Discussion

In this study, we observed a decrease, improvement, or delay in the progression of rheumatic aortic regurgitation and mitral regurgitation in rheumatic heart disease patients who regularly underwent benzathine penicillin G prophylaxis. Conversely, we found a significant increase in valve insufficiencies in those who underwent benzathine penicillin G prophylaxis irregularly. It is known that without regular benzathine penicillin G prophylaxis application to rheumatic heart disease patients, deterioration in carditis may occur over time. ^{Reference Araújo, Goulart and Meira11–Reference Tubridy-Clark and Carapetis13} The purpose of early diagnosis can be considered to halt or regress the disease to a less severe form with secondary benzathine penicillin G prophylaxis. The main cause of morbidity and mortality resulting from acute rheumatic fever is recurrent acute rheumatic fever attacks and rheumatic heart disease with its associated complications (heart failure, arrhythmia, stroke, thromboembolic events, death). ^{Reference Araújo, Goulart and Meira11,Reference Karthikeyan12}

Although some studies suggest that rheumatic heart disease lesions may persist or worsen despite secondary antibiotic prophylaxis, the existing data are insufficient and of low quality, so reliable conclusions about the prognosis of rheumatic heart disease cannot be made. Until better studies are conducted, we don’t have good evidence, but also we have to make evidence-based decisions. These decisions will have important practical implications, such as the use of echocardiography during the acute phase and follow-up, and the duration of secondary prophylaxis for acute rheumatic fever (ARF) diagnosis and rheumatic heart disease patients. ^{Reference Tubridy-Clark and Carapetis13} While reliable conclusions about the prognosis of rheumatic heart disease were not provided in some retrospective studies, we believe that the long-term follow-up of patients in our study by the same paediatric cardiologist for an average of 4.92 years (1–8 years) enhances the quality and reliability of the study. Meanwhile, the fact that some of our rheumatic heart disease patients with increased valve insufficiencies (although the number of cases is small) were in the group that applied irregular secondary antibiotic prophylaxis highlights the importance of antibiotic prophylaxis. Some rheumatic heart disease progressions can be prevented with regular benzathine penicillin G prophylaxis. ^{Reference Karthikeyan12,Reference Beaton, Okello and Rwebembera14} The prevalence of rheumatic heart disease in the population is five to ten times higher than clinical rheumatic heart disease. ^{Reference Marijon, Ou and Celermajer15,Reference Lamichhane, Patel and Al Mefleh16}

Incomplete adherence to secondary prevention measures increases the risk of recurrent acute rheumatic fever and worsening of rheumatic heart disease after each acute rheumatic fever recurrence. Optimising adherence and ensuring safe and adequate drug supply are key to the success of secondary prevention, and a distribution model involving special services, case management, and family support can enhance adherence to secondary prevention in the acute rheumatic fever/ rheumatic heart disease population. ^{Reference Kevat, Gunnarsson, Reeves and Ruben17–Reference Beaton, Okello and Aliku19} In fact, penicillin has been the cornerstone of acute rheumatic fever treatment for decades, and there is no other proven treatment that alters the likelihood or severity of rheumatic heart disease after an acute rheumatic fever attack. ^{Reference Beaton, Okello and Aliku19}

Approximately 55% (180/326) of our acute rheumatic fever/ rheumatic heart disease patients, who were followed up for an average of 4.92 years, were diagnosed with rheumatic heart disease. The patients diagnosed with rheumatic heart disease were typically referred to our clinic with other complaints (pre-sports assessment, chest pain, Syn. chorea, dizziness, syncope, etc.) and were asymptomatic. Results from studies conducted over the past 20 years, using echocardiography effectively in the diagnosis of acute rheumatic fever, have reported rheumatic heart disease rates up to 53%. Despite the absence of auscultation findings in most studies related to rheumatic heart disease, echocardiography has demonstrated mitral or aortic valve insufficiency in acute rheumatic fever patients. ^{Reference Zühlke, Beaton and Engel3,Reference Reményi, Wilson and Steer6,Reference Gerber, Baltimore and Eaton7,Reference Pandian, Kim and Arias-Godinez10,Reference Hunter, Monaghan, Lloyd, Pecoraro, Doubell and Herbst20} The high rate of rheumatic heart disease in our study suggests that the effectiveness and reliability of echocardiography in diagnosing rheumatic heart disease are higher than clinical examination. Both the World Health Organization and the World Heart Federation support rheumatic heart disease screening for rheumatic heart disease in moderate- and high-risk areas. ^{Reference Wyber, Grainger Gasser and Thompson21–Reference Bottomley, Jones and Claassens23}

