Subsequent Rheumatic Heart Disease Research Articles

Evaluation of a Community-Led Program for Primordial and Primary Prevention of Rheumatic Fever in Remote Northern Australia.

Environmental factors including household crowding and inadequate washing facilities underpin recurrent streptococcal infections in childhood that cause acute rheumatic fever (ARF) and subsequent rheumatic heart disease (RHD). No community-based ‘primordial’-level interventions to reduce streptococcal infection and ARF rates have been reported from Australia previously. We conducted a study at three Australian Aboriginal communities aiming to reduce infections including skin sores and sore throats, usually caused by Group A Streptococci, and ARF. Data were collected for primary care diagnoses consistent with likely or potential streptococcal infection, relating to ARF or RHD or related to environmental living conditions. Rates of these diagnoses during a one-year Baseline Phase were compared with a three-year Activity Phase. Participants were children or adults receiving penicillin prophylaxis for ARF. Aboriginal community members were trained and employed to share knowledge about ARF prevention, support reporting and repairs of faulty health-hardware including showers and provide healthcare navigation for families focusing on skin sores, sore throat and ARF. We hypothesized that infection-related diagnoses would increase through greater recognition, then decrease. We enrolled 29 participants and their families. Overall infection-related diagnosis rates increased from Baseline (mean rate per-person-year 1.69 [95% CI 1.10–2.28]) to Year One (2.12 [95% CI 1.17–3.07]) then decreased (Year Three: 0.72 [95% CI 0.29–1.15]) but this was not statistically significant (p = 0.064). Annual numbers of first-known ARF decreased, but numbers were small: there were six cases of first-known ARF during Baseline, then five, 1, 0 over the next three years respectively. There was a relationship between household occupancy and numbers (p = 0.018), but not rates (p = 0.447) of infections. This first Australian ARF primordial prevention study provides a feasible model with encouraging findings.

Increased Breadth of Group A Streptococcus Antibody Responses in Children With Acute Rheumatic Fever Compared to Precursor Pharyngitis and Skin Infections.

BackgroundGroup A Streptococcus (GAS) causes superficial pharyngitis and skin infections as well as serious autoimmune sequelae such as acute rheumatic fever (ARF) and subsequent rheumatic heart disease. ARF pathogenesis remains poorly understood. Immune priming by repeated GAS infections is thought to trigger ARF, and there is growing evidence for the role of skin infections in this process.MethodsWe utilized our recently developed 8-plex immunoassay, comprising antigens used in clinical serology for diagnosis of ARF (SLO, DNase B, SpnA), and 5 conserved putative GAS vaccine antigens (Spy0843, SCPA, SpyCEP, SpyAD, Group A carbohydrate), to characterize antibody responses in sera from New Zealand children with a range of clinically diagnosed GAS disease: ARF (n = 79), GAS-positive pharyngitis (n = 94), GAS-positive skin infection (n = 51), and matched healthy controls (n = 90).ResultsThe magnitude and breadth of antibodies in ARF was very high, giving rise to a distinct serological profile. An average of 6.5 antigen-specific reactivities per individual was observed in ARF, compared to 4.2 in skin infections and 3.3 in pharyngitis.ConclusionsARF patients have a unique serological profile, which may be the result of repeated precursor pharyngitis and skin infections that progressively boost antibody breadth and magnitude.

Primary prevention of acute rheumatic fever.

Acute rheumatic fever (ARF) is an abnormal immune reaction following Streptococcus pyogenes (Strep A) infection of the throat, and likely the skin. Primary prevention is the prompt and appropriate antibiotic treatment of StrepA infection, and it can reduce the risk of developing ARF and subsequent rheumatic heart disease. This article explores current recommendations for primary prevention of ARF in Australia. People at increased risk of ARF should beoffered empirical antibiotic treatment of Strep A infections to reduce this risk. People at increased ARF risk include young Aboriginal and Torres Strait Islander people in remote Australia as well as those with a personal or family history of ARF and people from migrant communities in urban areas, including Māori and Pacific Island people. Risk-stratified primary prevention can reduce the inequitable burden of ARF and rheumatic heart disease in Australia.

