trend towards increased risk of rheumatic heart disease in association with overcrowding and unemployment. There was interaction between overcrowding and distance from the nearest health center, suggesting that the effect of overcrowding on the risk of acquiring rheumatic heart disease increases with every kilometer increase from the nearest health center.

Management of rheumatic heart disease in uganda: the emerging epidemic of non-AIDS comorbidity in resource-limited settings.

The expansion of antiretroviral therapy (ART) in resource-limited settings (RLS) has dramatically changed the face of the AIDS epidemic in Sub-Saharan Africa over the past decade 1. The progress in HIV/AIDS care is in large part due to successful bilateral and multilateral collaborations of governments and non-governmental AIDS organizations. In Uganda, for example, with funding support from the National Institutes of Health (NIH) and the Presidents Emergency Plan for AIDS Relief, Case Western Reserve University (CWRU) and others have partnered with Ugandan institutions to develop a comprehensive HIV/AIDS infrastructure. Because of this concerted effort, the country has seen a fall in HIV prevalence from a peak of 25-30% in major urban areas to now less than 7% nationally, and nearly half of those who qualify for treatment are currently receiving it 2. These successes, however, bring new challenges. As HIV has now become a manageable chronic disease, the infected population has aged, and the higher prevalence of co-morbidities such as cardiovascular disease is increasingly recognized. The specter of a dual epidemic of HIV/AIDS and non-communicable disease threatens to place significant demands on these fragile healthcare systems 3. In addition to the higher risk of ischemic heart disease observed in the developed and developing world, the burden of endemic cardiovascular disease such as tuberculous pericarditis and rheumatic heart disease among persons living with HIV in RLS is unknown. Recognizing this emerging need, Makerere University School of Medicine, Mulago Hospital, and the Uganda Heart Institute have partnered with CWRU to extend collaboration beyond HIV/AIDS to cardiovascular disease (CVD), neurology, and oncology. Funded in part by the NIH/Fogarty International Medical Education Partnership Initiative (MEPI), the cardiology collaboration aims to provide contextually appropriate training of cardiovascular specialists and conduct research on CVD risk factors, including the impact of HIV/AIDS. As part of the MEPI collaboration, a team of cardiologists from CWRU traveled to Kampala, Uganda in August 2012 to perform procedures in the newly opened cardiac catheterization laboratory at the Uganda Heart Institute (UHI), Mulago Hospital, including the countrys first percutaneous mitral balloon valvuloplasties (PMBV) for rheumatic mitral stenosis (Figure 1A and B). Although rarely seen in the developed world, rheumatic heart disease (RHD) remains a leading cause of cardiovascular morbidity and mortality in RLS, affecting over 1 million children in Sub-Saharan Africa alone 4. RHD is a chronic complication of rheumatic fever, an auto-immune reaction to antecedent Group A streptococcus pharyngitis that causes varying degrees of carditis 5. Significant valvular regurgitation or stenosis may occur during the initial insult or after repeated damage to the valve from recurrent bouts of acute rheumatic fever 5. Congestive heart failure then develops insidiously and may lead to death in the 2nd to 5th decades of life if the valve is not repaired. The current treatment of choice in developed countries for rheumatic mitral valve stenosis without significant regurgitation is percutaneous balloon valvuloplasty6. Figure 1 A) Members of the Case Western Reserve University team with the Uganda Heart Institute physicians and cardiac catheterization lab staff. The new facility at the Uganda Heart Institute was completed in February of 2012. B) Dr. Marco Costa and Dr. Dan Simon ... The first patient to benefit from this minimally-invasive procedure in Uganda was HIV-infected. In a country with a high prevalence of HIV/AIDS, it may be coincidence that this patient happened to be HIV-infected. Nonetheless, several questions arise regarding the impact of HIV on RHD (and other endemic non-communicable disease) in the country. Are perinatally HIV-infected children more or less likely than their uninfected peers to acquire acute rheumatic fever? What is the role of