In a randomized controlled trial of close to 1000 Ugandan children and youth with latent rheumatic heart disease (RHD), those who received monthly injections of penicillin G benzathine for 2 years had less disease progression than those who did not.
RHD, a valvular heart disease caused by rheumatic fever that develops after untreated Streptococcus pyogenes infection, is the most common acquired cardiovascular disease among children and young adults.
"It is clear that secondary antibiotic prophylaxis can improve outcomes for children with echo-detected rheumatic RHD," co-lead author of the study, Andrea Z. Beaton, MD, told theheart.org | Medscape Cardiology.
"There is huge potential here, but we are not quite ready to advocate for this strategy as a broad public health approach," said Beaton, a pediatric cardiologist at Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
"We need to understand more the practical translation of this strategy to a low-resourced public health system at scale, improve [penicillin G benzathine] supply, and improve community and healthcare worker knowledge of this disease."
Beaton presented the findings in the at the American Heart Association (AHA) 2021 Scientific Sessions, and the study was simultaneously published in the New England Journal of Medicine on November 13.
The GOAL trial — or the Gwoko Adunu pa Lutino trial, meaning "protect the heart of a child" — screened 102,200 children and adolescents aged 5 to 17. Of these kids and teenagers, 926 (0.9%) were diagnosed with latent RHD based on a confirmatory electrocardiogram.
"For now, I would say, if you are screening, then kids found to have latent RHD should be put on prophylaxis," Beaton said.
"I think this is also a powerful call for more research [severely lacking in RHD]," to improve risk stratification, determine how to implement screening and prophylaxis programs, and develop new and better approaches for RHD prevention and care.
"This essential trial partially addresses the clinical equipoise that has developed regarding penicillin administration in latent RHD," said Gabriele Rossi, MD, MPH, who was not involved with this research.
It showed that out of the final 818 participants included in the modified intention-to-treat analysis, a total of 3 (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, compared with 33 participants (8.2%) in the control group (risk difference, −7.5 percentage points; 95% CI, −10.2 to −4.7; P < .001).
"This is a significant difference," Rossi, from Médecins Sans Frontières (Doctors Without Borders), Brussels, Belgium, told theheart.org | Medscape Cardiology in an email, noting that, however, it is not known what happens after 2 years.
The authors estimated that 13 children or adolescents with latent rheumatic heart disease would need to be treated to prevent disease progression in 1 person at 2 years, which is "acceptable," he continued.
However, "screening, diagnosis, clinical follow-up, treatment, and program management [would] require substantial strengthening of health systems and the workforce, which is still far from being realizable in many African and low-income-country settings," Rossi noted.
Related Study in Italy
Previously, Rossi and colleagues conducted a trial, published in 2019, that showed it was feasible to screen for asymptomatic RHD among refugee/migrant children and youths in Rome, Italy.
From February 2016–January 2018, they screened more than 650 refugee/migrant children and adolescents who were younger than 18. They came largely from Egypt (65%) but also from 22 other countries and were often unaccompanied or with just one parent.
The number needed to screen was 5 to identify a child/youth with borderline RHD and around 40 to identify a child/youth with definite RHD.
Rossi noted that local resurgences of RHD have also been also documented in high-income countries such as Europe, Australia, New Zealand, Canada and the US, often among disadvantaged indigenous people, as described in a 2018 Letter to the Editor in the New England Journal of Medicine.
Beaton noted that a review of 10-year data (2008-2018) from 22 US pediatric institutions showed that, in the US, the prevalence of RHD "is higher in immigrant children from RHD endemic areas, but because of total numbers, more RHD cases than not are domestic." Children living in more deprived communities are at risk for more severe disease, and the burden in US territories is also quite high. Beaton led that review, which was published this past August in the Journal of the American Heart Association.
Screening and Secondary Prophylaxis
The aim of the current GOAL study was to evaluate if screening and treatment with penicillin G benzathine could detect and prevent progression of latent rheumatic heart disease in 5- to 17-year-olds living in Gulu, Uganda. The trial was conducted from July 2018–October 2020.
"School education and community sensitization was done prior to the trial," through radio shows or school-based education, Beaton explained. About 99% of the children/adolescents/families agreed to be screened.
The group has been conducting echo screening research in Uganda for 10 years, she noted. They have developed peer group and case manager strategies to aid participant retention, as they describe in an article about the study protocol.
The screening echocardiograms were interpreted by about 30 providers and four cardiologists reviewed confirmatory echocardiograms.
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).
Once children and adolescents have moderate/severe RHD, there is not much that can be done in lower-middle income countries, where surgery for this is uncommon, Beaton explained. Around 30% of children and adolescents with this condition who come to clinical attention in Uganda die within 9 months.
Beaton and colleagues have just started a trial to investigate the burden of RHD among Native American youth, which has not been studied since the 1970s.
They also have an ongoing study looking at the efficacy of a pragmatic, community-based sore throat program to prevent RHD.
"Unfortunately, this strategy has not worked well in low-to-middle income countries, for a variety of reasons so far," Beaton noted, and the cost-effectiveness of this preventive strategy is questionable.
The trial was supported by the Thrasher Research Fund, Gift of Life International, Children's National Hospital Foundation (Zachary Blumenfeld Fund and Race for Every Child [Team Jocelyn]), the Elias–Ginsburg Family, Wiley Rein, Philips Foundation, AT&T Foundation, Heart Healers International, the Karp Family Foundation, Huron Philanthropies, and the Cincinnati Children’s Hospital Heart Institute Research Core. Beaton and Rossi have disclosed no relevant financial relationships.
American Heart Association (AHA) 2021 Scientific Sessions: Abstract 227. Presented November 13, 2021.
N Engl J Med. Published November 13, 2021. Abstract
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