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Assessing the risk factors in rheumatic heart disease

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Rheumatic heart disease is caused by untreated throat infections from the streptococcal bacterium. The infections progress into acute rheumatic fever and eventually weaken the valves of the heart.

Rheumatic heart disease (RHD) is the most commonly acquired cardiovascular disease in children and young adults. The devastating condition, which was endemic in the United States before 1950, is now relatively rare in the developed world due to social and economic development and the introduction of penicillin. But, in the developing world RHD remains nearly as common as HIV.

Fortunately, RHD is a cumulative disease and opportunities exist for early intervention. To further explore the utility of early diagnosis and intervention, a research team headed by Children’s National Heart Institute cardiologist Andrea Beaton, M.D., conducted a prospective natural history study of children with latent RHD.

RHD is caused by untreated streptococcal throat infections that progress into acute rheumatic fever (ARF) and eventually weaken the valves of the heart. While initial episodes of ARF occur almost exclusively during childhood, RHD most commonly presents in adolescents and young adults. This latent period between ARF and clinically apparent RHD is an ideal opportunity for early intervention, and screening echocardiography (echo) has emerged as a potentially powerful tool for early detection of RHD.

In their study published in the journal Circulation in September 2017, Dr. Beaton and her colleagues examined echocardiograms from children with latent RHD who were enrolled in the Ugandan National RHD registry. The researchers also developed models to search for risk factors and compare progression-free survival between patients who did and did not receive penicillin.

The team reports that children with moderate-to-severe latent RHD discovered by echo screening have poor outcomes. Children with both borderline and mild definite RHD have better outcomes but remain at substantial risk of progression. The researchers also found that children who are diagnosed at a younger age, and the presence of morphological mitral valve features, generally lead to unfavorable outcomes.

The authors conclude that children with moderate to severe RHD at screening should be considered for treatment as clinically diagnosed RHD, and that children with borderline or mild definite RHD at screening should, at a minimum, be maintained in close clinical follow up.

“It is clear that children found to have the earliest forms of RHD, seen only by echo, are at substantial risk for progression of disease. This study urges us forward to see if we can intervene to stop this progression once children are identified,” says Dr. Beaton.  “We are excited that our next project will be to do just that – a randomized clinical trial in Uganda to determine if penicillin can protect the hearts of children found to have latent RHD.”

Andrea Beaton and Craig Sable

Assessing the global burden of rheumatic heart disease

Andrea Beaton and Craig Sable

A research team that included Children’s National Heart Institute experts Andrea Beaton, M.D., and Craig Sable, M.D., examined data on fatal and nonfatal Rheumatic Heart Disease for a 25 year period from 1990 through 2015 to determine the current global burden of RHD.

Rheumatic Heart Disease (RHD) is the most commonly acquired heart disease in young people under the age of 25. It’s caused by untreated streptococcal throat infections that progress into acute rheumatic fever and eventually weaken the valves of the heart. Fortunately, the devastating condition, which was endemic in the United States before 1950, is now relatively rare in the developed world due to social and economic development and the introduction of penicillin. But, as shown in a recent study published in the New England Journal of Medicine, in the developing world, RHD remains nearly as common as HIV.

As part of the 2015 Global Burden of Disease Study, a research team that included Children’s National Heart Institute experts Andrea Beaton, M.D., and Craig Sable, M.D., examined data on fatal and nonfatal RHD for a 25 year period from 1990 through 2015 to determine the current global burden of RHD. The group employed epidemiologic modeling techniques to estimate the global, regional and national prevalence of RHD, as well as death rates and disability-adjusted life years attributable to the disease.

“This study provides more detail than ever before about the global impact of RHD,” explains Dr. Sable. “It utilizes global burden of disease tools that are updated on an annual basis. These tools are considered highly reputable and allow for ongoing tracking and comparison to other diseases.”

The researchers found that overall, death rates from RHD have declined: there were 347,500 deaths from RHD in 1990 and 319,400 deaths in 2015, a decrease of 8 percent. From 1990 to 2015, the global age-standardized death rate from RHD also decreased from 9.2 to 4.8 per 100,000 — a change of 48 percent.

However, a closer look at the data shows that progress on RHD remains uneven. Although the health-related burden of RHD has declined in most countries over the 25-year period, the condition persists in some of the poorest regions in the world, with the highest estimated death rates in Central African Republic, Federated States of Micronesia, Fiji, India, Kiribati, Lesotho, Marshall Islands, Pakistan, Papua New Guinea, the Solomon Islands and Vanuatu. In several regions, mortality from RHD and the number of individuals living with RHD did not appreciably decline between 1990 and 2015. The researchers estimate that 10 out of every 1,000 people living in South Asia and central sub-Saharan Africa and 15 out of 1,000 people in Oceania were living with RHD in 2015.

