Research priorities for the primordial prevention of acute rheumatic fever and rheumatic heart disease by modifying the social determinants of health.

The social determinants of health (SDH), such as access to income, education, housing and healthcare, strongly shape the occurrence of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) at the household, community and national levels. The SDH are systemic factors that privilege some more than others and result in poverty and inequitable access to resources to support health and well-being. Primordial prevention is the modification of SDH to improve health and reduce the risk of disease acquisition and the subsequent progression to RHD. Modifying these determinants using primordial prevention strategies can reduce the risk of exposure to Group A Streptococcus, a causative agent of throat and skin infections, thereby lowering the risk of initiating ARF and its subsequent progression to RHD.This report summarises the findings of the Primordial Prevention Working Group-SDH, which was convened in November 2021 by the National Heart, Lung, and Blood Institute to assess how SDH influence the risk of developing RHD. Working group members identified a series of knowledge gaps and proposed research priorities, while recognising that community engagement and partnerships with those with lived experience will be integral to the success of these activities. Specifically, members emphasised the need for: (1) global analysis of disease incidence, prevalence and SDH characteristics concurrently to inform policy and interventions, (2) global assessment of legacy primordial prevention programmes to help inform the co-design of interventions alongside affected communities, (3) research to develop, implement and evaluate scalable primordial prevention interventions in diverse settings and (4) research to improve access to and equity of services across the RHD continuum. Addressing SDH, through the implementation of primordial prevention strategies, could have broader implications, not only improving RHD-related health outcomes but also impacting other neglected diseases in low-resource settings.

Acute rheumatic fever and rheumatic heart disease in children and adolescents in Victoria, Australia.

AIM: To describe the epidemiology and clinical profile of children and adolescents with acute rheumatic fever (ARF) and rheumatic heart disease (RHD) in Victoria, Australia. METHODS: A retrospective audit was undertaken of children and adolescents with ARF and RHD attending the Royal Children's and Monash Children's Hospitals in Victoria, Australia between 2010 and 2019. Potential cases were identified by searching multiple sources for relevant ICD-10-AM codes and keywords, then reviewed manually. For confirmed cases, we collected data on patient demographics, clinical features, comorbidities and management. RESULTS: Of 179 participants included, there were 108 Victorian residents and 71 non-Victorian residents. 126 had at least one episode of ARF during the study period and 128 were diagnosed with RHD. In the Victorian resident group, the overall incidence of ARF was 0.8 per 100 000 5-14 year olds. This incidence was higher in Victorian Aboriginal and/or Torres Strait Islander (3.8 per 100 000) and Pacific Islander (32.1 per 100 000) sub-populations. Of 83 Victorian residents who had an ARF episode, 11 (13%) had a recurrence. Most Victorian residents with RHD had mixed aortic and mitral valve pathology (69.4%) and moderate to severe disease (61.9%). Most non-Victorian residents were Aboriginal and/or Torres Strait Islander people (80.3%) and were commonly transferred for tertiary or surgical management of RHD (83.1%). CONCLUSIONS: ARF and RHD continue to affect the health of significant numbers of children and adolescents living in Victoria, including severe and recurrent disease. Specialised services and a register-based control program may help to prevent complications and premature death.

Cytokine imbalance in acute rheumatic fever and rheumatic heart disease: Mechanisms and therapeutic implications.

Acute Rheumatic Fever (ARF) and Rheumatic Heart Disease (RHD) are autoimmune sequelae of Group A Streptococcus infection with significant global disease burden. The pathogenesis of these diseases is poorly understood, and no immune modulating therapies are available to stop progression from ARF to RHD. Cytokines and chemokines are immune signaling molecules critical to the development of autoimmune diseases. An increasing number of studies point to a central role for pro-inflammatory cytokines and chemokines in ARF and RHD pathogenesis, in particular IL-6, IL-8/CXCL8, and TNFα, which are elevated in circulation in both ARF and RHD patients. Histological studies of RHD valve tissue implicates Th1 and Th17 associated pro-inflammatory cytokines, chemokine CXCL9, and the fibrosis-associated cytokine TGF-ß in progressive cycles of inflammatory damage and fibrotic repair. Taken together, this suggests immune molecules contribute to both the acute inflammatory disease stage of ARF, as well as cardiac remodeling and valve dysfunction in RHD. Monoclonal antibody blockade of pro-inflammatory cytokines IL-6 and TNFα are approved therapies for many autoimmune diseases and the most successful immunomodulating therapies for rheumatoid arthritis. Current evidence suggests possible benefit for ARF patients from IL-6 and TNFα blockade, in particular to interrupt progression to RHD, and warrants immediate investigation.

