Diagnosis Of Acute Rheumatic Fever Research Articles

Determination of the upper limit of normal for serum anti-streptolysin-O titre in primary school children in Southern Nigeria; A model for other low resource settings

The prevention and treatment of Rheumatic Heart disease is hinged on antibiotic administration in children with Group A Streptococcal (GAS) pharyngitis and Acute Rheumatic Fever (ARF). The Upper Limit of Normal (ULN) for serum Anti-streptolysin O titre (ASOT) has been employed as proof of antecedent GAS pharyngitis to fulfil the Jones’ criteria for diagnosis of ARF. This value has not been generated among West African children. Generalization of values from Caucasians (200 IU/ml) is likely to result in over-diagnosis, owing to higher GAS pharyngitis incidence in Africa. We aimed to determine the serum ASOT and its ULN in apparently healthy school-aged children in Egor Local Government Area (LGA), south-south Nigeria and to determine their relationship with socio-demographic characteristics.We recruited 384 apparently healthy school-aged pupils across eleven schools. Serum ASOT was determined by turbidimetry. Statistical analysis was done using student's t-test and Analysis of Variance (ANOVA). Level of significance was set at p < 0.05.The mean age was 8.53 ± 1.97(range 6–12) years and male-female ratio was 1.1:1. The ULN and geometric mean serum ASOT were 390.76 IU/ml and 230.04 ± 1.86 IU/ml respectively. No significant correlation was found between serum ASOT and age (r-value of −4.8%). The ULN did not vary significantly with gender, socio-economic class and the presence/absence of over-crowding in homes. The ULN for serum ASOT in apparently healthy school-aged children in Egor LGA is higher than the currently used international value. Clinicians in West Africa should consider applying higher cut-off values for the diagnosis of ARF.

Outcomes of possible and probable rheumatic fever: A cohort study using northern Australian register data, 2013-2019.

In Australia, there is a high burden of acute rheumatic fever (ARF) among Aboriginal and Torres Strait Islander peoples. Clinical diagnostic criteria can result in a diagnosis of 'definite', 'probable' or 'possible' ARF and outcomes range from recovery to severe rheumatic heart disease (RHD). We compared outcomes by ARF diagnosis, where the main outcome was defined as disease progression from: possible to probable ARF, definite ARF or RHD; probable to definite ARF or RHD; or definite ARF to definite ARF recurrence or RHD. Data were extracted from the Northern Territory RHD register for Indigenous Australians with an initial diagnosis of ARF during the 5.5-year study period (01/01/2013-30/06/2019). Descriptive statistics were used to describe cohort characteristics, probability of survival, and cumulative incidence risk of disease progression. Cox proportional hazards regression was used to determine whether time to disease progression differed according to ARF diagnosis. Sub-analyses on RHD outcome, clinical manifestations, and antibiotic adherence were also performed. In total there were 913 cases with an initial ARF diagnosis. Of these, 92 (13%) experienced disease progression. The probability of disease progression significantly differed between ARF diagnoses (p = 0.0043; log rank test). Cumulative incidence risk of disease progression at 5.5 years was 33.6% (95% CI 23.6-46.2) for definite, 13.5% (95% CI 8.8-20.6) for probable and 11.4% (95% CI 6.0-21.3) for possible ARF. Disease progression was 2.19 times more likely in those with definite ARF than those with possible ARF (p = 0.026). Progression to RHD was reported in 52/732 (7%) of ARF cases with normal baseline echocardiography. There was a significantly higher risk of progression from no RHD to RHD if the initial diagnosis was definite compared to possible ARF (p<0.001). These data provide a useful way to stratify risk and guide prognosis for people diagnosed with ARF and can help inform practice.

