Plausible Role of NLRP3 Inflammasome and Associated Cytokines in Pathogenesis of Rheumatic Heart Disease.

Rheumatic heart disease (RHD) is a post-streptococcal sequela caused by Streptococcus pyogenes. The global burden of disease is high among people with low socio-economic status, with significant cases emerging every year despite global eradication efforts. The current treatment includes antibiotic therapies to target strep throat and rheumatic fever and valve replacement strategies as a corrective measure for chronic RHD patients. Valvular damage and valve calcification are considered to be the end-stage processes of the disease resulting from impairment of the endothelial arrangement due to immune infiltration. This immune infiltration is mediated by a cascade of events involving NLRP3 inflammasome activation. NLRP3 inflammasome is activated by wide range of stimuli including bacterial cell wall components like M proteins and leukocidal toxins like nicotinamide dehydrogenase (NADase) and streptolysin O (SLO) and these play a major role in sustaining the virulence of Streptococcus pyogenes and progression of RHD. In this review, we are discussing NLRP3 inflammasome and its plausible role in the pathogenesis of RHD by exploiting the host-pathogen interaction mainly focusing on the NLRP3 inflammasome-mediated cytokines IL-1ß and IL-18. Different therapeutic approaches involving NLRP3 inflammasome inactivation, caspase-1 inhibition, and blockade of IL-1ß and IL-18 are discussed in this review and may be promising for treating RHD patients.

Secondary prevention of rheumatic heart disease in Ethiopia: a multicenter study.

BACKGROUND: Ethiopia has a high acute rheumatic fever (ARF) and rheumatic heart disease (RHD) prevalence, and to our knowledge, there are no data on the status of secondary prevention in children with RHD. This study describes the status of secondary RHD prevention. METHODS: A multicenter, prospective study was performed on children aged 5-17 years with RHD in Ethiopia. Good adherence was defined as at least 80% completion of benzathine penicillin (BPG) or oral Amoxicillin within the previous year. The primary outcome measure was adherence to prophylaxis, expressed as a proportion. Socio-demographics, severity of RHD, and ARF recurrence were evaluated. RESULTS: A total of 337 children with a mean age of 12.9 ± 2.6 years were included. The majority (73%) had severe aortic/mitral disease. Participants were on BPG (80%) or Amoxicillin (20%) prophylaxis. Female sex (P = 0.04) use of BPG (0.03) and shorter mean duration of prophylaxis in months (48.5 ± 31.5 vs. 60.7 ± 33, respectively, P < 0.008) predicted good adherence. Running out of medications (35%), interrupted follow-up (27%), and the COVID-19 pandemic (26%) were the most common reasons for missing prophylaxis. Recurrence of ARF was higher in participants on Amoxicillin compared with BPG (40% vs. 16%, P < 0.001) and in those with poor adherence compared with good adherence (36.8% vs. 17.9%, respectively, P = 0.005). Type and duration of prophylaxis (OR 0.5, CI = 0.24, 0.9, P = 0.02; OR = 1.1, CI = 1.1, 1.2, P = 0.04, respectively), and sex (OR = 1.9, CI = 1.1, 3.4, P = 0.03) were independent predictors of poor adherence. CONCLUSION: Poor adherence is prevalent in Ethiopian children living with RHD. Amoxicillin is a suboptimal option for prophylaxis as its use is associated with lower adherence and a higher rate of ARF recurrence.

Intramuscular Immunization of Streptococcus pyogenes SF370 protein extract and identification of multiple virulence factors through proteomic profiling in RHD induced Balb/c mice.

Group A streptococcus (GAS) and autoimmunity are associated with heart related mitral valve damage, in adults. In this study Balb/c mice were intramuscularly immunized with S. pyogenes SF370 for 4 weeks. Prior to euthanization, physiological parameters like body weight and electrical signalling of the heart were recorded. After euthanization, the heart tissue homogenate was prepared and proteomic alterations were studied using SDS-PAGE and 2D electrophoresis. The expression levels of inflammatory genes like TNFα, IFNγ and TGF-ß were quantified using real time PCR. Insilico analysis was performed to identify the functions of hypothetical proteins and virulence factors involved in the induction of rheumatic carditis. The results showed a reduction in body weight, ulceration, inflammation, cardiac lesions and prolonged PR interval in mice immunized with S. pyogenes SF370, as a result of RHD. The heart related proteins like α-actinin, fatty acid binding protein-heart, myosin light chain 3, hemoglobin subunit alpha, myoglobin regulatory light chain 2, (ventricular/cardiac muscle isoform), myosin-6, troponin-1 were found to be up-regulated when compared with the control. The functional annotation of S. pyogenes (SF370) was carried out by retrieving 1696 identified proteins and 653 hypothetical protein sequences in NCBI genome database. The conserved domain was identified for 505 proteins. The pfam database documented that the super families of 279 sequences and 40 signal peptides enabled the classification of proteins in different categories like biological (20%), cellular (22%) and molecular functions (36%). Putative transcription repair coupling factor and putative lysine aminopeptidase N terminal are the two virulence factors identified by VICMPRED in S. pyogenes SF370. The two identified virulence factors are involved in altering the mice heart proteome and thereby controlling the streptococcus pyogenes infection. Thus, the results of the present study reveals the role of immunogenic proteins in induction of rheumatic carditis and to elucidate the molecular mechanisms leading to autoimmune reactions in Balb/c mice.