Transcatheter mitral valve-in-valve: treatment of rheumatic heart disease in young patients.

BACKGROUND: Rheumatic heart disease (RHD) in young people presents a complex management problem. In Australia a significant proportion of those affected are Aboriginal and Torres Strait Islanders. Transcatheter mitral valve-in-valve (TMViV) replacement has emerged as an alternative to redo surgery in high-risk patients with degenerated mitral bioprostheses. The aim of this study is to review outcomes of TMViV replacement in young patients with RHD. METHODS: A single-centre, retrospective review of prospectively collected data on patients undergoing TMViV from December 2017 to June 2021. Primary outcome was major adverse cardiovascular events. Secondary outcome was post-operative trans-thoracic echocardiogram (TTE) results. RESULTS: There were seven patients with a mean age of 33 years and predominantly female (n = 5). Pre-operative comorbidities included diabetes (29%), chronic obstructive pulmonary disease (43%), left ventricular dysfunction (43%) and current smoking status (80%). Post-operative median length of hospital stay was 4 days with no post-operative renal failure, stroke, return to theatre, valve embolization or in hospital mortality. Post-operative TTE showed either nil or trivial central mitral regurgitation, no paravalvular leak and a median gradient of 5 mmHg (IQR 4.5, 7) across the new bioprosthesis; sustained at median follow-up of 22 months. CONCLUSION: Current literature of TMViV replacement is focused on an older population with concurrent comorbidities. This study provides a unique insight into TMViV replacement in a young cohort of patients with complex social and geographical factors which sometimes prohibits the use of a mechanical valve. The prevalence of RHD remains high for Aboriginal and Torres Strait Islanders, planning for future repeat valve operations should be considered from the outset. We consider TMViV as a part of a staged procedural journey for young patients with RHD.

Prothymosin Alpha: A Novel Contributor to Estradiol Receptor Alpha-Mediated CD8+ T-Cell Pathogenic Responses and Recognition of Type 1 Collagen in Rheumatic Heart Valve Disease.

BACKGROUND: Rheumatic heart valve disease (RHVD) is a leading cause of cardiovascular death in low- and middle-income countries and affects predominantly women. The underlying mechanisms of chronic valvular damage remain unexplored and regulators of sex predisposition are unknown. METHODS: Proteomics analysis of human heart valves (nondiseased aortic valves, nondiseased mitral valves [NDMVs], valves from patients with rheumatic aortic valve disease, and valves from patients with rheumatic mitral valve disease; n=30) followed by system biology analysis identified ProTα (prothymosin alpha) as a protein associated with RHVD. Histology, multiparameter flow cytometry, and enzyme-linked immunosorbent assay confirmed the expression of ProTα. In vitro experiments using peripheral mononuclear cells and valvular interstitial cells were performed using multiparameter flow cytometry and quantitative polymerase chain reaction. In silico analysis of the RHVD and Streptococcuspyogenes proteomes were used to identify mimic epitopes. RESULTS: A comparison of NDMV and nondiseased aortic valve proteomes established the baseline differences between nondiseased aortic and mitral valves. Thirteen unique proteins were enriched in NDMVs. Comparison of NDMVs versus valves from patients with rheumatic mitral valve disease and nondiseased aortic valves versus valves from patients with rheumatic aortic valve disease identified 213 proteins enriched in rheumatic valves. The expression of the 13 NDMV-enriched proteins was evaluated across the 213 proteins enriched in diseased valves, resulting in the discovery of ProTα common to valves from patients with rheumatic mitral valve disease and valves from patients with rheumatic aortic valve disease. ProTα plasma levels were significantly higher in patients with RHVD than in healthy individuals. Immunoreactive ProTα colocalized with CD8+ T cells in RHVD. Expression of ProTα and estrogen receptor alpha correlated strongly in circulating CD8+ T cells from patients with RHVD. Recombinant ProTα induced expression of the lytic proteins perforin and granzyme B by CD8+ T cells as well as higher estrogen receptor alpha expression. In addition, recombinant ProTα increased human leukocyte antigen class I levels in valvular interstitial cells. Treatment of CD8+ T cells with specific estrogen receptor alpha antagonist reduced the cytotoxic potential promoted by ProTα. In silico analysis of RHVD and Spyogenes proteomes revealed molecular mimicry between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8+ T-cell activation in vitro. CONCLUSIONS: ProTα-dependent CD8+ T-cell cytotoxicity was associated with estrogen receptor alpha activity, implicating ProTα as a potential regulator of sex predisposition in RHVD. ProTα facilitated recognition of type 1 collagen mimic epitopes by CD8+ T cells, suggesting mechanisms provoking autoimmunity.

