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.

Previous Traditional Medicine Use for Sore Throat among Children Evaluated for Rheumatic Fever in Northern Uganda.

Timely diagnosis of group A streptococcal (GAS) sore throat coupled with appropriate antibiotic treatment is necessary to prevent serious post-streptococcal complications, including rheumatic fever (RF) and rheumatic heart disease (RHD). Traditional medicine (TM) is a known common adjunct to formal medical care in sub-Saharan Africa. A better understanding of health-seeking behavior for sore throat both within and outside the formal medical system is critical to improving primary prevention efforts of RF and RHD. A prospective mixed-methods study on the use of TM for sore throat was embedded within a larger epidemiological study of RF in Northern Uganda. Children presenting with symptoms of RF were interviewed about recent TM use as well as health services use for sore throat. One hundred children with a median age of 10 years (interquartile range: 6.8-13 years) completed the TM interview with their parent/guardian as part of a research study of RF. Seventeen, or 17%, accessed a TM provider for sore throat as part of the current illness, and 70% accessed TM for sore throat in the past (73% current or past use). Of the 20 parents who witnessed the TM visit, 100% reported use of crude tonsillectomy. Penicillin was the most frequently prescribed medication by TM providers in 52% of participants who were seen by a TM provider. The use of TM among children presenting with symptoms of sore throat in northern Uganda is common and frequently used in tandem with diagnostic services offered through the formal healthcare system. Engagement with TM practitioners may provide an important avenue for designing effective primary prevention and management strategies of RF and reduce the global burden of RHD.

Coexistence of acute poststreptococcal glomerulonephritis and acute rheumatic fever in a Japanese girl with primary Sjögren's syndrome.

Although acute poststreptococcal glomerulonephritis (APSGN) and acute rheumatic fever (ARF) are well-known complications of group A streptococcus infection, concomitant occurrence of both diseases is rare. We report an 11-year-old Japanese girl with primary Sjögren's syndrome complicated by acute renal failure about 2 weeks after the onset of pharyngitis. Although histopathological findings of the kidney were not confirmative, APSGN was suggested by the spontaneous recovery of her renal function, typical latent period with high levels of antistreptolysin O and low serum levels of C3 but not of C4. In addition, cardiac hypomotility and regurgitation of the 4 valves progressed in the convalescent phase of APSGN, which was accompanied by elevation of serum C-reactive protein and plasma brain natriuretic peptide (BNP) levels. Myocarditis was suggested by delayed gadolinium-enhancement of cardiac walls on cardiac magnetic resonance imaging. She was diagnosed with APSGN and ARF and was treated with a combination of short course prednisolone and prophylactic penicillin G. There is no relapse of renal or cardiac symptoms during 6 years follow-up. Unexpected elevation of plasma BNP in a convalescent stage of APSGN suggests the development of ARF. Underlying Sjögren's syndrome (SS) may modify the histopathological findings and make it difficult to differentiate APSGN from CTD-associated nephritis such as lupus nephritis (LN) even by renal biopsy.

Pediatrician's approach to diagnosis and management of group A streptococcal pharyngitis.

Group A streptococcal (GAS) pharyngitis is responsible for 20-30% of pharyngitis cases in children (Shulman et al. Clin Infect Dis 55(10):e86-e102, 2012). Recommendations for the diagnosis and treatment of GAS pharyngitis have been published by the Italian National Institute of Health guidelines in 2012 (ESCMID Sore Throat Guideline Group et al. Clin Microbiol Infect 18(Suppl 1):1-28, 2012). Adherence to such guidance is relevant for primary prevention of complications of GAS pharyngitis, above all rheumatic fever (RF). The aim of our study was to evaluate the application of Italian guidelines by the family pediatricians from the Abruzzo region. A validated questionnaire was completed by the family pediatricians and used for data collection. The 154 family pediatricians from Abruzzo (88% of the total number of family pediatricians) participated in the study. Out of the 1232 answers, 455 (37%) were wrong. Only 8% of the participants answered correctly all the questions, whereas 0.6% missed all the questions. Through the Spearman's correlation, our study found an inverse significant correlation between the questions regarding primary prophylaxis (Score B) and the work experience of pediatricians (Rho = - 0.276, p = 0.048). The majority of the family pediatricians from the Abruzzo region, in line with studies from other countries, have significant knowledge gaps about the diagnosis and treatment of GAS pharyngitis. Therefore, strategies to increase the pediatricians' awareness of the guidelines are needed, in order to reduce the RF incidence.