“These data are critically important for increasing awareness and funding to reduce the global burden of rheumatic heart disease,” says Dr. Sable. “Dr. Beaton and I are proud to be part of a small team of global investigators leading this effort.”

Children’s National Health System was recently awarded a grant from the American Heart Association to launch a Rheumatic Heart Disease Center, with the goal of developing innovative strategies and economic incentives to improve the prevention and diagnosis of RHD in high-risk, financially disadvantaged countries and low-income communities across the United States. The program will use Children’s robust telemedicine infrastructure to connect co-collaborators around the world, as well as train the next generation of globally minded cardiovascular researchers.

Angioletta Rheumatic Heart Disease

Rheumatic Heart Disease Center Launches with $3.7 Million AHA Grant

Angioletta Rheumatic Heart Disease

Ten-year-old Angioletta was clinically diagnosed with rheumatic heart disease in 2014 (severe leakage of her mitral valve). She’s been medically managed at the clinic Children’s helps support and conducts research at in Gulu, and she is a very active participant in the support group led by Children’s National research assistant, Amy Scheel. Angioletta hasn’t had any major complications, but her only hope for long-term survival is to undergo open heart surgery to replace her abnormal valve. Experts are looking towards the research from the new Center to help prevent future generations of children like Angioletta from developing RHD.

Known as the ‘world’s forgotten disease,’ Rheumatic Heart Disease (RHD) is caused by untreated streptococcal throat infections that progress into acute rheumatic fever (ARF) and eventually weaken the valves of the heart. It is the most common cardiovascular disease in children and young adults globally – affecting nearly 33 million people and causing 345,000 deaths annually – yet, it is preventable with early detection and access to penicillin.

To help end the epidemic, Children’s National Health System has been awarded a $3.7 million grant from the American Heart Association (AHA) to launch a Rheumatic Heart Disease Center, with the goal of developing innovative strategies and economic incentives to improve the prevention and diagnosis of RHD in high-risk, financially disadvantaged countries and low-income communities across the United States.

Children’s National is one of four centers in the AHA’s Strategically Focused Children’s Research Network, which is dedicated to improving children’s heart health and reducing the global burden of cardiovascular disease and stroke. AHA selected Children’s for the grant based on its proven record of global collaboration to solve complex health issues and the potential impact of this research. The program will use Children’s robust telemedicine infrastructure to connect co-collaborators around the world, as well as train the next generation of globally minded cardiovascular researchers.

“While it’s often thought that we’ve already beaten rheumatic heart disease, data shows there’s nearly no decrease in mortality rates in low-income countries. The disease is endemic in Sub-Saharan Africa, and some poverty-stricken communities in the U.S. are hit nearly as hard,” said Craig Sable, M.D., associate division chief of cardiology. “We are thrilled to receive this funding from the AHA, which will help us close the research gap for this neglected disease and change the plight of millions of children around the world.”

About the center and research focus areas

Over the next four years, the Rheumatic Heart Disease Center, led by Children’s National Heart Institute experts Dr. Sable and Andrea Beaton, M.D., cardiologist, along with RHD leaders around the globe, will develop evidence-based strategies to strengthen the health system’s response to RHD through synergistic basic, clinical and population science research along the entire spectrum of the disease.

Andrea Beaton and Craig Sable

The Rheumatic Heart Disease Center, led by Children’s National Heart Institute experts Andrea Beaton, M.D., and Craig Sable, M.D., along with RHD leaders around the globe, will develop evidence-based strategies to strengthen the health system’s response to RHD.

The basic research project, led by James Dale, M.D., chief of the division of infectious disease at the University of Tennessee in Memphis, will work to better define the immune system response to Group A Streptococcal (GAS) infection, or strep throat, paving the way for vaccine development. In collaboration with a partner site in Cape Town, South Africa, experts will recruit 300 children ages 5-15 to participate for 24 months in a study capturing and classifying various strains of the GAS bacteria. Similar to the common flu, the strains of GAS bacteria vary from region to region and year to year. By identifying immune system targets, or how our bodies fight GAS, the research can inform the creation of effective and long-lasting vaccines.

Dr. Beaton will lead the clinical project that will work to improve understanding and detection of ARF, the precursor to RHD. According to Dr. Beaton, the current, outdated paradigm is that patients with RHD at one point experienced a full-blown episode of ARF – including fever, severe joint pains and rash. These symptoms should be unmistakable and prompt treatment, but in truth the disease remains vastly underdiagnosed in high-risk regions. Through an on-the-ground partnership with experts at Mulago National Referral Hospital in Uganda, the clinical project will work to enroll over 1,000 children ages 3-18 with more subtle symptoms, potentially suggestive of ARF, in order to paint a more accurate picture of the disease in Africa today.

