L. Zuhlke, University of Cape Town: Etiological, intervention and outcome studies in African children, adolescents and young adults with heart disease

We plan to work in three heart diseases causing major health problems in millions of children and young adults in Africa and other parts of the developing world.

1. Rheumatic heart disease (RHD)
RHD is a condition in which the body's own immune system mounts an abnormal and potentially catastrophic response to a common and usually self-limiting health problem, a sore throat. Around a third of sore throats are caused by a bacterial infection with an organism called Group A Streptococcus (GAS). Particularly in conditions of poverty, overcrowding and repeated infection, the body can react to the GAS infection by producing an immune response which attacks a number of the patient's own organs - this is called acute rheumatic fever (ARF). Repeated attacks of ARF, or even one serious attack, can result in damage by the abnormal immune response to the valves of the heart. This can in turn result in heart failure, the need for heart valve surgery, and if untreated, death. Most people affected by RHD are children and young adults, and so the number of productive life years lost from this neglected disease of poverty is very high. If GAS sore throat is promptly diagnosed and treated with antibiotics, RHD is unlikely to develop. Although this has proved feasible in Western countries, where RHD is now rare, RHD remains a scourge in Africa. We urgently need to explore the blocks to prompt diagnosis and treatment of GAS infection and develop strategies to overcome these. We also need to develop a better understanding of the molecular processes involved in acute disease, so we can help that subset of patients who develop severe RHD early in life. We will address these questions in the proposed research.

2. Congenital heart disease (CHD)
CHD comprises a group of conditions in which the heart is not formed properly during the baby's development in the womb. CHD affects nearly 1% of births and is a major cause of childhood death and lifelong disability. In developed countries, there has been a dramatic improvement in survival of patients with CHD thanks to advances in care. Access to similar levels of care in Africa is, and will likely remain, unavailable for the vast majority of the population. So, healthcare teams caring for African CHD patients need to formulate and adopt strategies which will deliver the best outcomes in a setting of severe resource restriction. There is an absolute lack of an African-specific evidence base in CHD to inform such a process. Over the last year, our team has begun to change this, establishing a study of CHD patients in Cape Town which has enrolled over 500 patients in six months. We now plan to develop this study further, by establishing it in five further African countries, evaluating the outcomes in a group of patients with severe CHD in these centres, and exploring and evaluating a way to roll out practice improvements across African centres. The study will also attempt to better understand why CHD occurs at the molecular level, by taking patient samples suitable to study inherited and other factors.

3. Heart disease associated with HIV in children and young adults
South Africa has the world's largest HIV epidemic; some 7 million people are currently living with HIV infection. Babies can be infected with HIV by their mothers around the time of birth. Although rates of mother to child transmission have dropped considerably due to treatment of HIV positive mothers, as recently as 2010, around 20% of HIV positive mothers passed on HIV to their baby. Therefore, there is a substantial number of HIV positive children who need longterm treatment with Anti Retroviral Therapy (ART) to contain the virus. HIV can affect many different aspects of cardiovascular health including causing weakness of the heart muscle and heart failure. We will investigate this in a group of HIV infected adolescents taking long-term ART, using advanced imaging technologies to show the effect of the virus and its treatment.

In three areas of unmet need, we will examine specific scientific questions relating to healthcare delivery and disease mechanisms, which are directed towards providing better care for children with heart disease in Africa.

In RHD we will identify the barriers to effective care for acute GAS infection through a situational assessment of healthcare for suspected GAS sore throat using a Needs Assessment Tool we have developed specifically for use in Africa. We will carry out a real world evaluation of an RADT as an adjunct to the diagnosis of GAS, quantifying sensitivity and specificity of the test and evaluating the value added in an urban African setting. We will conduct clinical evaluation, echocardiographic and cardiac MR imaging, and establish a tissue resource suitable for immunophenotypic evaluation of children and young adults with rapidly progressive RHD.

