Latent rheumatic heart disease in West Africa: a pilot multi-country study

Rheumatic heart disease (RHD) is a disease of poverty affecting the poorest countries in the world, with Sub-Saharan Africa bearing a heavy toll. In 2015, over 33 millions clinical cases and >300,000 deaths worldwide were estimated to be due to RHD. RHD is caused by an excessive immune reaction ("rheumatic fever" (ARF)) to throat or skin infections by Group A Streptococcus (GAS) which further damages the heart valves. Complications include heart failure and stroke that result in premature death, usually before 25 years old, and women with RHD are at higher risk of complication during delivery. RHD patients with early symptoms can be treated with monthly injections of benzathin penicillin G which stops the evolution of the heart lesions. However, in many countries, including The Gambia, RHD is usually diagnosed in patients attending health facilities at a late stage, with heart failure or other complications, when the efficacy of penicilllin treatment to prevent RHD adverse outcomes is limited. Ideally, penicillin treatment should be started as early as possible although its benefits in individuals with latent RHD, i.e. with cardiac lesions diagnosed by echocardiography but without symptoms, is unknown. Latent RHD represents a potential window of opportunity for early treatment with penicillin to prevent its progression towards overt clinical disease. This intervention needs to be evaluated with a large randomized clinical trial that will recruit hundreds of individuals with latent RHD. Therefore, considering the prevalence of latent RHD is probably 0.5-1% in children (up to 3% in young adults), the study team would need to rapidly screen thousands of individuals to attain the required sample size within a reasonable time period. Handheld echocardiography (HHEC) by non expert users has been proved as a reliable tool to detect RHD and is considered the best option for mass screening. This Trial Development Grant (TDG) will determine i) the prevalence of RHD (latent- and symptomatic) among school-aged children and young adults in peri-urban areas of The Gambia, Senegal and Nigeria; ii) whether non-experts users in the three study sites can be adequately trained for RHD screening using HHEC, and iii) the feasibility and acceptability of community-based screening by HHEC in the three study sites. After HHEC training (3 months), 3,000 children and 3,000 adults per country will be screened and all suspected RHD cases will be confirmed by standard EC before referral to the nearest teaching hospital for adequate management. The feasibility and acceptability of HHEC screenings will be evaluated as an ongoing process through early and regular engagement with participants and all stakeholders involved. Therefore, this TGD will provide useful information on RHD prevalence (both latent and symptomaticin different age groups) and the feasibility and acceptability of mass screening with HHEC, allowing to adapt accordingly the future trial design in the three West African countries. Results of such trial are crucially needed to issue new consensus guidelines on the management of latent RHD and further improve the control of RHD.

This trial development grant (TDG) aims at generating epidemiological and feasibility data data to inform the design of a multicentric trial in West Africa to test the efficacy of penicillin to prevent the progression of latent RHD towards overt clinical disease. This is urgently needed to formulate long awaited guidelines for the management of latent RHD. There is little information on the burden of RHD in West Africa as most of . This TDG will determine the prevalence of latent RHD in three West African countries (Senegal, The Gambia, Nigeria), by carrying out mass screening at community level using handheld EC (HHEC) by non expert users. Study activities are divided in two phases, i.e. a training phase (3 months) and a screening phase (4 months). Two trainees from each country (1 expert cardiologist +1 nurse/midwife) will follow a 2-week intensive training on HHEC in Uganda. Each pair of trainees will become trainer for 3 additional health staff in its own country and continue on-site practical training for 6-10 weeks under the supervision (online) of the Ugandan expert. At the end of the training, each study team should have four trained non-expert staff (including 1 nurse, 1 midwife, and 1 community health worker) with two operators scanning in parallel. In each site, a total of 3,000 school children (5-18y) and 3,000 adults aged 19-40 years (pregnant and non pregnant women and their partners/relative men) will be screened in a pre-defined peri-urban community. Each suspect RHD case identified by HHEC will be referred for standard EC by a cardiologist. Confirmed latent RHD will be referred for regular EC monitoring while symptomatic RHD will be referred for appropriate care at the nearest teaching hospital. Quantitative and qualitative data will be collected on the feasibility and acceptability of the proposed approach in each site through continuous engagement with stakeholders and end users.

-The main direct beneficiaries of the TDG will be the children and adults participating in the RHD screening (i.e. 6,000 participants/country). We will be able to identify by handheld echocardiography (HHEC) any valvular changes suggestive of RHD and then confirm the diagnosis with standard echocardiography (EC) by an expert cardiologist. With an estimated average prevalence of 1%, we will be able to identify at least 180 patients with latent RHD (60 per country). They will benefit of annual monitoring with standard EC to assess disease progression as part of standard care and, in case funding is secured for the multi-centric trial, they will be invited to participate. TDG participants with symptomatic RHD or congenital heart disease will be referred to the nearest teaching hospital for appropriate management under the supervision of the expert cardiologist and according to each country standard procedures. In addition to study participants, entire study communities (including health staff and school staff) will benefit from health information and behavior change communication (BCC) on RHD prevention provided by the study team before, during and after completion of the screening through meetings and local community radio programs.
Other direct beneficiaries are local health staff (nurses, midwives, community health workers (CHW)) that will be trained on HHEC. Two trainees/country will benefit from intensive training in Uganda, and upon return, they will become trainers for other health staff in their home institutions. By the end of the training, each study team should have 1 cardiologist and 4 non-experts (composed by at least 1 nurse, 1 midwife and 1 CHW) fully trained and certified on HHEC.
-The Ministry of Health (MoH) in each participating country will benefit from the TDG. Indeed, the latter will allow to experience, adapt and validate the HHEC training for non-expert users in the three West African countries. Subsequently, this training can be made available to a larger audience of health workers (e.g. nurses, midwives) to screen for RHD either during special campaigns (e.g. in schools) or during primary health care activities (ANCs, EPIs, IMNCI programs). A training program and materials will be designed by the study team and proposed to the respective MoHs. Increasing national workforce skills on RHD screening will enable the establishment of national RHD registries as recommended by the WHF.
-At international level, the establishment of consensus guidelines for EC screening of latent RHD warrants evidence on the progression rate towards overt clinical disease and on the efficacy of penicillin to improve disease outcome. The proposed multicentric trial will fill crucial knowledge gaps on the natural history of RHD and the related effect of penicillin in adolescents and adults. Robust evidence provided by such a trial in West Africa, together with the ongoing trial in Ugandan children, will enable the formulation of new policy guidelines on the management of latent RHD to be endorsed by the World Heart Federation (WHF), PASCAR (http://www.pascar.org/) and other major advocates for RHD elimination (http://rhdaction.org/). In the event penicillin would not prove efficacious against latent RHD, the robust data generated by the TDG will still be useful to inform effective screening policies (e.g. target groups, venues, communication strategies) to establish national RHD registries. Indeed, early diagnosis and EC monitoring will allow to initiate penicillin timely in those patients with fast progressing RHD lesions.
-Finally the reasearch collaboration initiated by the thre West African countries within the TDG offers a unique opportunity to strengthen regional research capacity on RHD and leverage the advocacy for RHD control and elimination in West Africa.