Determining the impact of Benzathine penicillin G prophylaxis in children with latent rheumatic heart disease (GOAL trial): Study protocol for a randomized controlled trial.

Rheumatic heart disease (RHD) remains a high prevalence condition in low- and middle-income countries. Most individuals with RHD present late, missing the opportunity to benefit from secondary antibiotic prophylaxis. Echocardiographic screening can detect latent RHD, but the impact of secondary prophylaxis in screen-detected individuals is not known. METHODS/DESIGN: This trial aims to determine if secondary prophylaxis with every-4-week injectable Benzathine penicillin G (BPG) improves outcomes for children diagnosed with latent RHD. This is a randomized controlled trial in consenting children, aged 5 to 17 years in Northern Uganda, confirmed to have borderline RHD or mild definite RHD on echocardiography, according to the 2012 World Heart Federation criteria. Qualifying children will be randomized to every-4-week injectable intramuscular BPG or no medical intervention and followed for a period of 2 years. Ongoing intervention adherence and retention in the trial will be supported through the establishment of peer support groups for participants in the intervention and control arms. A blinded echocardiography adjudication panel consisting of four independent experts will determine the echocardiographic classification at enrollment and trajectory through consensus review. The primary outcome is the proportion of children in the BPG-arm who demonstrate echocardiographic progression of latent RHD compared to those in the control arm. The secondary outcome is the proportion of children in the BPG-arm who demonstrate echocardiographic regression of latent RHD compared to those in the control arm. A sample size of 916 participants will provide 90% power to detect a 50% relative risk reduction assuming a 15% progression in the control group. The planned study duration is from 2018-2021. DISCUSSION: Policy decisions on the role of echocardiographic screening for RHD have stalled because of the lack of evidence of the benefit of secondary prophylaxis. The results of our study will immediately inform the standard of care for children diagnosed with latent RHD and will shape, over 2-3 years, practical and scalable programs that could substantially decrease the burden of RHD in our lifetime. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03346525. Date Registered: November 17, 2017.

Group G Streptococcus Induces an Autoimmune Carditis Mediated by Interleukin 17A and Interferon γ in the Lewis Rat Model of Rheumatic Heart Disease.

Acute rheumatic fever and rheumatic heart disease (ARF/RHD) have long been described as autoimmune sequelae of Streptococcus pyogenes or group A streptococcal (GAS) infection. Both antibody and T-cell responses against immunodominant GAS virulence factors, including M protein, cross-react with host tissue proteins, triggering an inflammatory response leading to permanent heart damage. However, in some ARF/RHD-endemic regions, throat carriage of GAS is low. Because Streptococcus dysgalactiae subspecies equisimilis organisms, also known as ß-hemolytic group C streptococci and group G streptococci (GGS), also express M protein, we postulated that streptococci other than GAS may have the potential to initiate or exacerbate ARF/RHD. Using a model initially developed to investigate the uniquely human disease of ARF/RHD, we have discovered that GGS causes interleukin 17A/interferon γ-induced myocarditis and valvulitis, hallmarks of ARF/RHD. Remarkably the histological, immunological, and functional changes in the hearts of rats exposed to GGS are identical to those exposed to GAS. Furthermore, antibody cross-reactivity to cardiac myosin was comparable in both GGS- and GAS-exposed animals, providing additional evidence that GGS can induce and/or exacerbate ARF/RHD.

Genome-Wide Analysis of Genetic Risk Factors for Rheumatic Heart Disease in Aboriginal Australians Provides Support for Pathogenic Molecular Mimicry.