A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease: new insights for improved secondary prophylaxis strategies.

BackgroundBenzathine benzylpenicillin G (BPG) is recommended as secondary prophylaxis to prevent recurrence of acute rheumatic fever and subsequent rheumatic heart disease (RHD). Following intramuscular injection, BPG is hydrolysed to benzylpenicillin. Little is known of the pharmacokinetics of benzylpenicillin following BPG in populations at risk of RHD.MethodsWe conducted a longitudinal pharmacokinetic study of children and adolescents receiving secondary prophylaxis throughout six monthly cycles of BPG. Dried blood spot samples were assayed with LC-MS/MS. Benzylpenicillin concentrations were analysed using non-linear mixed-effects modelling with subsequent simulations based on published BMI-for-age and weight-for-age data.ResultsEighteen participants contributed 256 concentrations for analysis. None had benzylpenicillin concentrations >0.02 mg/L for the full time between doses. The median duration above this target was 9.8 days for those with a lower BMI (<25 kg/m2), who also had lower weights, and 0 days for those with a higher BMI (≥25 kg/m2). Although fat-free mass was a key determinant of benzylpenicillin exposure after a standard dose of BPG, having a higher BMI influenced absorption and almost doubled (increase of 86%) the observed t½.ConclusionsFew children and adolescents receiving BPG as secondary prophylaxis will achieve concentrations >0.02 mg/L for the majority of the time between injections. The discordance of this observation with reported efficacy of BPG to prevent rheumatic fever implies a major knowledge gap relating to pharmacokinetic/pharmacodynamic relationships between benzylpenicillin exposure and clinical outcomes.

Assessing the burden of rheumatic heart disease among refugee children: a call to action.

In a recent editorial in The Lancet, Langlois and colleagues are adamant in advocating for a better and more universal access to healthcare for refugees landing in Europe [1]. The arguments of equity, social justice and cost–effectiveness are clearly explained in their comment. Among the different suggestions to improve the refugees’ health, the authors invite the policy makers to opt for strategies favoring the “provision of preventive care, including primary and secondary prevention of cardiovascular disease” which “could generate savings for health–care systems by alleviating the burden of stroke, and myocardial infarction”. Their advice, geared towards the betterment of the refugees’ adult population, needs to be further complemented by a strong call for providing primary and secondary preventive care for acquired cardiac diseases in refugee children. While acute rheumatic fever (ARF) has essentially vanished from industrialised countries since the latter half of the 20th century, the condition and its major sequel, rheumatic heart disease (RHD) remains an important public health concern in poor, developing and war–torn countries. Poverty, inadequate and disrupted primary healthcare systems are major contributors to the persistence and resurgence of ARF/RHD in these countries [2]. The estimate of the global burden of RHD has been recently established at 33 million existing cases, which is higher than the previous conservative 15.6 to 19.6 million cases in 2005 [3]. Emerging echocardiographic data following the seminal work of Marijon and colleagues [4], have contributed in revising these data, suggesting for a higher prevalence of subclinical RHD. In particular, according to a recent meta–analysis by Rothenbuler et al [5], among children aged below 18 years from 37 pooled countries, the prevalence of clinically silent rheumatic heart disease (21.1 per 1000 people, 95% confidence interval CI 14.1–31.4) would be about seven to eight times higher than that of clinically manifest disease (2.7 per 1000 people, 95% CI 1.6–4.4). South Asia and some African countries have very high prevalence data [5]. Although the significance of subclinical RHD is still not clear, follow up studies indicate that most Subclinical Definite RHD (according to World Heart Federation Criteria) [6] and at least a proportion of Borderline RHD, are likely to be true RHD requiring secondary prophylaxis [7]. To tackle the evolution of RHD, specific control programs based on the concurrent development of disease registers along with the consistent delivering of benzathine penicillin G injections, need to be strengthened by a decentralized echocardio–based active case finding activities, comprehensively integrated into the existing primary health care services. In this sense, the World Heart Federation’s non–communicable disease action plan is calling for a 25% reduction in premature mortality from RHD by the year 2025 (“25 by 25”) [6]. Photo: Medecins Sans Frontieres assists Syrian refugees in Roske, at the Hungary-Serbia border. Among the refugees arriving in Europe, half of them are children. Courtesy of Ana Lemos/MSF (2015). Unfortunately, this cost–effective strategy has not been routinely implemented in low–income and middle–income countries, because of the structural weaknesses of their health systems. The current enormous refugee crisis in Europe represents a paradigmatic translational shift: the health systems of the wealthy countries are now called to deal, in a substantial way, with the poor people and their diseases. The Syrian children, suffering from more than five years of displacement, have been forced to live in very dire conditions. Being exposed to the effects of the detrimental combination of seasonal harsh cold weather, overcrowding, poverty and very limited access to healthcare [8], they hold the classic risky profile for the development of ARF and subsequent RHD [9]. With an expected echocardiography–based screening detection rate of around 2%, many migrant children landing in Europe (Syrian, Afghan, Eritrean, Bangladeshi, and many others) could be timely identified and placed under prophylactic treatment for RHD. In 2015, more than 1 million asylum seekers arrived in Europe and half of them were children: the figure of 10 000 diagnosed subclinical and clinical RHD could be anticipated. Many more refugees are expected to land in Europe in 2016. Pilot studies aimed at proving the validity of these assumptions, while assessing the prevalence of RHD among refugee children, are urgently warranted. Decentralised diagnostic services for ARF/RHD, framed as routine screening through point–of care technologies (echocardiography and antigen tests for the rapid diagnosis of group A streptococcal pharyngitis) should be then considered at migrant/refugee pediatric community level. In view of the fact that severe RHD is lethal in the absence of surgical treatment, with a death toll of 275 000/year [10], the same arguments of social justice, equity and cost–effectiveness mentioned by Langlois and colleagues should apply here, especially for the silent and marginalized population of refugee and migrant children, often arriving in Europe unaccompanied and defenseless. Europe has the infrastructures, human and financial resources, and knowledge to act accordingly. It must not turn a blind eye to them.