Characteristics of Ang-(1-7)/Mas-Mediated Amelioration of Joint Inflammation and Cardiac Complications in Mice With Collagen-Induced Arthritis.

Objectives: Rheumatoid arthritis (RA) is a disabling disease with a high incidence that is regularly accompanied by cardiovascular complications. Several studies have suggested that renin-angiotensin-aldosterone system (RAAS) is closely associated with RA. The aim of this study was to investigate the mechanisms underlying Angiotensin-(1-7) [Ang-(1-7)] and its Mas receptor agonist (AVE0991) on joint inflammation and cardiac complications in a collagen-induced arthritis (CIA) model. Methods: Collagen type II was injected into DBA/1 mice to construct an arthritis model. CIA mice were treated with Ang-(1-7) (2.0 mg/kg intraperitoneally) and AVE0991 (3.0 mg/kg intraperitoneally). The serum levels of inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 ß, IL-6, and C-reactive protein (CRP)] were determined by ELISA. The mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) signaling pathways in joint tissues and the transforming growth factor (TGF)-ß/Smad pathway and levels of α-Smooth muscle action (SMA) and ß-myosin heavy chain (MHC) protein expression in cardiac tissues were assessed by western blots. The levels of TGF-ß/Smad pathway, α-SMA, and ß-MHC RNA in cardiac tissues were analyzed by real time-PCR. The levels of receptor activator of nuclear factor kappa ligand (RANKL) and promoting matrix metalloproteinase (MMP)-3 expression in the ankle joints were detected by immunohistochemistry and real time-PCR. Results: Ang-(1-7) and AVE0991 reduced the levels of inflammatory cytokines and inhibited the MAPKs and NF-κB signaling pathways in ankle joint tissues, reduced RANKL and MMP3 expression, and ameliorated local joint inflammation and bone destruction compared with the control group. In addition, Ang-(1-7) and AVE0991 attenuated the TGF-ß/Smad signaling pathway, reduced the levels of α-SMA and ß-MHC expression, and diminished inflammatory cell infiltration into the myocardial interstitium and myocardial interstitial fibrosis in the hearts of CIA mice. Conclusions: Ang-(1-7) alleviated joint damage caused by inflammation likely through the attenuation of NF-κB and MAPK pathways and ameliorated inflammation-induced cardiac fibrosis and activation of the TGF-ß/Smad pathway. Moreover, Ang-(1-7) was likely mediated through the Mas receptor. This study provides theoretical evidence for exploring novel clinical therapeutic approaches for RA and its cardiac complications.

High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.