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.

Sydenham's Chorea.

BACKGROUND: Sydenham's chorea is the most common acquired movement disorder of adolescence. This clinical manifestation of acute rheumatic fever has a clear and documented relationship with Group A streptococcal infections. The symptoms are involuntary choreiform movements that can affect the face and all extremities. The pathophysiology remains unclear. CASE REPORT: A 12-year-old female was brought to the emergency department with a 2-week history of involuntary muscle spasms of her right arm and leg. Her parents reported intermittent slurred speech and difficulty grasping utensils. Physical examination revealed an awake, alert, age-appropriate female with normal cranial nerves. Patient was found to have choreoathetoid movements on the right extremities with dystonia of right leg with ambulation. Neurology consultation, computed tomography of the head, and magnetic resonance imaging of the brain did not show any acute pathology. Echocardiogram did show mild tricuspid regurgitation, suggestive of rheumatic fever. Anti-streptolysin O titer was markedly elevated, along with DNAse-B antibodies. The patient had marked improvement of movement disorder at just over 1 week later. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Sydenham's chorea is a rare but important movement disorder often related to Group A streptococcus and rheumatic fever. The incidence of rheumatic fever has been decreasing in North America but continues to be much more prevalent in developing countries as well as immigrant populations. This diagnosis is rare and can occasionally be misdiagnosed as a "fidgety" child or as a psychiatric manifestation. Sydenham's chorea is important to diagnose because acute treatment and prophylactic antibiotics can help improve symptoms and minimize cardiac damage.

Poststreptococcal Reactive Arthritis: Diagnostic Challenges.

Poststreptococcal reactive arthritis (PSRA) is associated with prior group A ß-hemolytic streptococcal infection and has a reported annual incidence of 1 to 2 cases per 100,000 persons, approximately twice that of acute rheumatic fever (ARF) in the US. Children who present with reactive arthritis are not uncommon in a busy general pediatric practice in the US, whereas children who present with ARF are very rare. Distinguishing PSRA from ARF can be challenging because the symptoms and signs are similar, but the diseases differ in long-term therapy, follow-up evaluation, and prognosis. We review the diagnostic criteria for PSRA, the pertinent features of the 2015 ARF diagnostic guideline from the American Heart Association, and the major characteristics that differentiate PSRA from ARF.

An old disease re-emerging: acute rheumatic fever.

We present the case of a 41-year-old Australian woman with a 3-day history of fevers and migratory polyarthritis. Three weeks prior she had been treated by her GP with phenoxymethylpenicillin for acute tonsillitis. Examination confirmed synovitis. Systemic assessment including cardiovascular, neurological and skin examination was unremarkable. Abnormal investigations included a leucocytosis with neutrophilia, C-reactive peptide of 116 mg/L, erythrocyte sedimentation rate of 103 mm/hour and acute transaminitis. The antistreptolysin O titre was 304 IU, which increased to 1,250 IU after 2 weeks. Troponin T, electrocardiogram and echocardiography were all normal. The patient was treated for acute rheumatic fever with corticosteroids and a 10-day course of cephalexin. After 8 weeks, she made a full recovery and had normalised inflammatory markers and liver biochemistry. She was then commenced on monthly prophylactic intramuscular benzathine penicillin. This case study aims to raise awareness of the presentation, diagnosis and management of acute rheumatic fever.

Poststreptococcal Illness: Recognition and Management.