Evolution, evidence and effect of secondary prophylaxis against rheumatic fever

The association between group A streptococcal infection and rheumatic fever (RF) was established in the early 20 th century. At the time, RF and subsequent rheumatic heart disease (RHD) were an untreatable scourge of young people in developed and developing countries. Resultingly, research efforts to understand, treat and prevent the disease were widepread. The development of antibiotics in the 1930s offered therapeutic promise, although antibotic treatment of acute RF had little impact. Improved understanding of the post-infectious nature of RF prompted attempts to use antibiotics prophylactically. Regular doses of sulphonamide antibiotics following RF appeared to reduce disease progression to RHD. Development of penicillin and later, benzathine penicillin G, was a further thereputic advance in the 1950s. No new prophylactic options against RF have emerged in the intervening 60 years, and delivery of regularly scheduled BPG injections remains a world wide challenge.

TCTAP A-126 Safety and Efficacy of Baloon Mitral Valvotomy in Juvenile Rheumatic Mitral Stenosis

Rheumatic fever and subsequent Rheumatic heart disease is still widely prevalent in many of Asian and African countries. Rheumatic heart disease causes major morbidity and mortality in younger population in such highly prevalent areas. Juvenile mitral stenosis in age group < 20 years varies

Primary Prevention of Acute Rheumatic Fever and Rheumatic Heart Disease With Penicillin in South African Children With Pharyngitis

