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.

Whole genome sequencing and molecular epidemiology of paediatric Staphylococcus aureus bacteraemia.

OBJECTIVES: The role Staphylococcus aureus antimicrobial resistance genes and toxins play in disease severity, management and outcome in childhood is an emerging field requiring further exploration. METHODS: A prospective multisite study of Australian and New Zealand children hospitalised with S. aureus bacteraemia (SAB) occurred over 24 months (2017-2018). Whole genome sequencing (WGS) data were paired with clinical information from the ISAIAH cohort. RESULTS: 353 SAB isolates were sequenced; 85% methicillin-susceptible S. aureus ([MSSA], 301/353) and 15% methicillin-resistant S. aureus ([MRSA], 52/353). There were 92 sequence types (STs), most commonly ST5 (18%) and ST30 (8%), grouped into 23 clonal complexes (CCs), most frequently CC5 (21%) and CC30 (12%). MSSA comprised the majority of healthcare-associated SAB (87%, 109/125), with principal clones CC15 (48%, 11/21) and CC8 (33%, 7/21). Panton-Valentine leukocidin (PVL)-positive SAB occurred in 22% (76/353); predominantly MSSA (59%, 45/76), community-onset (92%, 70/76) infections. For community-onset SAB, the only microbiological independent predictor of poor outcomes was PVL positivity (aOR 2.6 [CI 1.0-6.2]). CONCLUSION: From this WGS paediatric SAB data, we demonstrate the previously under-recognized role MSSA has in harbouring genetic virulence and causing healthcare-associated infections. PVL positivity was the only molecular independent predictor of poor outcomes in children. These findings underscore the need for further research to define the potential implications PVL-producing strains may have on approaches to S. aureus clinical management.

Pediatric Staphylococcus aureus Bacteremia: Clinical Spectrum and Predictors of Poor Outcome.

BACKGROUND: Staphylococcus aureus is a common cause of bacteremia, yet the epidemiology and predictors of poor outcome remain inadequately defined in childhood. METHODS: ISAIAH (Invasive Staphylococcus aureus Infections and Hospitalizations in children) is a prospective, cross-sectional study of S. aureus bacteremia (SAB) in children hospitalized in Australia and New Zealand over 24 months (2017-2018). RESULTS: Overall, 552 SABs were identified (incidence 4.4/100 000/year). Indigenous children, those from lower socioeconomic areas and neonates were overrepresented. Although 90-day mortality was infrequent, one-third experienced the composite of: length of stay >30 days (26%), intensive care unit admission (20%), relapse (4%), or death (3%). Predictors of mortality included prematurity (adjusted odds ratio [aOR],16.8; 95% confidence interval [CI], 1.6-296.9), multifocal infection (aOR, 22.6; CI, 1.4-498.5), necrotizing pneumonia (aOR, 38.9; CI, 1.7-1754.6), multiorgan dysfunction (aOR, 26.5; CI, 4.1-268.8), and empiric vancomycin (aOR, 15.7; CI, 1.6-434.4); while infectious diseases (ID) consultation (aOR, 0.07; CI .004-.9) was protective. Neither MRSA nor vancomycin trough targets impacted survival; however, empiric vancomycin was associated with nephrotoxicity (OR, 3.1; 95% CI 1.3-8.1). CONCLUSIONS: High SAB incidence was demonstrated and for the first time in a pediatric setting, necrotizing pneumonia and multifocal infection were predictors of mortality, while ID consultation was protective. The need to reevaluate pediatric vancomycin trough targets and limit unnecessary empiric vancomycin exposure to reduce poor outcomes and nephrotoxicity is highlighted. One in 3 children experienced considerable SAB morbidity; therefore, pediatric inclusion in future SAB comparator trials is paramount to improve outcomes.

Comprehensive analysis of SARS-CoV-2 antibody dynamics in New Zealand.