Group A beta-hemolytic streptococcus can cause several postinfectious, nonsuppurative immune- mediated diseases including acute rheumatic fever, poststreptococcal reactive arthritis, pediatric autoimmune neuropsychiatric disorders, and poststreptococcal glomerulonephritis. Except for sporadic outbreaks, poststreptococcal autoimmune syndromes occur most commonly in sub-Saharan Africa, India, Australia, and New Zealand. Children younger than three years are rarely affected by group A streptococcus pharyngitis or rheumatic fever, and usually do not require testing. Rheumatic fever is a rare condition that presents as a febrile illness characterized by arthritis, carditis or valvulitis, and neurologic and cutaneous disease, followed many years later by acquired valvular disease. Recurrence rates are high. In addition to evidence of recent streptococcal infection, two major or one major and two minor Jones criteria are required for diagnosis. Electrocardiography, chest radiography, erythrocyte sedimentation rate, and an antistreptolysin O titer are the most useful initial tests. Echocardiography is recommended to identify patients with subclinical carditis. The arthritis usually responds within three days to nonsteroidal anti-inflammatory drugs. Poststreptococcal reactive arthritis is nonmigratory, can affect any joint, and typically does not respond to aspirin. Pediatric autoimmune neuropsychiatric disorders affect the basal ganglia and are manifested by obsessive-compulsive and tic disorders. The presentation of poststreptococcal glomerulonephritis ranges from asymptomatic microscopic hematuria to gross hematuria, edema, hypertension, proteinuria, and elevated serum creatinine levels.

Using preceding hospital admissions to identify children at risk of developing acute rheumatic fever.

AIMS: New Zealand (NZ) Maori and Pacific children have high rates of acute rheumatic fever (ARF). Around 150 new cases arise each year. As part of the national ARF prevention programme, funding is available to improve housing. To obtain maximum benefit from interventions, an effective tool is needed for targeting high-risk children. This study aimed to assess the effectiveness of using hospitalisations for identifying children at risk of subsequent ARF. METHODS: Three potentially avoidable hospitalisation (PAH) groups were investigated, including diseases thought to be influenced by housing. All were developed using expert opinion or systematic reviews. These were: (i) the PAH conditions associated with the housing environment (PAHHE) group; (ii) the Crowding group; and (iii) the Ministry of Health (MoH) group. We analysed NZ public hospital discharge data (2000-2014). The prevalence of ARF among patients hospitalised in each group was calculated to estimate sensitivity and potential effectiveness. The number needed to screen (NNS) to identify one ARF case was estimated as a measure of efficiency. RESULTS: Nearly one-third of ARF patients experienced a PAH as children (before developing ARF). Sensitivity for detecting future ARF ranged from <5% (MoH group) to 27% (PAHHE group). NNS ranged from 502.4 (PAHHE) to 707.5 (MoH). CONCLUSIONS: Because ARF is relatively rare, observing hospitalisations is not particularly efficient for targeting prevention activities for this condition alone. However, housing interventions are likely to improve multiple outcomes; thus, the hospital setting is still useful for identifying at-risk children who could benefit from such programmes.

Rheumatic Heart Disease: Pathogenesis and Vaccine.

Rheumatic fever (RF) and rheumatic heart disease (RHD) follow untreated S. pyogenes throat infections in children who present susceptible genes that favor the development of autoimmune reactions. In this review, we focus on the genes that confer susceptibility and on the autoimmune reactions that occur due to molecular mimicry between human-tissue proteins and streptococcal M protein. Polyarthritis is the initial manifestation, which can evolve to carditis and severe valve damage; these culminate in rheumatic heart disease (RHD) or Sydenham's chorea, which affects the central nervous system. A perspective on vaccine development to prevent the disease is also discussed.

School-based surveillance for detection of children with acute pharyngitis, rheumatic fever/rheumatic heart disease in Shimla district, Himachal Pradesh, India-A cluster randomized controlled trial.