Tenascin-C: as a diagnostic biomarker for rheumatic heart disease

BackgroundRheumatic fever is a long-term inflammatory disease that can happen if group A beta-hemolytic streptococci bacteria are not treated well enough. Rheumatic fever is recognized globally as the leading cause of heart disease in the pediatric population. This disease destroys the heart muscle, progressively deteriorating its structure and impairing the function of its valves over time.AimThe aim of this study is to determine the role of serum tenascin-C in the diagnosis of acute rheumatic fever and chronic rheumatic heart disease.MethodsThis case–control study involved a group of 60 Egyptian children. Among them, 20 were diagnosed with acute rheumatic fever, identified using the updated Jones criteria from 2015. Another 20 children, who were suffering from chronic rheumatic heart disease, were also act as a part of the study. The remaining 20 participants, healthy children carefully matched in age and sex, served as the control group.ResultsSerum tenascin-C level was significantly increased in acute rheumatic fever (ARF) and highly significantly increased in chronic rheumatic heart disease (CRHD) groups when compared with control group (P = 0.04, 0.01), respectively. There were highly significant difference between and within the studied groups regarding the mean of serum tenascin-C. Serum tenascin-C mean of ARF, CRHD, and control was 4.82 ± 18.7, 5.46 ± 1.6, and 3.78 ± 2.4, respectively, P = 0.02. Level of serum tenascin-C was lower in cases with severe mitral valve insufficiency. No significant link was found between the level of serum tenascin-C and C-reactive protein (CRP), ESR, and ASO titer, with a P-value greater than 0.5. ROC curve for serum tenascin-C in ARF patients was area under the curve = 0.682 (P = 0.05) with optimal serum tenascin-C cut-off point (> 3.76 ng/ml); ROC curve for serum tenascin-C in CRHD patients was AUC = 0.73 (P = 0.01) with cut-off point level (73.76 ng/ml).ConclusionPatients with ARF and CRHD have increased level of serum tenascin-C. Serum tenancin-C is superior in the diagnosis of ARF in comparison to CRP, ESR, and ASOT. Tenascin-C level can be used as a diagnostic marker for ARF and CRHD.

Abstract 12362: High Rates of Mortality in Uganda Following Acute Rheumatic Fever: Findings From a Community-Based Prospective Cohort Study

Introduction: Rheumatic heart disease (RHD) is the largest contributor to cardiac mortality in children worldwide. Little contemporary data exist on its antecedent illness, acute rheumatic fever (ARF). There is an urgent need to understand outcomes following ARF in RHD-endemic settings. We aimed to describe medium-term mortality, disease recurrence, and change in carditis among Ugandan children following ARF diagnosis, and to identify correlates of mortality. Methods: We conducted a prospective cohort study of children diagnosed with definite ARF in 2017-2020 during a community-based incidence study. Patients were enrolled in a national registry and followed with annual review, most recently in August 2022. Kaplan-Meier (KM) survival analysis was used to describe all-cause mortality and individual Cox proportional hazards regression models were used to identify correlates of death. Descriptive statistics were used to characterize changes in carditis. Results: Among 135 children with definite ARF, 22/135 (16.3%) experienced death, 19/135 (14.1%) cardiac death, 5/135 (3.7%) ARF recurrence, and 5/135 (3.7%) surgery over a median (interquartile range) of 4.25 (3.4, 5.1) years. KM analysis saw 14/22 (63.6%) of deaths occur by one year, 16/22 (72.7%) by two years, and 20/22 (90.9%) by three years. The presence of moderate/severe carditis (HR 14.1, 95% CI 4.2, 47.7) and PR prolongation (HR 3.9, 95% CI 1.5, 9.9) at diagnosis was associated with increased cardiac mortality. Among 107 survivors included in echocardiographic sub-analysis, 27/107 (25.2%) had improvement in carditis, 70/107 (65.4%) no change, and 10/107 (9.4%) progression. Conclusions: These are the first contemporary data from sub-Saharan Africa reviewing medium-term outcomes following ARF. Adverse outcome rates exceeded those reported elsewhere. Most decedents already had advanced cardiac involvement upon first ARF diagnosis, as evidenced by PR prolongation and high-grade carditis, suggesting a history of prior undiagnosed ARF recurrences that had already compounded into RHD. These data indicate that a high burden of ARF exists in the community that is undetected by current methods, emphasizing the need for better point-of-care diagnostics to improve early ARF detection.