OBJECTIVES: Circulating antibodies are important markers of previous infection and immunity. Questions remain with respect to the durability and functionality of SARS-CoV-2 antibodies. This study explored antibody responses in recovered COVID-19 patients in a setting where the probability of re-exposure is effectively nil, owing to New Zealand's successful elimination strategy. METHODS: A triplex bead-based assay that detects antibody isotype (IgG, IgM and IgA) and subclass (IgG1, IgG2, IgG3 and IgG4) responses against Nucleocapsid (N) protein, the receptor binding domain (RBD) and Spike (S) protein of SARS-CoV-2 was developed. After establishing baseline levels with pre-pandemic control sera (n = 113), samples from PCR-confirmed COVID-19 patients with mild-moderate disease (n = 189) collected up to 8 months post-infection were examined. The relationship between antigen-specific antibodies and neutralising antibodies (NAbs) was explored with a surrogate neutralisation assay that quantifies inhibition of the RBD/hACE-2 interaction. RESULTS: While most individuals had broad isotype and subclass responses to each antigen shortly after infection, only RBD and S protein IgG, as well as NAbs, were relatively stable over the study period, with 99%, 96% and 90% of samples, respectively, having responses over baseline 4-8 months post-infection. Anti-RBD antibodies were strongly correlated with NAbs at all time points (Pearson's r ≥ 0.87), and feasibility of using finger prick sampling to accurately measure anti-RBD IgG was demonstrated. CONCLUSION: Antibodies to SARS-CoV-2 persist for up to 8 months following mild-to-moderate infection. This robust response can be attributed to the initial exposure without immune boosting given the lack of community transmission in our setting.

Collaborative networks enable the rapid establishment of serological assays for SARS-CoV-2 during nationwide lockdown in New Zealand.

BACKGROUND: Serological assays that detect antibodies to SARS-CoV-2 are critical for determining past infection and investigating immune responses in the COVID-19 pandemic. We established ELISA-based immunoassays using locally produced antigens when New Zealand went into a nationwide lockdown and the supply chain of diagnostic reagents was a widely held domestic concern. The relationship between serum antibody binding measured by ELISA and neutralising capacity was investigated using a surrogate viral neutralisation test (sVNT). METHODS: A pre-pandemic sera panel (n = 113), including respiratory infections with symptom overlap with COVID-19, was used to establish assay specificity. Sera from PCR­confirmed SARS-CoV-2 patients (n = 21), and PCR-negative patients with respiratory symptoms suggestive of COVID-19 (n = 82) that presented to the two largest hospitals in Auckland during the lockdown period were included. A two-step IgG ELISA based on the receptor binding domain (RBD) and spike protein was adapted to determine seropositivity, and neutralising antibodies that block the RBD/hACE­2 interaction were quantified by sVNT. RESULTS: The calculated cut-off (>0.2) in the two-step ELISA maximised specificity by classifying all pre-pandemic samples as negative. Sera from all PCR-confirmed COVID-19 patients were classified as seropositive by ELISA ≥7 days after symptom onset. There was 100% concordance between the two-step ELISA and the sVNT with all 7+ day sera from PCR­confirmed COVID-19 patients also classified as positive with respect to neutralising antibodies. Of the symptomatic PCR-negative cohort, one individual with notable travel history was classified as positive by two-step ELISA and sVNT, demonstrating the value of serology in detecting prior infection. CONCLUSIONS: These serological assays were established and assessed at a time when human activity was severely restricted in New Zealand. This was achieved by generous sharing of reagents and technical expertise by the international scientific community, and highly collaborative efforts of scientists and clinicians across the country. The assays have immediate utility in supporting clinical diagnostics, understanding transmission in high-risk cohorts and underpinning longer­term 'exit' strategies based on effective vaccines and therapeutics.

Normal echocardiographic mitral and aortic valve thickness in children.