Recent studies have strongly supported the use of portable echocardiography for rheumatic heart disease screening in developing countries. The detection rate of rheumatic heart disease patients by echocardiography has been shown to be 10 times higher compared to auscultation. ^{Reference Marijon, Ou and Celermajer15} In some school screenings, this rate was found to be 2.3%, and in some studies using echocardiography for screening, the prevalence was detected to be 2.3 per 1000. ^{Reference Chillo, Mutagaywa and Nkya25–Reference Beaton, Okello, Lwabi, Mondo, McCarter and Sable28} Optimising case detection in this way maximises the chance of preventing advanced rheumatic heart disease. ^{Reference Marijon, Celermajer and Tafflet29} Adding echocardiography to rheumatic heart disease screening protocols leads to a much higher estimated prevalence, which is 10 times higher than that detected by clinical screening alone. However, in many echocardiographic screening studies, rheumatic heart disease prevalence has been found to range from 8 to 57 per 1000 children. Globally, it is estimated that there could be rheumatic heart disease in 62–78 million individuals, resulting in nearly 1.4 million deaths annually. ^{Reference Dougherty, Khorsandi and Herbst30} When the child population rates of the 27 European Union member states were examined, it was found that while the child population rate was 18.1% on average in the European Union in 2022, it was higher in Turkey at 26.5%. According to the Address-Based Population Registration System, as of the end of 2022, there were 22,578,378 children aged 0–17 in Turkey. Among these children, 16,911,205 (74.9%) are aged between 5 and 17. ^{Reference Dougherty, Khorsandi and Herbst30} Although there are many differences between countries (such as socio-economic status, genetic predisposition, possible pathogenicity of group A β-haemolytic streptococcal), when we adapt the rheumatic heart disease prevalence found in echocardiographic screening studies in medium- and high-risk countries like ours to Turkey, it is between 135,000 and 963,000 in the 5–17 age group. However, we think that more screening programmes and special studies should be conducted to investigate the incidence of rheumatic heart disease in Turkey.

In clinical practice, the use of echocardiography and Doppler technology has increased the detection rate of rheumatic heart disease, allowing for early diagnosis and intervention even in asymptomatic, latent rheumatic heart disease cases. This has contributed to the reduction of morbidity and mortality associated with rheumatic heart disease. ^{Reference Reményi, Wilson and Steer6}

Recent technological advancements in echocardiography and other diagnostic methods, along with the development of new and modified diagnostic criteria, have achieved significant progress in the diagnosis and monitoring of rheumatic heart disease. The use of echocardiography in rheumatic heart disease and acute phases of rheumatic carditis has proven beneficial, surpassing clinical examination alone. This is because the rate of detecting carditis on echocardiography is higher, even in cases of acute rheumatic fever without clinical symptoms. ^{Reference Araújo, Goulart and Meira11,Reference Karthikeyan12}

Although 7.8% of our patients had moderate rheumatic heart disease, these patients lacked symptoms and auscultatory findings. In studies reporting rheumatic heart disease, despite the absence of auscultatory findings, echocardiography has shown mitral regurgitation and aortic regurgitation in acute rheumatic fever patients. ^{Reference Pandian, Kim and Arias-Godinez10,Reference Hunter, Monaghan, Lloyd, Pecoraro, Doubell and Herbst20} Sydenham chorea is a hyperkinetic disorder characterised by irregular, jerky movements affecting the face, extremities, and trunk, associated with emotional variability and hypotonia. Sydenham chorea is a widely recognised post-streptococcal autoimmune disorder of the central nervous system. ^{Reference Marques-Dias, Mercadante, Tucker and Lombroso32} Studies have reported the co-occurrence of rheumatic carditis with Sydenham chorea to range between 60% and 87.8% (34–36.)