Sydenham chorea in the top end of Australia's Northern Territory: A 20-year retrospective case series.

Sydenham chorea is an immune-mediated neuropsychiatric condition, and a major criterion for diagnosis of acute rheumatic fever (ARF). Children in remote Northern Australia experience disproportionately high rates of ARF, yet studies looking at the epidemiology, clinical presentation and management of Sydenham chorea are limited in this population. We conducted a retrospective case series from January 2002 to April 2022 of all paediatric patients aged ≤18 years admitted to Royal Darwin Hospital with Sydenham chorea. Cases were identified using the hospital's clinical coding system (ICD10). Medical records were reviewed and data on demographics, clinical presentation, investigation results, treatment and outcome were extracted, deidentified and analysed. One hundred ten presentations of Sydenham chorea occurred between 2002 and 2022, 109 (99%) of these were in First Nations children, with 85% residing in very remote locations. Most commonly, chorea presented as a generalised movement disorder affecting all four limbs (49%). Neuropsychiatric symptoms were reported in 33 (30%), and there was evidence of rheumatic heart disease on echocardiogram in 86 (78%) at presentation. All patients received benzathine penicillin, but there was significant variation in management of chorea, ranging from supportive management, to symptomatic management with anticonvulsants, to immunomodulatory medications including corticosteroids. This case series highlights the significant burden of Sydenham chorea among First Nations children living in Northern Australia and demonstrates wide variation in treatment approaches. High-quality clinical trials are required to determine the best treatment for this disabling condition.

Positive impact of training rural health workers in identification and prevention of acute rheumatic fever in eastern Uganda.

Diagnosis of acute rheumatic fever (ARF) is mainly clinical. Delayed or missed diagnosis and failure to administer appropriate and timely treatment of ARF leads to rheumatic heart disease (RHD), which could necessitate expensive treatments such as open-heart surgery. Implementation of preventative guidelines depends on availability of trained healthcare workers. As part of the routine support supervision, the Uganda Heart Institute sent out a team to rural eastern Uganda to evaluate health workers' knowledge level regarding management of ARF. Health workers from selected health facilities in Tororo district, eastern Uganda, were assessed for their knowledge on the clinical features and role of benzathine penicillin G (BPG) in the treatment and prevention of ARF recurrence. Using the RHD Action Needs assessment tool, we generated and administered a pre-test, then conducted training and re-administered a post-test. Eight months later, health workers were again assessed for knowledge retention and change in practices. Statistical analysis was done using Stata version 15. During the initial phase, 34 of the 109 (31%) health workers passed the pre-test, indicating familiarity with clinical features of ARF. The level of knowledge of BPG use in ARF was very poor in all the health units [25/109 (22.6%)] but improved after training to 80%, as shown by the chi-squared test ( χ2 = 0.000). However, retention of this knowledge waned after eight months and was not significantly different compared to pre-training (χ2 ≥ 0.2). A critical knowledge gap is evident among health workers, both in awareness and treatment of ARF, and calls for repetitive training as a priority strategy in prevention.