INTRODUCTION: Intramuscular benzathine penicillin G (BPG) injections are a cornerstone of secondary prophylaxis to prevent acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Uncertainties regarding inter-ethnic and preparation variability, and target exposure profiles of BPG injection are key knowledge gaps for RHD control. METHODS: To evaluate BPG pharmacokinetics (PK) in patients receiving 4-weekly doses in Ethiopia, we conducted a prospective cohort study of ARF/RHD patients attending cardiology outpatient clinics. Serum samples were collected weekly for one month after injection and assayed with a liquid chromatography-mass spectroscopy assay. Concentration-time datasets for BPG were analyzed by nonlinear mixed effects modelling using NONMEM. RESULTS: A total of 190 penicillin concentration samples from 74 patients were included in the final PK model. The median age, weight, BMI was 21 years, 47 kg and 18 kg/m2, respectively. When compared with estimates derived from Indigenous Australian patients, the estimate for median (95% confidence interval) volume of distribution (V/F) was lower (54.8 [43.9-66.3] l.70kg-1) whilst the absorption half-life (t1/2-abs2) was longer (12.0 [8.75-17.7] days). The median (IQR) percentage of time where the concentrations remained above 20 ng/mL and 10 ng/mL within the 28-day treatment cycle was 42.5% (27.5-60) and 73% (58.5-99), respectively. CONCLUSIONS: The majority of Ethiopian patients receiving BPG as secondary prophylaxis to prevent RHD do not attain target concentrations for more than two weeks during each 4-weekly injection cycle, highlighting the limitations of current BPG strategies. Between-population variation, together with PK differences between different preparations may be important considerations for ARF/RHD control programs.

The prevalence of enteroviral RNA and protein in mitral valves of chronic rheumatic heart disease.

INTRODUCTION: Acute Rheumatic Fever/ Rheumatic Heart Disease (ARF/RHD), a sequel of group A streptococcal (GAS) infection, even today constitutes a public health issue in developing countries including India. Differences in the prevalence of ARF/RHD in countries with a similar prevalence of GAS infections indicate the role of other cofactors in pathogenesis of RHD. METHODOLOGY: We investigated the prevalence of enterovirus (EV) in RHD by probing for both EV RNA and VP1 protein using Nonisotopic In Situ Hybridization (NISH) and Immunohistochemistry (IHC) respectively in 75 valvectomy specimens obtained from RHD cases. RESULTS: Twenty-eight (37%) of the valves showed tissue inflammation with lymphocytic infiltration in a majority of the cases. Twenty-six and 27 (38% and 40%) of the 68 valves showed the presence of EV by IHC and NISH respectively, indicating a very good association between the two tests; however, only about 46 to 48% of them exhibited tissue inflammation. In eight cases (12%) the EV genome was detectable in absence of VP1 protein perhaps indicating a latent viral infection. CONCLUSIONS: Due to a high degree of endemicity of EV in India, we are tempted to speculate that EV may be responsible for the severity and rapid progression of RHD. The virus could either be working synergistically with GAS or could be an opportunist infecting damaged valves.

Cardiovascular disease risks in younger versus older adult B-cell non-Hodgkin's lymphoma survivors.

INTRODUCTION: Young cancer survivors may be at increased risk of early-onset chronic health conditions. The aim of this population-based study is to estimate cardiovascular disease (CVD) risk among younger versus older B-cell non-Hodgkin's lymphoma (B-NHL) survivors compared with their respective general population cohorts. METHODS: B-NHL survivors diagnosed from 1997 to 2015 in the Utah Cancer Registry were matched with up to five cancer-free individuals on birth year, sex, and birth state, using the statewide Utah Population Database. Electronic medical records and statewide health care facility data were used to identify disease outcomes ≥5 years after cancer diagnosis. Cox Proportional Hazards models were used to estimate hazard ratios for B-NHL survivors diagnosed at <65 years and ≥65 years old. RESULTS: Younger B-NHL survivors had higher relative risks than older cancer survivors of chronic rheumatic disease of the heart valves (HR = 4.14, 99% CI = 2.17-7.89; P valueheterogeneity = 0.004); peri-, endo-, and myocarditis (HR = 2.43, 99% CI = 1.38-4.28; P valueheterogeneity = 0.016); diseases of the arteries (HR = 1.63, 99% CI = 1.21-2.21; P valueheterogeneity = 0.044); and hypotension (HR = 2.44, 99% CI = 1.58-3.75; P valueheterogeneity = 0.048). B-NHL survivors of both age groups had elevated relative risks of heart disease overall and congestive heart failure. CONCLUSION: Younger B-NHL survivors had higher risks than older B-NHL survivors of specific cardiovascular diseases compared to their respective general population cohorts.

Rheumatic pericarditis: a rare cause of constrictive pericarditis.