Acute rheumatic fever and subsequent rheumatic heart disease remain significant in developing countries. We describe a cost-effective analysis of 7 strategies for the primary prevention of acute rheumatic fever and rheumatic heart disease in children presenting with pharyngitis in urban primary care clinics in South Africa. We used a Markov model to assess the cost-effectiveness of treatment with intramuscular penicillin using each of the following strategies: (1) empirical (treat all); (2) positive throat culture (culture all); (3) clinical decision rule (CDR) score ≥2 (CDR 2+); (4) CDR score ≥3 (CDR 3+); (5) treating those with a CDR score ≥2 plus those with CDR score <2 and positive cultures (CDR 2+, culture CDR negatives); (6) treating those with a CDR score ≥3 plus those with CDR score <3 and positive cultures (CDR 3+, culture CDR negatives); and (7) treat none. The strategies ranked in order from lowest cost were treat all ($11.19 per child), CDR 2+ ($11.20); the CDR 3+ ($13.00); CDR 2+, culture CDR negatives ($16.42); CDR 3+, culture CDR negatives ($23.89); and culture all ($27.21). The CDR 2+ is the preferred strategy at less than $150/quality-adjusted life year compared with the treat all strategy. A strategy of culturing all children compared with the CDR 2+ strategy costs more than $125 000/quality-adjusted life year gained. Treating all children presenting with pharyngitis in urban primary care clinics in South Africa with intramuscular penicillin is the least costly. A strategy of using a clinical decision rule without culturing is overall the preferred strategy. A strategy of culturing all children may be prohibitively expensive.

Potential of lipid core peptide technology as a novel self-adjuvanting vaccine delivery system for multiple different synthetic peptide immunogens.

This study demonstrates the effectiveness of a novel self-adjuvanting vaccine delivery system for multiple different synthetic peptide immunogens by use of lipid core peptide (LCP) technology. An LCP formulation incorporating two different protective epitopes of the surface antiphagocytic M protein of group A streptococci (GAS)--the causative agents of rheumatic fever and subsequent rheumatic heart disease--was tested in a murine parenteral immunization and GAS challenge model. Mice were immunized with the LCP-GAS formulation, which contains an M protein amino-terminal type-specific peptide sequence (8830) in combination with a conserved non-host-cross-reactive carboxy-terminal C-region peptide sequence (J8) of the M protein. Our data demonstrated immunogenicity of the LCP-8830-J8 formulation in B10.BR mice when coadministered in complete Freund's adjuvant and in the absence of a conventional adjuvant. In both cases, immunization led to induction of high-titer GAS peptide-specific serum immunoglobulin G antibody responses and induction of highly opsonic antibodies that did not cross-react with human heart tissue proteins. Moreover, mice were completely protected from GAS infection when immunized with LCP-8830-J8 in the presence or absence of a conventional adjuvant. Mice were not protected, however, following immunization with an LCP formulation containing a control peptide from a Schistosoma sp. These data support the potential of LCP technology in the development of novel self-adjuvanting multi-antigen component vaccines and point to the potential application of this system in the development of human vaccines against infectious diseases.

Intramuscular penicillin is more effective than oral penicillin in secondary prevention of rheumatic fever--a systematic review.

People with a history of rheumatic fever (RF) are at high risk of recurrent attacks and of developing rheumatic heart disease following a streptococcal throat infection. Giving penicillin to these people can prevent recurrent attacks of RF and subsequent rheumatic heart disease. However, there is no agreement on the most effective method of giving penicillin. To assess the effects of different penicillin regimens and formulations for preventing streptococcal infection and RF recurrence. We searched the Controlled Trials Register (Cochrane Library Issue 2, 2001), Medline (January 1966-July 2000), Embase (January 1985-July 2000), reference lists of articles, and contacted experts in the field. Randomised and quasi-randomised studies comparing: (i) oral with intramuscular penicillin; and (ii) 2- or 3-weekly with 4-weekly intramuscular penicillin in patients with previous RF. Two reviewers independently assessed trial quality and extracted data. Six studies were included (1,707 patients). Data were not pooled because of clinical and methodological heterogeneity of the trials. Four trials (1,098 patients) compared intramuscular with oral penicillin and all showed that intramuscular penicillin was more effective in reducing RF recurrence and streptococcal throat infections than oral penicillin. One trial (360 patients) compared 2-weekly with 4-weekly intramuscular penicillin. Penicillin given every 2 weeks was better at reducing RF recurrence (relative risk (RR) 0.52, 95% confidence interval (CI): 0.33-0.83) and streptococcal throat infections (RR 0.60, 95% CI: 0.42-0.85). One trial (249 patients) showed that 3-weekly intramuscular penicillin injections reduced streptococcal throat infections (RR 0.67, 95% CI: 0.48-0.92) compared with 4-weekly intramuscular penicillin. Intramuscular penicillin seemed to be more effective than oral penicillin in preventing RF recurrence and streptococcal throat infections. Two-weekly or 3-weekly injections appeared to be more effective than 4-weekly injections. However, the evidence is based on poor-quality trials and the use of outdated formulations of oral penicillin.