NOVEL BIOMARKERS AND ECHOCARDIOGRAPHIC FINDINGS IN ACUTE RHEUMATIC FEVER PATIENTS

Aim: Acute rheumatic fever (ARF) is an inflammatory disease that develops after Group A Streptococcal (GAS) tonsillopharyngitis in genetically susceptible individuals. We aimed to examine the clinical, laboratory, and echocardiographic findings of the patients diagnosed and followed up with ARF. &#x0D; Methods: 55 patients under the age of 18 who were hospitalized and followed up with the diagnosis of ARF between January 2017 and January 2019 were included in this retrospective study. All cases were diagnosed with ARF according to the 2015 revised Jones criteria according to the intermediate-risk group. Gender, age, time of admission, physical examination findings, laboratory findings, echocardiographic findings, and data meeting major and minor diagnostic criteria of all patients diagnosed with ARF were recorded. Echocardiography and electrocardiography were performed on all patients. Inflammatory biomarkers were calculated using laboratory parameters. The data before the treatment and at the 8th week of the treatment were compared.&#x0D; Results: 31 (56.4%) of the patients were female and 24 (43.6%) were male, the mean age was 13.70±2.44 years (7-18 years). The highest number of patients was in the 9-14 age group. The most frequent hospital admission season was winter. Arthritis and carditis were the most common major criteria. Post-treatment body weight, height, body mass index, and systolic and diastolic blood pressure values of the patients were statistically significantly higher than before treatment (p

Figurate annulare erythemas.

T. Colcott Fox (1849-1916) first introduced in 1889 the term "figurate erythemas." According to the clinical pattern, figurate erythemas are annular, circinate, concentric, polycyclic, or arciform. The most important figurate annulare erythemas are erythema annulare centrifugum, erythema marginatum, erythema gyratum repens, erythema migrans, erythema chronicum migrans, and the pediatric annular erythemas. Erythema annulare centrifugum might be due to fungal, bacterial, or viral infections or drugs. It tends to spread centrifugally while developing central clearing. The most common locations are the trunk and the proximal extremities. Individual lesions last from several days to weeks and may resolve spontaneously. Erythema marginatum is one of the criteria for the diagnosis of acute rheumatic fever, but it also might be seen as a symptom of other diseases such as hereditary angioedema with C1-inhibitor deficiency and psittacosis. The typical clinical picture is presented by serpiginous erythematous macules and plaques with central clearing and accentuated borders. Erythema gyratum repens is a figurate erythema associated with internal malignancy. It has been linked especially to lung, esophageal, and breast cancers. Erythema gyratum repens is characterized by multiple erythematous, rounded macules or papules, rapidly progressing and forming concentric bands with an unique wood-grained appearance with desquamation on the edges of the erythema. Erythema chronicum migrans is the most common sign of infection with Borrelia burgdorferi and other Borrelia species. It is characterized by a round or oval erythematous or livid macule with a central depressed or raised area on the spot of a previous tick bite. Erythema migrans grows centrifugally and slowly in a matter of days or weeks. Central clearing is observed in 60% of patients, thus forming a targetoid appearance of the lesion. Many other figurate erythemas can be observed in infancy (pediatric annular erythemas). To this group belong neonatal lupus, erythema gyratum atrophicans transiens neonatale, annular centrifugal erythema, familial annular erythema, annular erythema of infancy, eosinophilic annular erythema, and figurate neutrophilic erythema of infancy. The treatment of the various types of figurate erythemas should be etiologic, and when the underlying condition is addressed, the therapy usually is successful.

IgG2 rules: N-acetyl-β-D-glucosamine-specific IgG2 and Th17/Th1 cooperation may promote the pathogenesis of acute rheumatic heart disease and be a biomarker of the autoimmune sequelae of Streptococcus pyogenes.