Constrictive pericarditis is a relatively uncommon form of cardiac failure and presents due to scarring and consequent loss of the normal elasticity of the pericardial sac. This results in abnormal/limited ventricular filling and symptoms of heart failure. The aetiology is varied, from infective causes to idiopathic causes, or can manifest after cardiothoracic surgery. This case involves a 46-year-old man presenting with acute group A beta haemolytic streptococcus infection, and over the subsequent 6 months develops constrictive pericarditis due to what is believed to be a rheumatic aetiology. The patient subsequently underwent pericardiectomy and had restoration of normal filling dynamics confirmed on follow-up echocardiography. This case provides a subject matter for the review of the features of constrictive pericarditis and its investigation and management. This case is that it highlights the fact that pericarditis is not a benign condition. Emerging evidence suggests that pericarditis is due to a failure in inflammatory regulatory mechanisms, and patients suffering this condition have a preponderance to 'autoinflammation'. Pericarditis should be recognised early and treated fully with anti-inflammatory agents.

Ficolin-3 in rheumatic fever and rheumatic heart disease.

Rheumatic fever (RF) and chronic rheumatic heart disease (RHD) are complications of oropharyngeal infection caused by Streptococcus pyogenes. Despite the importance of the complement system against infections and autoimmunity diseases, studies on the role of the lectin pathway in RF and RHD are scarce. Thus, our aim was to evaluate the association of ficolin-3 serum levels, FCN3 polymorphisms and haplotypes with the susceptibility to RF and RHD. We investigated 179 patients with a history of RF (126 RHD and 53 RF only) and 170 healthy blood donors as control group. Ficolin-3 serum concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Three FCN3 single nucleotide polymorphisms (SNPs rs532781899, rs28362807 and rs4494157) were genotyped through the sequence-specific PCR method. Lower ficolin-3 serum levels were observed in RF patients when compared to controls (12.81 µg/mL vs. 18.14 µg/mL respectively, p < 0.0001, OR 1.22 [1.12-1.34]), and in RHD in comparison to RF only (RFo) (12.72 µg/mL vs. 14.29 µg/mL respectively, p = 0.016, OR 1.38 [1.06-1.80]). Low ficolin-3 levels (<10.7 µg/mL) were more common in patients (39.5 %, 30/76) than controls (20.6 %, 13/63, p = 0.018, OR = 2.51 [1.14-5.31]), and in RHD (44.4 %, 28/63) than RFo (15.4 %, 2/13, p = 0.007, OR = 3.08 [1.43-6.79]). On the other hand, FCN3 polymorphism/haplotypes were not associated with ficolin-3 serum levels or the disease. Low ficolin-3 levels might be associated with RF, being a potential marker of disease progression.

Activation of activin/Smad2 and 3 signaling pathway and the potential involvement of endothelial­mesenchymal transition in the valvular damage due to rheumatic heart disease.

Rheumatic heart disease (RHD) is an autoimmune disease caused by rheumatic fever following group A hemolytic streptococcal infection and primarily affects the mitral valve. RHD is currently a major global health problem. However, the exact pathological mechanisms associated with RHD­induced cardiac valve damage remain to be elucidated. The endothelial­mesenchymal transition (EndMT) serves a key role in a number of diseases with an important role in cardiac fibrosis and the activin/Smad2 and 3 signaling pathway is involved in regulating the EndMT. Nevertheless, there are no studies to date, to the best of the authors' knowledge, investigating the association between RHD and EndMT. Thus, the aim of the current study was to investigate the potential role of EndMT in cardiac valve damage and assess whether activin/Smad2 and 3 signaling was activated during RHD­induced valvular injury in a rat model of RHD induced by inactivated Group A streptococci and complete Freund's adjuvant. Inflammation and fibrosis were assessed by hematoxylin and eosin and Sirius red staining. Serum cytokine and rheumatoid factor levels were measured using ELISA kits. Expression levels of activin/Smad2 and 3 signaling pathway­related factors [activin A, Smad2, Smad3, phosphorylated (p­)Smad2 and p­Smad3], EndMT­related factors [lymphoid enhancer factor­1 (LEF­1), Snail1, TWIST, zinc finger E­box­binding homeobox (ZEB)1, ZEB2, α smooth muscle actin (α­SMA) and type I collagen α 1 (COL1A1)], apoptosis­related markers (BAX and cleaved caspase­3) and valvular inflammation markers (NF­κB and p­NF­κB) were detected using reverse transcription­quantitative PCR and western blot analyses. Compared with the control group, the degree of valvular inflammation and fibrosis, serum levels of IL­6, IL­17, TNF­α and expression of apoptosis­related markers (BAX and cleaved caspase­3) and valvular inflammation marker (p­NF­κB), activin/Smad2 and 3 signaling pathway­related factors (activin A, p­Smad2 and p­Smad3), EndMT­related factors (LEF­1, Snail1, TWIST, ZEB 1, ZEB2, α­SMA and COL1A1) were significantly increased in the RHD group. These results suggested that the activin/Smad2 and 3 signaling pathway was activated during the development of valvular damage caused by RHD and that the EndMT is involved in RHD­induced cardiac valve damage.