Background: Rheumatic heart disease (RHD) after group A streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers proinflammatory cardiac valve-reactive T cells. Methods: Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single-nucleotide polymorphisms were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fine-map the human leukocyte antigen (HLA) region. Epitope binding affinities were mapped for human cross-reactive GAS proteins, including M5 and M6. Results: The strongest genetic association was intronic to HLA-DQA1 (rs9272622; P = 1.86 × 10-7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.09-1.90; P = 9.56 × 10-3) and HLA-DQA1*0103_DQB1*0601 (OR, 1.27; 95% CI, 1.07-1.52; P = 7.15 × 10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P = 2.36 × 10-3) was protective. Human myosin cross-reactive N-terminal and B repeat epitopes of GAS M5/M6 bind with higher affinity to DQA1/DQB1 alpha/beta dimers for the 2-risk haplotypes than the protective haplotype. Conclusions: Variation at HLA_DQA1-DQB1 is the major genetic risk factor for RHD in Aboriginal Australians studied here. Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of RHD pathogenesis.

Interleukin-10: Role in increasing susceptibility and pathogenesis of rheumatic fever/rheumatic heart disease.

Streptococcus pyogenes (group A streptococcus) causes rheumatic fever (RF) which later progresses towards rheumatic heart disease (RHD) in the susceptible individuals. RF and RHD both contribute towards increasing global burden of disease, especially in developing countries. RHD is one of the most common acquired heart diseases causing permanent damage to heart valves which ultimately leads to heart failure. In RHD, heart valve lesions are formed which are mediated by autoimmune reaction between streptococcal antigens (M protein and group A carbohydrate epitope GlcNAc) and heart tissues. On the other hand, inflammatory response generated by cytokines promotes chronicity of the disease. Varying concentrations of interleukin-10 (IL-10) in patients and controls are reported and are also found to be associated with IL-10 gene polymorphism in RF/RHD patients. Although the effect of IL-10 gene polymorphism on the functionality of IL-10 is unknown, many investigations suggest an important role of IL-10 and its polymorphism in immune regulation and progression of disease in RF/RHD. This review summarizes the studies based on association of interleukin-10 with RHD in different populations to understand the role of IL-10 in susceptibility and pathogenesis of the disease.

Association of rheumatic fever & rheumatic heart disease with plausible early & late-stage disease markers.

BACKGROUND & OBJECTIVES: Rheumatic fever (RF) and rheumatic heart disease (RHD) are the autoimmune sequelae caused by Group A Streptococcus. RHD still remains a major concern in the developing countries due to its poor diagnosis, lack of vaccines and social awareness among population. This study was aimed to identify the plausible early- and late-stage disease markers associated with RF/RHD. METHODS: A total of 84 patients with confirmed pharyngitis (n=18), RF (n=23) and RHD (n=43) were included in the comparative analysis of different factors involved in host-pathogen interaction during RF/RHD pathogenesis. RESULTS: This study revealed high titre of serum antistreptolysin O (ASO) antibody in pharyngitis compared to RF and RHD patients, whereas procollagen type 1 C-peptide (PICP) level was elevated in RHD which showed an inverse correlation with serum ASO titre. The significant elevation of serum anti-peptide associated with RF (PARF) antibody in RF patients was correlated as a probable stage-specific determinant. In addition, pro-inflammatory cytokine profile revealed high levels of interleukin-12 (IL-12)/IL-23p40, IL-17A in RF, whereas IL-6 concentration was higher in RHD compared to healthy controls. INTERPRETATION & CONCLUSIONS: The overall assessment of the factors/ disease markers involved in host-pathogen interaction in RF/RHD may be suggestive of plausible disease marker in different groups of patients. Further studies with larger sample need to be done to better understand RF/RHD pathogenesis.

Group C Streptococcus Causing Rheumatic Heart Disease in a Child.