Antecedent group A streptococcal pharyngitis is a well-established cause of acute rheumatic fever (ARF) where rheumatic valvular heart disease (RHD) and Sydenham chorea (SC) are major manifestations. In ARF, crossreactive antibodies and T cells respond to streptococcal antigens, group A carbohydrate, N-acetyl-β-D-glucosamine (GlcNAc), and M protein, respectively, and through molecular mimicry target heart and brain tissues. In this translational human study, we further address our hypothesis regarding specific pathogenic humoral and cellular immune mechanisms leading to streptococcal sequelae in a small pilot study. The aims of the study were to (1) better understand specific mechanisms of pathogenesis in ARF, (2) identify a potential early biomarker of ARF, (3) determine immunoglobulin G (IgG) subclasses directed against GlcNAc, the immunodominant epitope of the group A carbohydrate, by reaction of ARF serum IgG with GlcNAc, M protein, and human neuronal cells (SK-N-SH), and (4) determine IgG subclasses deposited on heart tissues from RHD. In 10 pediatric patients with RHD and 6 pediatric patients with SC, the serum IgG2 subclass reacted significantly with GlcNAc, and distinguished ARF from 7 pediatric patients with uncomplicated pharyngitis. Three pediatric patients who demonstrated only polymigrating arthritis, a major manifestation of ARF and part of the Jones criteria for diagnosis, lacked the elevated IgG2 subclass GlcNAc-specific reactivity. In SC, the GlcNAc-specific IgG2 subclass in cerebrospinal fluid (CSF) selectively targeted human neuronal cells as well as GlcNAc in the ELISA. In rheumatic carditis, the IgG2 subclass preferentially and strongly deposited in valve tissues (n = 4) despite elevated concentrations of IgG1 and IgG3 in RHD sera as detected by ELISA to group A streptococcal M protein. Although our human study of ARF includes a very small limited sample set, our novel research findings suggest a strong IgG2 autoantibody response against GlcNAc in RHD and SC, which targeted heart valves and neuronal cells. Cardiac IgG2 deposition was identified with an associated IL-17A/IFN-γ cooperative signature in RHD tissue which displayed both IgG2 deposition and cellular infiltrates demonstrating these cytokines simultaneously. GlcNAc-specific IgG2 may be an important autoantibody in initial stages of the pathogenesis of group A streptococcal sequelae, and future studies will determine if it can serve as a biomarker for risk of RHD and SC or early diagnosis of ARF.

Abstract 15393: Low Risk of Rheumatic Heart Disease Among Children Found to Have an Alternate Diagnosis to Acute Rheumatic Fever in a High Risk Setting

Introduction: In 2015, the American Heart Association revised the Jones Criteria, the gold standard for diagnosis of acute rheumatic fever (ARF). This revision included changes to increase the sensitivity for ARF in high-risk settings. The objective of this study was to determine if there were children who were found to be ARF-negative by strict application of these criteria in a high risk setting but found to have rheumatic heart disease (RHD) on follow-up evaluation. Methods: Between 2017 and 2020, we conducted an epidemiological study to determine the incidence of ARF in Uganda. Children and adolescents, 3-17 years, presenting with clinical concern for ARF (fever and joint pain, suspicion of carditis, or suspicion of chorea) were enrolled and evaluated using the Jones Criteria. Children ultimately found to have a laboratory-confirmed alternate diagnosis and those who did not meet ARF criteria but had an unknown final diagnosis, were asked to participate in a longitudinal echocardiographic follow-up study to monitor for development of RHD. Presence of RHD was considered a false negative test and used to calculate the false negative error of not receiving a diagnosis of ARF. Results: There were 351 children determined to have an alternate diagnosis during the study period; 180 with a laboratory confirmed final diagnosis (127 malaria, 20 non-rheumatic cardiac disease, 15 influenza, 18 other) and 171 with an unknown final diagnosis. Of these, 220 (62.7%) had at least one follow-up visit (median 366 days, range 10-1054). One child (1/220, &lt;1%) developed echocardiographic evidence of borderline RHD during the follow-up period. Diagnostic overlap (met Jones Criteria but found to have a laboratory confirmed alternate diagnosis) was seen in 18% (33/180) of those with laboratory confirmed alternate diagnosis. Of these, 21 of 33 attended at least one follow-up (median 340 days, range 10-1054), and none showed echocardiographic evidence of RHD. Conclusions: Application of the 2015 Jones Criteria showed an exceptionally low rate of subsequent RHD, even in cases of diagnostic overlap. Clinicians working in ARF-endemic settings can have high confidence that children who do not meet criteria for ARF have a low risk of false negative diagnosis and short-term risk of RHD.

Psychopathological Impact in Patients with History of Rheumatic Fever with or without Sydenham's Chorea: A Multicenter Prospective Study.