Ending rheumatic heart disease in Australia: the evidence for a new approach.

■The RHD Endgame Strategy: the blueprint to eliminate rheumatic heart disease in Australia by 2031 (the Endgame Strategy) is the blueprint to eliminate rheumatic heart disease (RHD) in Australia by 2031. Aboriginal and Torres Strait Islander people live with one of the highest per capita burdens of RHD in the world. ■The Endgame Strategy synthesises information compiled across the 5-year lifespan of the End Rheumatic Heart Disease Centre of Research Excellence (END RHD CRE). Data and results from priority research projects across several disciplines of research complemented literature reviews, systematic reviews and narrative reviews. Further, the experiences of those working in acute rheumatic fever (ARF) and RHD control and those living with RHD to provide the technical evidence for eliminating RHD in Australia were included. ■The lived experience of RHD is a critical factor in health outcomes. All future strategies to address ARF and RHD must prioritise Aboriginal and Torres Strait Islander people's knowledge, perspectives and experiences and develop co-designed approaches to RHD elimination. The environmental, economic, social and political context of RHD in Australia is inexorably linked to ending the disease. ■Statistical modelling undertaken in 2019 looked at the economic and health impacts of implementing an indicative strategy to eliminate RHD by 2031. Beginning in 2019, the strategy would include: reducing household crowding, improving hygiene infrastructure, strengthening primary health care and improving secondary prophylaxis. It was estimated that the strategy would prevent 663 deaths and save the health care system $188 million. ■The Endgame Strategy provides the evidence for a new approach to RHD elimination. It proposes an implementation framework of five priority action areas. These focus on strategies to prevent new cases of ARF and RHD early in the causal pathway from Streptococcus pyogenes exposure to ARF, and strategies that address the critical systems and structural changes needed to support a comprehensive RHD elimination strategy.

Circulating follicular T helper cells and humoral reactivity in rheumatic heart disease.

AIMS: This study aimed to profile circulating T follicular helper cells (cTfh) and their effect on B cells in rheumatic heart disease (RHD). MATERIALS AND METHODS: Participants were divided into healthy control (HC, n = 30) and RHD (n = 30) groups. Percentages of cTfh subpopulations, based on CD4, CXCR5, CXCR3, CCR6, Foxp3, Ki67, and PD-1 cell markers, and of CD19+ B cell subgroups were measured by flow cytometry and compared between the groups. Also, IL-21 concentration in plasma and mitral valve were quantitated by cytometric bead array, immunofluorescence, and western blotting. KEY FINDINGS: The PD-1+ cTfh, B cells (naive B cells, plasmablasts, and plasma B cells) proportion and cTfh17/cTfh ratios in RHD group were significantly increased, compared to HC (p < 0.01 in all cases), while different types of memory B cells were diminished (p < 0.001). In RHD patients, percentages of PD-1+ cTfh and switched memory B cells were negatively correlated (r = -0.565, p = 0.009); meanwhile, percentages of plasmablasts and PD-1+ cTfh cells were positively correlated (r = 0.594, p = 0.005). Additionally, IL-21 levels in plasma and mitral valve of RHD group were higher than those in HC. Also, IL-21 levels correlated with PD-1+ cTfh(r = 0.557, p = 0.010), cTfh17 (r = 0.567, p = 0.009), and plasmablast (r = -0.5957, p = 0.005) cell proportions, and (cTh2 + cTh17)/cTfh1 ratio (r = -0.547, p = 0.013). SIGNIFICANCE: The activation of PD-1+ cTfh and cTfh17 subtype was highly correlated with plasmablast maturation and IL-21 production in rheumatic heart disease. Thus indicating the prominent role of cTfh and humoral reactivity in the immune pathogenesis of RHD.