In CHD we will establish a multi-centre registry focusing on the long-term outcomes of patients undergoing palliative and staged cardiac surgical procedures (for example, those with a Fontan circulation). We will carry out a baseline situational analysis of pediatric cardiology and cardiac catheter laboratory activities in collaborating African centres, and evaluate the impact of a quality improvement tool we have devised at Red Cross War Memorial Children's Hospital in these centres. We will extend our cohort study of congenital heart disease in Cape Town to at least five further African countries, and bank bioresources suitable for genetic and proteomic investigation of aetiology and outcome.

We will apply advanced imaging including 3-D and 4-D Echo, and cardiac MRI to a sub-study of children, in the Cape Town Adolescent Antiretroviral Cohort, a unique group of 515 perinatally HIV-infected adolescents who have received prolonged antiretroviral therapy. We will quantify left ventricular diastolic function using echocardiography and myocardial fibrosis using CMR with late gadolinium enhanceme

The key areas of impact of this work include (1) advancement in scientific and health knowledge, (2) development of clinical, imaging and laboratory expertise in Africa, (3) addressing the contribution of RHD, CHD and HIV associated heart disease to adverse outcomes in children and young people's health, (4) delivering highly skilled people to the labour market in participating countries, (5) engaging the public on the value of prompt diagnosis and treatment in GAS infection and facilitating their uptake of services, (6) creating patient and family-informed and accountable research in the conditions of interest, (7) consolidating international and continental networks, and (8) direct improved patient benefit in a transitional country as outlined in our pathways to impact statement.

In RHD, our results will indicate the principal actionable obstacles to prompt diagnosis and treatment of GAS infection, and will enable detailed clinical and molecular study of the subset of patients who following ARF progress rapidly to severe RHD. This will potentially reveal opportunities for early recognition of these patients, and indicate personalized medicine approaches to slow disease and remove the need for valve surgery in childhood or young adulthood.

Data on outcomes in severe CHD in a number of low-income country settings, the identification of what constitutes best practice, and evaluation of appropriate tools to drive improvement in the African context will have immediate benefit to patients. Establishment of a database of comprehensively phenotyped CHD patients in multiple African countries, building on our success in Cape Town with the PROTEA study, will enable epidemiological, clinical and genetic studies to be conducted to the benefit of patients and healthcare systems across the continent. Formation of an African CHD research network will be a catalyst for important academic outputs, but also clinical change and attention from policymakers. Indeed, our findings could rapidly inform the development of health and social policy: for example regarding the impact of late presentation and delayed referral to specialist care on prognosis and the occurrence of complications of CHD. We will connect with local and national Ministers of Health in South Africa (building on already-established relationships with these directorates) to stimulate action on our findings demonstrating the contribution of CHD to adverse outcomes in maternal and child health. We will engage the patient and family CHD community to improve outcomes through better education and understanding.

Describing in detail the cardiovascular consequences of perinatal HIV infection and the effects of antiretroviral therapy, using advanced imaging modalities, will advance understanding of the pathophysiology of HIV cardiomyopathy and the beneficial - and any possible detrimental - effects of long-term HAART treatment. These findings will have immediate impact on the large cohort of young Sub-Saharan Africans who were perinatally infected with HIV.

We will have additional impact through training a cadre of CHD researchers and healthcare professionals in Southern Africa: physicians and surgeons, research nurses, cardiac clinical physiologists, research officers (through exposure to new research methods e.g. ITS) and basic scientists. This will not only enhance the quality of care for patients enrolled in the study, but new knowledge and practices will be disseminated in the participating centres. Drs Zuhlke, Mayosi and Ntsekhe have leadership roles in the Pan African Society of Cardiology, South Africa Heart Association and the African interventional cardiology meeting AfricaPCR, which will facilitate this. We will further the practice of evidence-based medicine in the care of children and young people with heart disease by adding substantially to the resource of high-quality African data on epidemiology, management and outcomes in the conditions of interest.