Our patients had a clinical presentation of Sydenham chorea in 7.8% of cases, with no auscultatory findings or murmurs detected during cardiac examination. However, all patients referred due to Sydenham chorea were found to have subclinical rheumatic heart disease on echocardiography. The incidence of acute rheumatic fever varies greatly depending on socio-economic development, remaining a public health issue in low- and middle-income countries. The adherence to secondary antibiotic prophylaxis was found to be higher in patients with Sydenham chorea. This could be attributed to the physical and psychological impact of Sydenham chorea, which may affect patients more significantly than other clinical manifestations.

Preventing recurrent Group A streptococcal pharyngitis attacks is the most effective method to prevent the development of serious rheumatic heart disease. In populations where the incidence of rheumatic fever is particularly high, it is recommended to administer benzathine penicillin G every 3 weeks, as serum drug levels can fall below a protective level before the fourth week following the administration of this penicillin dose (Class I, Level of Evidence A). ^{Reference Lue, Wu, Wang, Wu and Wu36} In our patients, the frequency of irregular secondary benzathine penicillin G prophylaxis was 22.2%, and it was found that mitral valve insufficiency increased in these patients. Possible reasons for irregular secondary benzathine penicillin G prophylaxis in acute rheumatic fever include difficulties in accessing healthcare centres, painful intramuscular administration, lack of awareness about the importance of prophylaxis, freezing of the preparation in the syringe, concerns about allergic reactions to the medication, and the long duration of secondary penicillin prophylaxis.

Secondary prevention is a strategy aimed at preventing the recurrence of acute rheumatic fever and the progression of rheumatic heart disease to a severe form by continuing antibiotics in individuals who have previously experienced acute rheumatic fever or already have rheumatic heart disease. Regular administration of secondary benzathine penicillin G prophylaxis reduces the rates of streptococcal pharynx/tonsil infections and recurrence of acute rheumatic fever. ^{Reference Carapetis, Beaton and Cunningham37,Reference Katzenellenbogen, Ralph, Wyber and Carapetis38} Early detection of acute rheumatic fever and antibiotic use for secondary prevention are essential in combating rheumatic heart disease. However, a treatment strategy involving intramuscular benzathine penicillin G prophylaxis injections every 4 weeks for at least 5–10 years becomes the key determinant of success in preventing acute rheumatic fever and rheumatic heart disease recurrence. Lack of funding, distance to facilities, shortage of medical resources, fear of side effects, painful injections, and lack of awareness about the importance of treatment have been reported as the main reasons for poor adherence to secondary prevention. ^{Reference Kevat, Gunnarsson, Reeves and Ruben17,Reference Lue, Wu, Wang, Wu and Wu36}

The early detection of subclinical rheumatic heart disease can contribute to the reversal of mild lesions, delay the progression of the disease, reduce morbidity and mortality, and improve the quality of life for patients. Echocardiography is the gold standard method for screening and confirming latent rheumatic heart disease cases. Although there are doubts about the effectiveness of secondary antibiotic prophylaxis in randomised controlled trials, ^{Reference Zühlke, Engel and Lemmer39} we believe that adherence to secondary antibiotic prophylaxis following the diagnosis of subclinical rheumatic heart disease with echocardiography in children from regions with moderate to high risk for rheumatic heart disease, such as Turkey, demonstrates the effectiveness and safety profile of reducing the risk of rheumatic heart disease. Nevertheless, it is important to confirm these results with large-scale randomised controlled trials.

Further research is needed before implementing population level screening. Secondary benzathine penicillin G prophylaxis alone may not be sufficient to prevent rheumatic heart disease; therefore, there is a need for improvements in health literacy, access to adequate healthcare services, increasing community awareness about the disease through technology and internet tools, improving overcrowded conditions and housing, and addressing socio-economic conditions, along with advancements in group A streptococcus vaccination.

Limitations of the study may include its retrospective nature and the small number of cases.