BACKGROUND: Human infection with group C Streptococcus is extremely rare and a select number of cases have been reported to cause acute pharyngitis, acute glomerulonephritis, skin and soft tissue infections, septic arthritis, osteomyelitis, pneumonitis, and bacteremia. In pediatrics, this bacteria is known to cause epidemic food-borne pharyngitis, pneumonia, endocarditis, and meningitis, and has reportedly been isolated in the blood, meninges, sinuses, fingernail, peritonsillar abscess, and thyroglossal duct cyst, among others. CASE REPORT: Our patient was a 7-year-old previously healthy female who presented with abnormal movements of her upper body and grimaces of her face that progressively worsened over time. Initial laboratory resulted revealed 3+ protein on urinalysis and elevated antistreptolysin-O and anti-DNAse antibody levels, and echocardiogram showed mild-to-moderate mitral regurgitation. We describe a rare case of group C Streptococcus resulting in rheumatic heart disease in a child, with a detailed review of the literature pertaining to the diagnosis and management of this infection. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Early recognition of rheumatic heart disease is crucial in the overall outcome of the condition and therefore knowledge of the symptoms associated with condition is also imperative. Group C Streptococcus is rarely associated with rheumatic heart disease and most children exhibiting acute onset of common symptoms, such as chorea, fever, carditis, and rash (erythema marginatum) will present to the emergency department first. Increased awareness and prompt recognition, as done with this child, will result in proper follow-up and adequate management of this condition in all patients.

A population pharmacokinetic modeling approach shows that serum penicillin G concentrations are below inhibitory concentrations by two weeks after benzathine penicillin G injection in the majority of young adults.

Serum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group A Streptococcus pyogenes (GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.

Gold-mercaptopropionic acid-polyethylenimine composite based DNA sensor for early detection of rheumatic heart disease.

The first gold-mercaptopropionic acid-polyethylenimine composite based electrochemical DNA biosensor was fabricated for the early detection of Streptococcus pyogenes infection in humans causing rheumatic heart disease (heart valve damage). No biosensor is available for the detection of rheumatic heart disease (RHD). Therefore, the mga gene based sensor was developed by the covalent immobilization of a 5'-carboxyl modified single stranded DNA probe onto the gold composite electrode. The immobilized probe was hybridized with the genomic DNA (G-DNA) of S. pyogenes from throat swabs and the electrochemical response was measured by cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance (EI). Covalent immobilization of the probe onto the gold composite and its hybridization with G-DNA was characterized by FTIR and SEM. The sensitivity of the sensor was 110.25 µA cm(-2) ng(-1) with DPV and the lower limit of detection was 10 pg per 6 µL. The sensor was validated with patient throat swab samples and results were compared with available methods. The sensor is highly specific to S. pyogenes and can prevent damage to heart valves by the early detection of the infection in only 30 min.

Streptococcal pharyngitis, rheumatic fever and rheumatic heart disease: Eight-year prospective surveillance in Rupnagar district of Punjab, India.

BACKGROUND: Rheumatic fever (RF)/rheumatic heart disease (RHD) continue to be a neglected public health priority. We carried out a registry-based control project, prospective surveillance and sample surveys to estimate the burden of disease. METHODS: We trained healthcare providers and established a surveillance system for the 1.1 million population of Rupnagar district in Punjab. In sample surveys conducted among schools, physicians examined the sampled children. Children with a cardiac murmur were investigated by echocardiography. Throat swabs were obtained from a sub-sample, and group A streptococci (GAS) were identified and emm typed by standard laboratory methods. We estimated the morbidity rates for RF/RHD from surveillance data and school surveys using a correction factor to account for under-registration of cases in the registry. RESULTS: A total of 813 RF/RHD cases were registered from 2002 to 2009. Of the 203 RF and 610 RHD cases, respectively, 51.2% and 36.7% were males. In the age group of 5-14 years, RF was more common (80%) than RHD (27%). The prevalence of RF/RHD in 5-14-year-old students was 1.0/1000 (95% CI 0.8-1.3). The school survey indicated that about two-thirds of the RF/RHD cases were enrolled in the hospital-based registries. Based on the school survey, the prevalence of RF/RHD was estimated to be 143/100,000 population. In the registry, the annual incidence of acute RF was estimated to be at least 8.7/100 000 children in the age group of 5-14 years. The prevalence of GAS was 2% (13/656) in children with sore throat and 0.5% (14/2920) among those not having sore throat. Typing of 27 GAS revealed 16 emm types. We estimate that about 1000 episodes of GAS pharyngitis lead to one episode of acute RF. CONCLUSION: RF/RHD continue to be a public health problem in Punjab, India.

Exploring gut microbiota's role in rheumatic valve disease: insights from a Mendelian randomization study and mediation analysis.