Sydenham’s chorea (SC) is a post-streptococcal autoimmune disorder of the central nervous system, and it is a major criterium for the diagnosis of acute rheumatic fever (ARF). SC typically improves in 12–15 weeks, but patients can be affected for years by persistence and recurrencies of both neurological and neuropsychiatric symptoms. We enrolled 48 patients with a previous diagnosis of ARF, with or without SC, in a national multicenter prospective study, to evaluate the presence of neuropsychiatric symptoms several years after SC’s onset. Our population was divided in a SC group (n = 21), consisting of patients who had SC, and a nSC group (n = 27), consisting of patients who had ARF without SC. Both groups were evaluated by the administration of 8 different neuropsychiatric tests. The Work and Social Adjustment Scale (WSAS) showed significantly (p = 0.021) higher alterations in the SC group than in the nSC group. Furthermore, 60.4% (n = 29) of the overall population experienced neuropsychiatric symptoms other than choreic movements at diagnosis and this finding was significantly more common (p = 0.00) in SC patients (95.2%) than in nSC patients (33.3%). The other neuropsychiatric tests also produced significant results, indicating that SC can exert a strong psychopathological impact on patients even years after its onset.

Revisiting QT prolongation in acute rheumatic fever – Relevance for hydroxychloroquine treatment

In-vitro evidence suggests hydroxychloroquine could be a potential immunomodulator for the inflammatory carditis of acute rheumatic fever (ARF). Hydroxychloroquine used as an anti-inflammatory agent has a low side effect profile but its use in the Covid-19 pandemic raised concerns about QTc interval prolongation and cardiac arrhythmias. The prolongation of QTc in ARF appears benign but has not been widely studied. We aim to report QTc intervals in a contemporary ARF population and consider implications for hydroxychloroquine use in ARF. The study cohort was 197 children <15 years of age with a clinical diagnosis of ARF. The QTc mean (SD) was 445 msec (28), range 370-545 msec. Eighteen percent of the cohort had a QTc > 99th percentile for normal by age and 8 patients (4%) had a QTc over 500 msec. There was no difference of QTc by age or gender. Inter-observer repeatability for QTc (n = 33) was 35 msec.The QTc is often prolonged in the early phase of ARF, meaning that QT prolonging medications should be used with caution in this setting. Serial ECG monitoring of the QT interval is recommended if hydroxycholoroquine is used in ARF.

An Uncommon Association of Ebstein’s Anomaly and Acute Rhumatic Fever

Background: Ebstein’s anomaly is a relatively rare congenital heart disease (atrialisation of the right ventricle). Anomalies of left side of the heart have been described with this condition. We however present a case of Ebstein's anomaly with recurrent acute rheumatic fever (ARF) and mitral stenosis. Case report: A 13-year-old boy with not followed for heart disease and with a history of notion of repetitive angina, is admitted to the pediatric emergency room for fever and polyarthritis. General examination not showed subcutaneous nodules and laboratory investigations revealed leucocytosis, elevated erythrocyte sedimentation rate (ESR) and antistreptolysin O (ASO) titre. Echocardiography revealed Ebstein anomaly with moderate mitral stenosis. A diagnosis of recurrent ARF was made based on the carditis, arthritis, history of recurrence of sore throat and evidence of recent streptococcal infection. He was transferred to the cardiology department and initially put on medical treatment. Its clinical course was marked by the appearance of unresolved ventricular tachycardia despite drug cardioversion. His prognosis was unfavorable with death after 10 days of hospitalization under antiarrhythmic treatment. Conclusion: Ebstein's disease is a rare disease. Cardiac arrhythmias are deleterious and the association of rheumatic fever with co-morbidity increases its lethality.

Acute Rheumatic Fever and Rheumatic Heart Disease: Highlighting the Role of Group A Streptococcus in the Global Burden of Cardiovascular Disease.