Penicillin for secondary prevention of rheumatic fever.

People with a history of rheumatic fever are at high risk of recurrent attacks of rheumatic fever and developing rheumatic heart disease following a streptococcal throat infection. Giving penicillin to these people can prevent recurrent attacks of rheumatic fever and subsequent rheumatic heart disease. However, there is no agreement on the most effective method of giving penicillin. To assess the effects of penicillin compared to placebo and the effects of different penicillin regimens and formulations for preventing streptococcal infection and rheumatic fever recurrence. We searched the Controlled Trials Register (Cochrane Library Issue 2, 2001), MEDLINE (1997 to July 2000), EMBASE (1998 to July 2000), reference lists of articles and we contacted experts in the field. Randomised and quasi-randomised studies comparing (i) penicillin with control, (ii) oral with intramuscular penicillin (iii) 2- or 3-weekly with 4-weekly intramuscular penicillin in patients with previous rheumatic fever. Two reviewers independently assessed trial quality and extracted data. Nine studies were included (n=3008). Data were not pooled because of heterogeneity. Overall, the methodological quality of included studies was poor. Three trials (n= 1301) compared penicillin with control. Only one of three studies showed that penicillin reduced rheumatic fever recurrence (RR 0.45, 95% CI 0.22 to 0.92) and streptococcal throat infection (RR 0.84, 95% CI 0.72 to 0.97). Four trials (n=1098) compared intramuscular with oral penicillin and all showed that intramuscular penicillin reduced rheumatic fever recurrence and streptococcal throat infections compared to oral penicillin. One trial (n= 360) compared 2-weekly with 4-weekly intramuscular penicillin. Penicillin given every two-weeks was better at reducing rheumatic fever recurrence (RR 0.52, 95% CI 0.33 to 0.83) and streptococcal throat infections (RR 0.60, 95% CI 0.42 to 0.85). One trial (n= 249) showed 3-weekly intramuscular penicillin injections reduced streptococcal throat infections (RR 0.67, 95% CI 0.48 to 0.92) compared to 4-weekly intramuscular penicillin. Intramuscular penicillin seemed to be more effective than oral penicillin in preventing rheumatic fever recurrence and streptococcal throat infections. Two-weekly or 3-weekly injections appeared to be more effective than 4-weekly injections. However, the evidence is based on poor quality of trials.

Molecular analysis of group A Streptococcus type emm18 isolates temporally associated with acute rheumatic fever outbreaks in Salt Lake City, Utah.

Acute rheumatic fever (ARF) and subsequent rheumatic heart disease are rare but serious sequelae of group A Streptococcus (GAS) infections in most western countries. Salt Lake City (SLC), Utah, and the surrounding intermountain region experienced a resurgence of ARF in 1985 which has persisted. The largest numbers of cases were encountered in 1985-1986 and in 1997-1998. Organisms with a mucoid colony phenotype when grown on blood agar plates were temporally associated with the higher incidence of ARF. To develop an understanding of the molecular population genetic structure of GAS strains associated with ARF in the SLC region, 964 mucoid and nonmucoid pharyngeal isolates recovered in SLC from 1984 to 1999 were studied by sequencing the emm gene. Isolates with an emm18 allele were further characterized by sequencing the spa, covR, and covS genes. Peak periods of ARF were associated with GAS isolates possessing an emm18 allele encoding the protein found in serotype M18 isolates. Among the serotype M18 isolates, the difference in the number of C repeats produced three size variants. Variation was limited in spa, a gene that encodes a streptococcal protective antigen, and covR and covS, genes that encode a two-component regulatory system that, when inactivated, results in a mucoid phenotype and enhanced virulence in mouse infection models. Pulsed-field gel electrophoresis showed a single restriction profile for serotype M18 organisms isolated during both peak periods of ARF. In SLC, the incidence of ARF coresurged with the occurrence of GAS serotype M18 isolates that have very restricted genetic variation.