Background: Investigating the relationship between gut microbiota and Rheumatic Valve Disease (RVD) is crucial for understanding the disease's etiology and developing effective interventions. Our study adopts a novel approach to examine the potential causal connections between these factors. Methods: Utilizing a two-sample Mendelian Randomization (MR) framework, we incorporated a multi-variable MR (MVMR) strategy to assess the mediatory mechanisms involved. This approach involved analyzing data from the MiBioGen consortium for gut microbiota and the FinnGen for RVD, among other sources. Instrumental variables (IVs) were carefully selected based on rigorous MR principles, and statistical analysis was conducted using bidirectional two-sample MR, such as inverse variance-weighted (IVW), weighted median, MR-Egger regression and MR Steiger Test methods. The MR-PRESSO strategy was employed for outlier detection, and MVMR was used to untangle the complex relationships between multiple microbiota and RVD. Results: Our analysis highlighted several gut microbiota classes and families with potential protective effects against RVD, including Lentisphaerae, Alphaproteobacteria, and Streptococcaceae. In contrast, certain genera, such as Eubacterium eligens and Odoribacter, were identified as potential risk factors. The MVMR analysis revealed significant mediation effects of various immune cell traits and biomarkers, such as CD4-CD8- T cells, CD3 on Terminally Differentiated CD8+ T cell and Pentraxin-related protein PTX, elucidating the complex pathways linking gut microbiota to RVD. Conclusion: This study underscores the intricate and potentially causal relationship between gut microbiota and RVD, mediated through a range of immune and hormonal factors. The use of MVMR in our methodological approach provides a more comprehensive understanding of these interactions, highlighting the gut microbiota's potential as therapeutic targets in RVD management. Our findings pave the way for further research to explore these complex relationships and develop targeted interventions for RVD.

The developmental origins of chronic rheumatic heart disease.

OBJECTIVES: Programming is the phenomenon whereby the body's structures and functions are permanently set by nutrition and other influences during early development. There is increasing evidence that programming in utero initiates cardiovascular disease. We hypothesized that susceptibility to developing chronic rheumatic heart disease on exposure to Streptococcus pyogenes is programmed. METHODS: We studied hospital admissions and deaths from chronic rheumatic heart disease in 20,431 people born in Helsinki, Finland, during 1924-1944. One hundred and one people, 56 men, and 45 women, had chronic rheumatic heart disease. RESULTS: The disease was not associated with body or placental size at birth. It was, however, associated with a long umbilical cord so that the hazard ratio for the disease was 1.23 (95% CI 1.04-1.45, P = 0.02) for every 10 cm increase in cord length. This association was present in people with mitral valve disease, hazard ratio 1.5 (1.20-1.89, P < 0.0001), but not in people with aortic valve disease, hazard ratio 1.0 (0.76-1.33, P = 0.97). Growing up in large households increased the risk of rheumatic heart disease. CONCLUSION: Longer umbilical cords have more spirals and a greater density of spirals per unit of length. Increased spiraling will increase the resistance to flow and the pressure load on the fetal heart. This could affect the development of the heart's valves and make them more vulnerable to the autoimmune process initiated by Streptococcus pyogenes. The mitral valve may be more vulnerable than the aortic valve because the valve leaflets are larger and therefore have greater wall stress.

Streptococcal skin infection and rheumatic heart disease.

PURPOSE OF REVIEW: In resource-limited tropical settings, both impetigo and rheumatic disease are endemic. The major cause of impetigo in these regions is the group A streptococcus and there is a growing body of opinion implicating impetigo in the pathogenesis of rheumatic fever and rheumatic heart disease (RHD). This potentially has major implications for control of these neglected diseases, which account for at least 350  000 deaths worldwide, annually. In this review, we summarize recent advances in the epidemiology of group A streptococcal skin disease and examine evidence for the relationship between group A streptococcal skin disease and rheumatic fever. RECENT FINDINGS: Detailed epidemiologic studies of impetigo, particularly among indigenous communities in the Pacific among whom rheumatic fever is endemic, find the disease remarkably prevalent. In contrast, group A streptococcal pharyngitis occurs no more frequently than in regions wherein rheumatic fever is now rare. Studies of molecular epidemiology reveal that overall there is a greater diversity of group A streptococcal strains in tropical regions, and skin-associated strains appear predominant. These skin strains may move between skin and throat, and there is increasing evidence of skin-associated strains being linked to cases of rheumatic fever. SUMMARY: The available data support the hypothesis that group A streptococcal impetigo plays a role in the pathogenesis of RHD. There is considerable scope to investigate this question through studies of pathogenesis, employing advances in both human and bacterial genetics, molecular immunology, and carefully designed trials aimed at control of impetigo.

speB gene as a specific genetic marker for early detection of rheumatic heart disease in human.