chronic inflammation and immune activation associated with HIV on outcomes among children with RHD? In patients with AIDS, does the CD4+ lymphopenia associated with acute rheumatic fever lead to further immunosuppression and increased susceptibility to opportunistic infections? Is someone with subclinical RHD acquired in childhood more or less likely to develop progressive disease if they become HIV-infected as an adult? Among patients colonized with Group A streptococci who are started on ART therapy, can subclinical rheumatic carditis develop within the spectrum of immune reconstitution inflammatory syndromes (IRIS)? Although RHD is rare in the developed world, other rheumatic/immunologic complications of HIV/AIDS are not uncommon. The spectrum of disease has changed since the introduction of combination ART in the mid-1990s 8,9. Autoimmunity appears to be increased in chronic HIV-infection, and molecular mimicry may be an important mechanism 10. For example, in a recent study from South Africa, anti-cyclic citrullinated peptide (anti-CCP) antibody titers were increased in advanced HIV-infection compared to controls and decreased after initiation of antiretroviral therapy 11. In this context, the anti-CCP antibodies lacked the typically high specificity for rheumatoid arthritis. In some cases, inflammatory arthritis such as psoriatic arthritis 12 or rheumatoid arthritis 13 may be the initial presentation of HIV/AIDS. On the other hand, advanced immunosuppression may suppress the clinical manifestations of pre-existing auto-immune conditions such as inflammatory bowel disease, systemic lupus erythematosis and rheumatoid arthritis 14. Despite this literature, little is known about the interaction of HIV with rheumatic fever and RHD. Some studies have demonstrated an increased risk for group A streptococcal infection with underlying HIV infection15; however, to our knowledge, only one case of acute rheumatic fever in an AIDS patient has been reported previously 16. The CWRU team continues to return quarterly to Uganda as part of a comprehensive skills transfer program that also includes training for Ugandan physicians in Cleveland, Ohio. In addition, CWRU has partnered with the UHI and the Joint Clinical Research Centre (a center in existence in Uganda for care and research in HIV/AIDS) to focus specifically on RHD through an innovative foundation-funded project. This program will utilize an existing network of HIV/AIDS infrastructure to create community-based RHD treatment centers of excellence. If successful, this program may serve as a model for leveraging HIV/AIDS resources for the treatment of non-communicable diseases among both HIV-infected and uninfected patients in RLS. We are now at a crossroads. An opportunity exists to build upon the dramatic improvements in healthcare infrastructure that HIV/AIDS investment has brought over the past decade. To extend the benefits of the ART rollout to the treatment of non-AIDS co-morbidities such as RHD will require a coordinated research effort and capital investment in health systems, particularly in human resources. Multilateral collaborations in medical specialties beyond infectious diseases that share the tripartite mission of research, education, and clinical care such as the one described in this report will be needed to move to the next level of HIV/AIDS treatment in Sub-Saharan Africa and other RLS.

Cardiac Conduction Safety during Coadministration of Artemether-Lumefantrine and Lopinavir/Ritonavir in HIV-Infected Ugandan Adults.

Background. We aimed to assess cardiac conduction safety of coadministration of the CYP3A4 inhibitor lopinavir/ritonavir (LPV/r) and the CYP3A4 substrate artemether-lumefantrine (AL) in HIV-positive Ugandans. Methods. Open-label safety study of HIV-positive adults administered single-dose AL (80/400 mg) alone or with LPV/r (400/100 mg). Cardiac function was monitored using continuous electrocardiograph (ECG). Results. Thirty-two patients were enrolled; 16 taking LPV/r -based ART and 16 ART naïve. All took single dose AL. No serious adverse events were observed. ECG parameters in milliseconds remained within normal limits. QTc measurements did not change significantly over 72 hours although were higher in LPV/r arm at 24 (424 versus 406; P = .02) and 72 hours (424 versus 408; P = .004) after AL intake. Conclusion. Coadministration of single dose of AL with LPV/r was safe; however, safety of six-dose AL regimen with LPV/r should be investigated.