Group A Streptococcus (GAS) causes superficial and invasive infections and immune mediated post-infectious sequalae (including acute rheumatic fever/rheumatic heart disease). Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are important determinants of global cardiovascular morbidity and mortality. ARF is a multiorgan inflammatory disease that is triggered by GAS infection that activates the innate immune system. In susceptible hosts the response against GAS elicits autoimmune reactions targeting the heart, joints, brain, skin, and subcutaneous tissue. Repeated episodes of ARF—undetected, subclinical, or diagnosed—may progressively lead to RHD, unless prevented by periodic administration of penicillin. The recently modified Duckett Jones criteria with stratification by population risk remains relevant for the diagnosis of ARF and includes subclinical carditis detected by echocardiography as a major criterion. Chronic RHD is defined by valve regurgitation and/or stenosis that presents with complications such as arrhythmias, systemic embolism, infective endocarditis, pulmonary hypertension, heart failure, and death. RHD predominantly affects children, adolescents, and young adults in LMICs. National programs with compulsory notification of ARF/RHD are needed to highlight the role of GAS in the global burden of cardiovascular disease and to allow prioritisation of these diseases aimed at reducing health inequalities and to achieve universal health coverage.

Modelling study of the ability to diagnose acute rheumatic fever at different levels of the Ugandan healthcare system

ObjectiveTo determine the ability to accurately diagnose acute rheumatic fever (ARF) given the resources available at three levels of the Ugandan healthcare system.MethodsUsing data obtained from a large epidemiological database...

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.

Toward the Knowledge of the Epidemiological Impact of Acute Rheumatic Fever in Italy.

Background: To estimate the incidence of Acute Rheumatic Fever (ARF) in Tuscany, a region of Central Italy, evaluating the epidemiological impact of the new diagnostic guidelines, and to analyse our outcomes in the context of the Italian overview.Methods: A multicenter and retrospective study was conducted involving children <18 years old living in Tuscany and diagnosed in the period between 2010 and 2019. Two groups were established based on the new diagnostic criteria: High-Risk (HR) group patients, n = 29 and Low-Risk group patients, n = 96.Results: ARF annual incidence ranged from 0.91 to 7.33 out of 100,000 children in the analyzed period, with peak of incidence registered in 2019. The application of HR criteria led to an increase of ARF diagnosis of 30%. Among the overall cohort joint involvement was the most represented criteria (68%), followed by carditis (58%). High prevalence of subclinical carditis was observed (59%).Conclusions: Tuscany should be considered an HR geographic area and HR criteria should be used for ARF diagnosis in this region.

An eight-plex immunoassay for Group A streptococcus serology and vaccine development

Group A Streptococcus (GAS) is a major human pathogen responsible for superficial infections through to life-threatening invasive disease and the autoimmune sequelae acute rheumatic fever (ARF). Despite a significant global economic and health burden, there is no licensed vaccine available to prevent GAS disease. Several pre-clinical vaccines that target conserved GAS antigens are in development. Assays that measure antigen-specific antibodies are essential for vaccine research. The aim of this study was to develop a multiplex beadbased immunoassay that can detect and quantify antibody responses to multiple GAS antigen targets in small volume blood samples. This builds on our existing triplex assay comprised of antigens used in clinical serology for the diagnosis of ARF (SLO, DNase B and SpnA). Five additional conserved putative GAS vaccine antigens (Spy0843, SCPA, SpyCEP, SpyAD and the Group A carbohydrate), were coupled to spectrally unique beads to form an 8-plex antigen panel. After optimisation of the assay protocol, standard curves were generated, and assessments of assay specificity, precision and reproducibility were conducted. A broad range of antibody (IgG) titres were able to be quickly and accurately quantified from a single serum dilution. Assay utility was assessed using a panel of 62 clinical samples including serum from adults with GAS bacteraemia and children with ARF. Circulating IgG to all eight antigens was elevated in patients with GAS disease (n = 23) compared to age-matched controls (n = 39) (P < 0.05). The feasibility of using dried blood samples to quantify antigen-specific IgG was also demonstrated. In summary, a robust and reproducible 8-plex assay has been developed that simultaneously quantifies IgG antibodies to GAS vaccine and diagnostic antigens.