Streptococcus pyrogenic exotoxin B gene (speB) is chromosomally encoded pyrogenic and cardiotoxic virulence factor of S. pyogenes. Exotoxin B is produced only in a secreted form, as a 40 KD proprotein, which is subsequently processed to 28 KD in the mature form. Streptococcus pyogenes infection in human, causes initially pharyngitis due to inhalation of aerosols emitted by infected persons, develops rheumatic fever which leads to the rheumatic heart disease (damage of heart valves). The available detection methods are bacterial culture, ß-hemolysis, bacitracin sensitivity, hippurate test, phadebact test, CRP (C-reactive protein), ESR and PCR. All these methods are either expensive or non-confirmatory and have some limitations. Available PCR methods take more time and require other test to confirm the disease. Our PCR based detection of Streptococcus pyogenes in human using specific primers of speB gene completes overall analysis in 80 min which is the minimum time reported so far for the confirmation of the disease. Amplicon of 423bp of speB gene can be used as a specific genetic marker as it does not show homology with other organisms for early detection of rheumatic heart disease. Our method is specific virulence gene based which is quick, economical and more sensitive as compared with other methods.

Infective endocarditis and rheumatic heart disease in the north of Australia.

BACKGROUND: To prevent infective endocarditis (IE), Australian guidelines recommend providing prophylactic antibiotics to Indigenous patients with rheumatic heart disease (RHD) prior to procedures which may cause bacteremia. In northern Australia RHD remains prevalent. We aimed to determine whether RHD is associated with an increased risk of IE, which risk factors are associated with IE, and the incidence and aetiology of IE. METHODS: A retrospective review of IE patients who fulfilled modified Duke criteria at two tertiary centres in northern Australia. RESULTS: 89 patients were reviewed. The rate of IE was 6.5/100,000 person-years. IE was more common in people with RHD (relative risk (RR) 58), Indigenous Australians (RR 2.0) and men (RR 1.7). RHD-associated IE was not confined to Indigenous Australians with 42% being non-Indigenous. The commonest risk factors for IE were intracardiac prosthetic material, injecting drug use and previous IE. One in five patients died. CONCLUSIONS: In northern Australia the principle risk factor for IE is not RHD. Whilst RHD increased the risk of IE it was not restricted to Indigenous Australians. Current Australian recommendations of providing prophylactic antibiotics to Indigenous patients with RHD prior to procedures which may cause bacteremia may need to be broadened to include non-Indigenous patients.

New understandings in Streptococcus pyogenes.

PURPOSE OF REVIEW: A resurgence of invasive group A streptococcal infections highlights the need for better knowledge of streptococcal biology. This review summarizes the recent advances in our understanding of the field. RECENT FINDINGS: Invasive group A streptococcal infections cause significant morbidity and mortality worldwide. The current upsurge of invasive infections in developed countries is predominantly linked to the spread of a clonal hypervirulent population of M1T1 serotype strains (emm1), although sporadic increases in other types have been reported, including emm3 strains in the UK, and emm28 strains among cases of puerperal sepsis. Mutations of a regulatory system, CovR/S (control of virulence), are important in the transition of emm1 strains from noninvasive to invasive phenotype. New research has been undertaken to identify major virulence factors that typify the invasive phenotype. In less-developed regions, the importance of rheumatic carditis and need for a vaccine that addresses a much wider range of streptococcal emm types predominates research efforts. SUMMARY: Advances in molecular technology have furthered our understanding of virulence factors that underpin group A streptococcus invasiveness. The increased prevalence of invasive disease coupled with the devastating effects of chronic rheumatic heart disease, affecting predominantly low-income regions, underline the need for the development of an effective vaccine.

sof gene as a specific genetic marker for detection of Streptococcus pyogenes causing pharyngitis and rheumatic heart disease.

Streptococcus pyogenes is a human pathogen causing invasive and non—invasive diseases, as well as severe sequels, such as rheumatic fever. Rheumatic heart disease is a sequel of rheumatic fever results from an untreated strep throat causing damage of the heart valves. The usual detection methods of strep throat are culture, virulent test, antibiotic sensitivity, CRP, ESR and PCR. These methods are expensive, time consuming and have some limitations. All reported PCR methods are based on either 16S rRNA or specific gene based along with other methods to confirm the disease in more than 1h. Here, we have developed a PCR based diagnosis of streptococcus pyogenes using specific primers of virulent sof gene (serum opacity factor) of S. pyogenes. Our method is an improvement of the existing methods and the overall analysis completes in 1 h which is the least time reported so far for the confirmation of the disease. Amplicon of 228 bp of sof gene does not show homology with other organisms and can be used as genetic marker for S. pyogenes.