BACKGROUND: The lack of surveillance system is a major barrier in prevention and control of rheumatic fever/rheumatic heart disease (RF/RHD). Efficacy of school-based surveillance was evaluated for detection of acute pharyngitis and RF/RHD in Shimla district, HP. METHODS: The schools in district Shimla were randomly assigned to intervention and controlled arm (442 vs. 441 schools). The trained nodal teachers reported children with symptoms of acute pharyngitis and or RF/RHD in intervention arm and children taken to hospitals by parents for symptoms of acute pharyngitis and or RF/RHD under control arm through mobile phone to coordinating centre. Final outcome for presence of RF/RHD or other heart Diseases was recorded after examination at nearest primary health centers and/or at Indira Gandhi Medical College Hospital, Shimla. Difference in detection rate between intervention arm and control arm was compared using Z test. RESULTS: The number of school children reported from intervention group was significantly higher than in control due to suspected symptoms of acute pharyngitis and or RF/RHD were 65 (2.84/1000) and 15 (0.60/1000), respectively (p < 0.01). Only 4 children in each arm were found to have heart diseases, with prevalence of (0.17/1000 and 0.16/1000), respectively, after clinical and echocardiography evaluation. In intervention arm, one child had RHD while three had congenital heart disease; in control arm, one child had congenital heart disease and three had RHD. CONCLUSIONS: School based surveillance had higher rate of suspecting children with acute pharyngitis and or RF/RHD although with low specificity. There is a need of future studies to demonstrate the effectiveness of the proposed intervention in endemic regions of the state.

The initiation of autoimmunity at epithelial surfaces: a focus on rheumatoid arthritis and systemic lupus erythematosus.

It is well established that the autoantibodies that characterize both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are present systemically years before patients develop disease. In both these autoimmune rheumatic diseases, evidence is growing that local autoimmune processes occur at epithelial surfaces potentially initiating localized autoimmunity. For RA, these are mucosal surfaces including the oral mucosa, lung, and gut. At the oral mucosa and lung, risk factors such as periodontal disease and smoking may contribute to autoimmunity by driving the local generation of citrullinated autoantigens. For SLE, the skin may be integral in pathogenesis. It is proposed that defective clearance of apoptotic debris leads to initial innate immune responses preceding autoimmunity. Many tissues may be implicated but the frequency of skin disease, even without autoantibodies, and the role of UV light as a trigger suggest that keratinocytes may be a key site of initiation. In both diseases, a local break in immune tolerance could lead to systemic autoimmunity, and, in the gut, bacterial organisms that colonize the intestine may influence the localized gut immune response through T-cells and promote the development of systemic autoimmunity. In this review, we discuss the evidence for localized epithelial autoimmunity in those at risk of RA and SLE and early disease. Localized autoimmunity at the oral mucosa, lung, gut, and skin will be considered as potential initiating sites of ARD-related autoimmunity.

Epidemiology of pharyngitis as reported by Zambian school children and their families: implications for demand-side interventions to prevent rheumatic heart disease.