Anti-streptococcal antibody and T-cell interactions with vascular endothelial cells initiate the development of rheumatic carditis.

The role of group A streptococcal and Streptococcus dysgalactiae subspecies equisimilis M-protein specific Abs and T-cells in endothelial cell activation was investigated using cultured rat aortic endothelial cells, and in a rat model of autoimmune valvulitis. Heat inactivated serum and mononuclear cells from streptococcal M-protein immunized rats independently induced upregulation of the endothelial cell adhesion molecules, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in cultured cells. We also observed T-cell migration across endothelial cell monolayers incubated with serum from M-protein-immunized rats. Furthermore, we observed VCAM-1 and ICAM-1 expression in the myocardium of rats injected with M-protein compared to control animals. These observations support the contention that initial interactions between streptococcal M-protein specific Abs and/or T-cells with the heart endothelium lead to endothelial cell activation followed by transmigration of M-protein specific T-cells into heart tissue leading to an inflammatory process that leads to carditis in rheumatic fever and rheumatic heart disease.

High burden and seasonal variation of paediatric scabies and pyoderma prevalence in The Gambia: A cross-sectional study.

BACKGROUND: Scabies is a WHO neglected tropical disease common in children in low- and middle-income countries. Excoriation of scabies lesions can lead to secondary pyoderma infection, most commonly by Staphyloccocus aureus and Streptococcus pyogenes (group A streptococcus, GAS), with the latter linked to acute post-streptococcal glomerulonephritis (APSGN) and potentially rheumatic heart disease (RHD). There is a paucity of data on the prevalence of these skin infections and their bacterial aetiology from Africa. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study, conducted over a four-month period that included the dry and rainy season, was conducted to determine the prevalence of common skin infections in Sukuta, a peri-urban settlement in western Gambia, in children <5 years. Swabs from pyoderma lesions were cultured for S. aureus and GAS. Of 1441 children examined, 15.9% had scabies (95% CI 12.2-20.4), 17.4% had pyoderma (95% CI 10.4-27.7) and 9.7% had fungal infections (95% CI 6.6-14.0). Scabies was significantly associated with pyoderma (aOR 2.74, 95% CI 1.61-4.67). Of 250 pyoderma swabs, 80.8% were culture-positive for S. aureus, and 50.8% for GAS. Participants examined after the first rains were significantly more likely to have pyoderma than those examined before (aRR 2.42, 95% CI 1.38-4.23), whereas no difference in scabies prevalence was seen (aRR 1.08, 95% CI 0.70-1.67). Swab positivity was not affected by the season. CONCLUSIONS/SIGNIFICANCE: High prevalence of scabies and pyoderma were observed. Pyoderma increased significantly during the rainy season. Given the high prevalence of GAS pyoderma among children, further research on the association with RHD in West Africa is warranted.

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

BACKGROUND: Benzathine 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. METHODS: We 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. RESULTS: Eighteen 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. CONCLUSIONS: Few 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.

Rheumatic heart disease in the modern era: recent developments and current challenges.

Rheumatic heart disease (RHD) remains a major cause of preventable death and disability in children and young adults. Despite significant advances in medical technology and increased understanding of disease mechanisms, RHD continues to be a serious public health problem throughout the world, especially in low- and middle-income countries. Echocardiographic screening has played a key role in improving the accuracy of diagnosing RHD and has highlighted the disease burden. Most affected patients present with severe valve disease and limited access to life-saving cardiac surgery or percutaneous valve intervention, contributing to increased mortality and other complications. Although understanding of disease pathogenesis has advanced in recent years, key questions remain to be addressed. Preventing or providing early treatment for streptococcal infections is the most important step in reducing the burden of this disease.