Mitral valve thickening in acute rheumatic fever as a predictor of late valvar dysfunction.

BackgroundRheumatic heart disease (RHD) complicating acute rheumatic fever (ARF) remains an important health problem in developing countries. No definitive diagnostic test for ARF exists and the role of Doppler echocardiography (DEC) for long-term prognostic evaluation following ARF is not well established.ObjectiveTo investigate the prognostic value of DEC in patients with ARF as a predictor of chronic valve dysfunction.MethodsProspectively enrolled patients with clinical ARF had a DEC performed soon after diagnosis and repeated at 1, 3, 6 and 12 months and thereafter at every 1–2 years. We defined chronic valve dysfunction by ≥ 3 of the following: increased valve thickening, commissure fusion, subvalvular thickening, reduced leaflet mobility, non-trivial mitral and/or aortic regurgitation. We performed univariate analysis and developed multivariate logistic regression models to identify variables that may influence evolution to RHD. p <0.05 was considered significant.ResultsWe evaluated 70(57% men) patients, 10.8±5.6 years-old during the ARF episode and followed for 95±26 months. Chronic valve dysfunction was identified in 36(51.4%) which fulfilled criteria for RHD and 10(27.8%) of them died or underwent valve surgery. Univariate analysis showed that mitral valve thickening and presence of mitral regurgitation at baseline DEC, were associated with RHD(p<0.01). Multivariate logistic regression showed that only mitral valve thickness either as a continuous (Odds-Ratio:5.8;95%CI:1.7–19.7) or as a categorical variable (Odds-Ratio:4.04;95%CI:1.06–15.3) was an independent predictor of chronic valve dysfunction.ConclusionsMitral leaflets thickening documented at the time of diagnosis of ARF is a consistent prognostic marker for the subsequent evolution to RHD.

Abstract 13788: Systematic Review: Utility of Human Immune Responses to Group A Streptococcus Antigens as a Diagnostic Indicator for Acute Rheumatic Fever

Introduction: Previous studies have established that group A streptococcus (GAS) antibody titre is correlated with a diagnosis of acute rheumatic fever (ARF). However, results vary in the usefulness of GAS antibodies, particularly anti-Streptolysin-O (ASO) and anti-DNase B, in confirming a recent GAS infection. Therefore, we sought to provide, from published studies, an evidence-based synthesis of the correlation of streptococcal serology to establish the usefulness of immunological data in aiding the diagnosis of ARF. These findings are anticipated to have implications where echocardiography is not freely available, especially where ARF is rampant. Methods: We conducted a comprehensive search across a number of databases. Applying a priori criteria, we selected articles reporting on studies, regardless of study design, that evaluate the levels of antibodies against GAS-specific antigens in ARF subjects against control values or a published standard. Data were extracted onto data extraction forms, captured electronically and analysed using STATA software. Risk of bias was assessed in included studies using the Newcastle-Ottawa Scale . Results: The search strategy yielded 534 studies, from which 24 met the inclusion criteria, reporting on evaluation of titres for SLO (n=10), DNase B (n=9), anti-streptokinase (ASK) (n=3) amongst others. Elevation in titres was determined by comparison with controls and upper limit of normal (ULN) antibody values as determined in healthy individuals. Meta-analysis of case-controlled studies revealed moderate odds ratio (OR) correlations between ARF diagnosis and elevated titres for SLO (OR=10.57; 95% CI, 3.36 to 33.29; 10 studies) and DNase B (OR=6.97; 95% CI, 2.99 to 16.27; 7 studies). Conclusions: While providing support for incorporating SLO and DNase B in the diagnosis of ARF, we present the following reflections: an elevation in SLO and DNase B levels are not consistently associated with an ARF diagnosis; increasing the number of GAS proteins in the test is warranted to improve sensitivity; paired (acute and convalescent) samples could provide a more accurate indication of a rising titre. Use of community-based controls as a standard is not a reliable marker by which to gauge recent GAS infection