BACKGROUND: Prompt and appropriate treatment of streptococcal pharyngitis decreases the risk of acute rheumatic fever and rheumatic heart disease (RHD). Understanding public perceptions and behaviors related to sore throat is fundamental to inform health programs aimed at eliminating new cases of RHD in endemic regions. We sought to describe the epidemiology of pediatric pharyngitis and its treatment, as reported by children and their parents or guardians in Lusaka, Zambia. METHODS: This was a cross-sectional investigation using interviews and written surveys, nested in a school-based RHD prevalence study. Students and their parents were asked to report number of sore throats in the previous 12 months, treatment received, and type and place of treatment. A focused history and physical examination to detect pharyngitis was conducted and children were referred for follow-up as indicated. RESULTS: A total of 3462 students from 47 schools participated in the study, along with their parents or guardians. Six hundred and fifty eight (19%) parents/guardians reported their child had at least one sore throat in the previous year, and 835 (24%) of students reported at least one sore throat in the same time period. Girls were reported to have pharyngitis 50% more often than boys, and also made up two-thirds of the total students treated. Approximately two-thirds of children who had at least one episode of pharyngitis during the previous year were also reported to have received some form of treatment. The majority of treatments were received in government clinics (36.6%) and at home (26.3%). Half of treatments included an antibiotic. Nineteen students (0.5%) had clinically-apparent pharyngitis at screening. CONCLUSION: Pharyngitis is common among school-aged children and adolescents in Zambia, with females reporting significantly more sore throat episodes than males. Parents/guardians have variable knowledge about the frequency of sore throat in their children, and management of pharyngitis may be suboptimal for many children since more than a quarter were reported to have received treatment without skilled assessment. These results provide insight into current perceptions and practices related to sore throat in Zambia and will be used to design public awareness activities aimed at reducing RHD.

A retrospective study: Acute rheumatic fever and post-streptococcal reactive arthritis in Japan.

BACKGROUND: Acute rheumatic fever (ARF) and post-streptococcal reactive arthritis (PSRA) are immune-mediated consequences of group A streptococcal pharyngitis. ARF has declined in developed nations. No prevalence survey of PSRA has been conducted. This study evaluated the incidence and characteristics of ARF and PSRA in Japanese children. METHODS: From 2010 to 2015, ARF and PSRA were evaluated using clinical data retrospectively collected by chart review from 528 hospitals. RESULTS: From 323 hospitals (61% response rate), 44 cases of ARF and 21 cases of PSRA were reported. Patients with ARF and/or PSRA were mainly from large cities in Japan. The mean age of ARF occurrence was 8.5 years, and the ratio of female/male patients was 16:28. Major manifestations in the acute phase included carditis, 27 cases (61.4%); polyarthritis, 22 cases (50%); erythema marginatum, 7 cases (15.9%); Sydenham chorea, 3 cases (6.8%); and subcutaneous nodules, 1 case (2.3%). Twenty-one (58.3%) patients had migratory arthritis. During the follow-up period, 6 patients (13.6%) showed mild carditis. For PRSA, the mean age was 8.2 years, and the ratio of female/male patients was 12:9. Six (28.6%) patients had monoarthritis, and 4 (19%) patients had migratory arthritis. No patient had carditis. CONCLUSIONS: Although ARF and PSRA are rare in the Japanese pediatric population, substantial numbers of patients with both conditions were identified in this study. We observed a high incidence of arthritis and carditis in ARF patients. No PSRA case was complicated with carditis. General pediatricians need to have updated information about ARF and PSRA, even in industrialized countries.

Sugar, dental caries and the incidence of acute rheumatic fever: a cohort study of Maori and Pacific children.

OBJECTIVE: To determine whether dental caries, as an indicator of cumulative exposure to sugar, is associated with the incidence of acute rheumatic fever and chronic rheumatic heart disease, in Maori and Pacific children aged 5 and 6 years at their first dental visit. MATERIALS AND METHODS: A cohort study was undertaken which linked school dental service records of caries with national hospital discharge and mortality records. Cox models were used to investigate the strength of the association between dental caries and rheumatic fever incidence. RESULTS: A total of 20 333 children who were free of rheumatic heart disease at enrolment were available for analysis. During a mean follow-up time of 5 years, 96 children developed acute rheumatic fever or chronic rheumatic heart disease. After adjustment for potential confounders, children with five or more primary teeth affected by caries were 57% (95% CI: 20% to 106%) more likely to develop disease during follow-up, compared to children whose primary teeth were caries free. The population attributable to the risk for caries in this cohort was 22%. CONCLUSIONS: Dental caries is positively associated with the incidence of acute rheumatic fever and chronic rheumatic heart disease in Maori and Pacific children. Sugar intake, an important risk factor for dental caries, is also likely to influence the aetiology of rheumatic fever.