Group A Streptococcus: allelic variation, population genetics, and host-pathogen interactions.

Group A Streptococcus (GAS) is a Gram-positive bacterium that is responsible for a wide range of human infections, including pharyngitis and tonsillitis, skin infections (impetigo, erysipelas, and cellulitis), sepsis, osteomyelitis, a toxic-shock syndrome, and necrotizing fasciitis (1). The organism is also responsible for nonsuppurative sequelae such as acute rheumatic fever and acute glomerulonephritis. Globally, GAS causes extensive human morbidity and mortality (1). In the US, approximately 10,000 cases of severe invasive GAS disease occur each year. Direct costs associated with pharyngitis in the US have been estimated to be $1 billion annually. Although antibiotic treatment has largely eliminated rheumatic fever and subsequent rheumatic heart disease in North America and Western Europe, these crippling forms of heart disease are still very common in the developing world and in certain indigenous populations in developed countries. The resurgence of GAS as a cause of serious human infections in the US, Europe, and elsewhere in the 1980s and into the 1990s has been thoroughly documented and has heightened public awareness about this organism (1). Disease resurgence, coupled with the lack of a licensed GAS vaccine and ongoing concern about acquisition of penicillin resistance, has stimulated renewed interest in the molecular pathogenesis of GAS disease. The return of GAS as a cause of serious infections was a strong reminder that biomedical science knows relatively little about the evolutionary and other forces that drive temporal variation in bacterial disease frequency and severity. GAS’s revival has also taught the importance of understanding the molecular basis of pathogen variation, not merely as a means to discriminate between clinically relevant strains, but to provide data relevant to pathogenesis, host adaptation, and the origin of new pathogenic forms. In this Perspective, we highlight certain aspects of the genetic variation present in GAS, and we stress the biomedical relevance of this diversity.

Cardiovascular Diseases in Nonwestern Societies

Cardiovascular Diseases in Nonwestern Societies* IN DISCUSSING cardiovascular disease in third and fourth world countries, I assume that we are referring to cardiovascular diseases in nonWestern societies. Considering the West, specifically including the United States, one finds very similar, although not homogeneous, characteristics as far as socioeconomic factors, dietary factors, and to some extent, even genetic and hereditary factors are concerned. However, as one studies the countries that are more undeveloped or those parts of the world such as India and Africa where there is still undevelopment, he expects to see a striking difference in all diseases but particularly in heart diseases. Although we will mention cardiovascular diseases other than coronary diseases, the bulk of this presentation will be concerned with coronary disease since this is the number one cardiovascular disease in the developed nations; and one may, therefore, infer that as countries move towards development, coronary disease will become more prevalent. I am sure that the racial differences in this country as far as cardiovascular diseases are concerned will be or have already been discussed, for these diseases are quite notable among American blacks. In my own experience, I have seen a tremendous change in the coronary disease attack rate among the American blacks over the last ten years. This is also true in the area of rheumatic fever and subsequent rheumatic heart disease. Approximately ten years ago, when I opened the Coronary Care Unit at Provident Hospital in Baltimore (90-95 percent black population), the most common problems treated in this four-bed unit were cardiac arrhythmias, congestive failure due to hypertensive disease, and occasionally ischemic heart disease of the subendocardial or incomplete variety. However, over the next ten years, we have noted a definite increase in the prevalence of ischemic heart disease, and it is not unusual in our present eleven-bed unit to find one-half of the patients with full-blown, transmural myocardial infarctions, a situation which was very difficult to come by, certainly, five to ten years ago. This experience has been noted by other cardiologists practicing primarily among a black population. As we explore cardiovascular disease outside of the Western countries, we will attempt to look into the various risk factors in terms of how they present themselves in other countries, since we believe that there are certain factors that tend to predispose persons (black or white) to coronary artery disease. Coronary artery disease affects all races of mankind, but there are important ethnic differences in the extent to