“The gap between the low number of children diagnosed with ARF and the high number of young adults with advanced RHD remains one of the most challenging mysteries and barriers to improved RHD prevention,” said Dr. Beaton. “For the first time, we will systematically characterize the clinical, laboratory and echocardiographic features of ARF in low-resource settings, with the goal of developing a biological signature for ARF that can be translated into a diagnostic test and improve detection.”

Dr. Beaton expects that this research could benefit other related diseases too, such as kidney disease or serious skin infections.

The population research project, led by David Watkins, M.D., M.P.H., an expert in epidemiological and economic modeling at the University of Washington in Seattle, will work to build an economic case for prevention around the world, using the data from the basic and clinical work. The goal is to identify local gaps in delivery of health services for disease prevention and treatment and to measure the cost-effectiveness of RHD interventions, as well as the cost of inaction – especially as patients suffering from advanced RHD are often in the prime of their productive, adult lives. Researchers anticipate the findings will provide effective tools for addressing RHD in other endemic countries too.

Taking telemedicine to heart

For seven years, a Children’s National team has worked on new technologies to blunt the severity of rheumatic heart disease around the world, vastly improving patients’ chances of avoiding serious complications.

Rheumatic heart disease (RHD) is caused by repeated infections from the same bacteria that cause strep throat, which progressively lead to worsening inflammation of the heart’s valves with each successive infection. Over time, these valves thicken with scar tissue and prevent the heart from effectively pumping life-sustaining, oxygenated blood. The devastating condition, which was endemic in the United States before 1950, is now so rare that few outside the medical community have even heard of it. But in the developing world, explains Craig Sable, M.D., director of echocardiography and pediatric cardiology fellowship training and medical director of telemedicine at Children’s National Health System, RHD is nearly as common as HIV.

“RHD is the world’s forgotten disease,” Dr. Sable says. An estimated 32.9 million people worldwide have this condition, most of whom reside in low- to middle-income countries — places that often lack the resources to effectively diagnose and treat it.

Dr. Sable, Andrea Z. Beaton, M.D., and international colleagues plan to overturn this paradigm. For the last seven years, the team has worked on developing new technologies that could blunt the severity of RHD, vastly improving patients’ chances of avoiding its most serious complications.

At the heart of their approach is telemedicine — the use of telecommunications and information technology to provide clinical support for doctors and other care providers who often practice a substantial distance away. Telemedicine already has proven extremely useful within resource-rich countries, such as the United States, according to Dr. Sable. He and Children’s National colleagues have taken advantage of it for years to diagnose and treat pediatric disease from a distance, ranging from diabetes to asthma to autism. In the developing world, he says, it could be a game-changer, offering a chance to equalize healthcare between low- and high-resource settings.

In one ongoing project, a team led by Drs. Sable and Beaton is using telemedicine to screen children for RHD, a critical step to making sure that kids whose hearts already have been damaged receive the antibiotics and follow-up necessary to prevent further injury. After five years of working in Africa, the team recently expanded their project to Brazil, a country riddled with the poverty and overcrowding known to contribute to RHD.

Starting in 2014, the researchers began training four non-physicians, including medical technicians and nurses, to use handheld ultrasound machines to gather the precise series of heart images required for RHD diagnosis. They deployed these healthcare workers to schools in Minas Gerais, the second-most populous state in Brazil, to screen children between the ages of 7 and 18, the population most likely to be affected. With each worker scanning up to 30 children per day at 21 area schools, the researchers eventually amassed nearly 6,000 studies in 2014 and 2015.

Each night, the team on the ground transmitted their data to a cloud server, from which Children’s cardiologists, experts in RHD, and a regional hospital, Universidade Federal de Minas Gerais, accessed and interpreted the images.

“There was almost zero downtime,” Dr. Sable remembers. “The studies were transferred efficiently, they were read efficiently, and the cloud server allowed for easy sharing of information if there was concern about any questionable findings.”

In a study published online on November 4, 2016 in the Journal of Telemedicine and Telecare, Dr. Sable and colleagues reported the project’s success. Together, the team diagnosed latent heart disease in 251 children — about 4.2 percent of the subjects screened — allowing these patients to receive the regular antibiotics necessary to prevent further valve damage, and for those with hearts already badly injured to receive corrective surgery.

The researchers continued to collect data after the manuscript was submitted for publication. The team, which includes Drs. Bruno R. Nascimento, Adriana C. Diamantino, Antonio L.P. Ribeiro and Maria do Carmo P. Nunes, has screened a total of roughly 12,000 Brazilian schoolchildren to date.

Dr. Sable notes there is plenty of room for improvement in the model. For example, he says, the research team has not found a low-bandwidth solution to directly transmit the vast amount of data from each screening in real time, which has caused a slight slowdown of information to the hospital teams. The team eventually hopes to incorporate RHD screenings into annual health exams at local health clinics, sidestepping potential drawbacks of school day screenings.

Overall, being able to diagnose RHD using non-physicians and portable ultrasounds could eventually help Minas Gerais and additional low- to middle-income areas of the world where this disease remains endemic reach the same status as the United States and other resource-heavy countries.

“We’re putting ultrasound technology in the hands of people who otherwise wouldn’t have it,” says Dr. Sable, “and it could have a huge impact on their overall health.”

This work was supported by a grant from the Verizon Foundation and in-kind donations from General Electric and ViTelNet.

Rheumatic heart disease is a family affair

Parasternal long axis echocardiographic still frames in early systole in black and white and color Doppler of RHD-positive index case, sibling, and mother.

Parasternal long axis echocardiographic still frames in early systole in black and white and color Doppler of RHD-positive index case, sibling, and mother.

Siblings of children in Northern Uganda with latent rheumatic heart disease (RHD) are more likely to have the disease and would benefit from targeted echocardiographic screening to detect RHD before it causes permanent damage to their heart valves, according to an unprecedented family screening study.

RHD results from a cascade of health conditions that begin with untreated group A β-hemolytic streptococcal infection. In 3 percent to 6 percent of cases, repeat strep throat can lead to acute rheumatic fever. Almost half of children who experience acute rheumatic fever later develop chronic scarring of the heart valves, RHD.  RHD affects around 33 million people and occurs most commonly in low-resource environments, thriving in conditions of poverty, poor sanitation, and limited primary healthcare. Treating streptococcal infections can prevent a large percentage of children from developing RHD, but these infections are difficult to diagnose in low-resource settings.

Right now, kids with RHD often are not identified until they reach adolescence, when the damage to their heart valves is advanced and severe cardiac symptoms or complications develop. In such countries, cardiac specialists are rare, and intervention at an advanced stage is typically too expensive or unavailable.  Echocardiographic screening can “see” RHD before symptoms develop and allow for earlier, more affordable, and more practical intervention. A team led by Children’s National Health System clinicians and researchers conducted the first-ever family echocardiographic screening study over three months to help identify optimal strategies to pinpoint the families in Northern Uganda at highest RHD risk.

“Echocardiographic screening has the potential to be a powerful public health strategy to lower the burden of RHD around the world,” says Andrea Beaton, M.D., a cardiologist at Children’s National and the study’s senior author. “Finding the 1 percent of vulnerable children who live in regions where RHD is endemic is a challenge. But detecting these silent illnesses would open the possibility of providing these children monthly penicillin shots – which cost pennies and prevent recurrent streptococcal infections, rheumatic fever, and further valve damage.”

The research team leveraged existing school-based screening data in Northern Uganda’s Gulu District and recruited 60 RHD-positive children and matched them with 67 kids attending the same schools who were similar in age and gender but did not have RHD. After screening more than 1,000 parents, guardians, and first-degree family members, they found that children with RHD were 4.5 times as likely to have a sibling who definitely had RHD.

“Definite RHD was more likely to be found in mothers, with 9.3 percent (10/107 screened) having echocardiographic evidence of definite RHD, compared to fathers 0 percent (0/48 screened, p = 0.03), and siblings 3.3 percent (10/300 screened, p = 0.02),” writes lead author Twalib Aliku, School of Medicine, Gulu University, and colleagues. “There was no increased familial, or sibling risk of RHD in the first-degree relatives of RHD-positive cases (borderline & definite RHD) versus RHD-negative cases. However, RHD-positive cases had a 4.5 times greater chance of having a sibling with definite RHD (p = 0.05) and this risk increased to 5.6 times greater chance if you limited the comparison to RHD-positive cases with definite RHD (n = 30, p = 0.03.”

The paper, “Targeted Echocardiographic Screening for Latent Rheumatic Heart Disease in Northern Uganda,” was published recently by PLoS and is among a dozen papers published this year about the group’s work in Africa, done under the aegis of the Children’s Research Institute global health initiative.

The World Health Organization previously has prioritized screening household contacts when an index case of tuberculosis (TB) is identified, the authors note. Like TB, RHD has a strong environmental component in that family members are exposed to the same poverty, overcrowding, and circulating streptococcal strains. In a country where the median age is 15.5, it is not practical to screen youths without a detailed plan, Dr. Beaton says. Additional work would need to be done to determine which tasks to shift to nurses, who are more plentiful, and how to best leverage portable, hand-held screening machines.

“Optimal implementation strategies, the who, when, in what setting, and how often to screen, have received little study to date, yet these details are critical to developing cost-effective and sustainable screening programs,” Aliku and co-authors write. “Our study suggests that siblings of children identified with latent RHD are a high-risk group, and should be prioritized for screening.”

Related resources:  Research at a Glance