OBJECTIVE: We aimed to define the normal range of aortic and mitral valve thickness in healthy schoolchildren from a high prevalence rheumatic heart disease (RHD) region, using a standardised protocol for imaging and measurement. METHODS: Measurements were performed in 288 children without RHD. Anterior mitral valve leaflet (AMVL) thickness measurements were performed at the midpoint and tip of the leaflet in the parasternal long axis (PSLA) in diastole, when the AMVL was approximately parallel to the ventricular septum. Thickness of the aortic valve was measured from PSLA imaging in systole when the leaflets were at maximum excursion. The right coronary and non-coronary closure lines of the aortic valve were measured in diastole in parasternal short axis (PSSA) imaging. Results were compared with 51 children with RHD classified by World Heart Federation diagnostic criteria. RESULTS: In normal children, median AMVL tip thickness was 2.0 mm (IQR 1.7-2.4) and median AMVL midpoint thickness 2.0 mm (IQR 1.7-2.4). The median aortic valve thickness was 1.5 mm (IQR 1.3-1.6) in the PSLA view and 1.4 mm (IQR 1.2-1.6) in the PSSA view. The interclass correlation coefficient for the AMVL tip was 0.85 (0.71 to 0.92) and for the AMVL midpoint was 0.77 (0.54 to 0.87). CONCLUSIONS: We have described a standardised method for mitral and aortic valve measurement in children which is objective and reproducible. Normal ranges of left heart valve thickness in a high prevalence RHD population are established. These results provide a reference range for school-age children in high prevalence RHD regions undergoing echocardiographic screening.

Acute Rheumatic Fever After Group A Streptococcus Pyoderma and Group G Streptococcus Pharyngitis.

A case of acute rheumatic fever (ARF) in an Indigenous Maori child in New Zealand after Group A Streptococcus pyoderma and Group G Streptococcus pharyngitis is reported. The case demonstrates that ARF can develop in the absence of GAS pharyngitis and highlights a need for further research into the role of pyoderma and non-Group A Streptococci infections in ARF pathogenesis.

Valvular Regurgitation Using Portable Echocardiography in a Healthy Student Population: Implications for Rheumatic Heart Disease Screening.

BACKGROUND: There is increasing use of portable echocardiography as a screening test for rheumatic heart disease (RHD). The prevalence of valvular regurgitation in healthy populations as determined using portable echocardiography has not been well defined. Minimal echocardiographic criteria for RHD have recently been clarified, but the overlap of normal and abnormal valvular regurgitation warrants further study. The aim of this study was to determine the spectrum of echocardiographic findings using portable echocardiography in children from a population with low prevalence of RHD. METHODS: Screening echocardiography was conducted in 396 healthy students aged 10 to 12 years using portable echocardiographic equipment. Echocardiograms were assessed according to 2012 World Heart Federation criteria for RHD. The prevalence of physiologic valvular regurgitation was compared with that found in previous studies of children using large-platform machines. RESULTS: Physiologic mitral regurgitation (MR) was present in 14.9% of subjects (95% CI, 11.7%-18.7%) and pathologic MR in 1.3% (95% CI, 0.6%-2.9%). Two percent (95% CI, 1.0%-3.9%) had physiologic aortic regurgitation, and none had pathologic aortic valve regurgitation. Physiologic tricuspid regurgitation was present in 72.7% of subjects (95% CI, 68.1%-76.9%) and physiologic pulmonary regurgitation in 89.6% (95% CI, 85.7%-91.8%). After cardiology review, no cases of definite RHD were found, but 0.5% of patients (95% CI, 0.1%-1.8%) had pathologic MR meeting World Heart Federation criteria for borderline RHD. Two percent (95% CI, 1.4%-4.6%) of the cohort had minor forms of congenital heart disease. CONCLUSIONS: The spectrum of physiologic cardiac valvular regurgitation in healthy children as determined using portable echocardiography is described and is within the range of previous studies using large-platform echocardiographic equipment. The finding of two children with pathologic-grade MR, likely representing the upper limit of physiologic regurgitation, has implications for echocardiographic screening for RHD in high-prevalence regions.

When to start, what to start and other treatment controversies in pediatric HIV infection.

Over the last decade there have been dramatic changes in the management of pediatric HIV infection. Whilst observational studies and several randomized control trials (RCTs) have addressed some questions about when to start antiretroviral therapy (ART) in children and what antiretrovirals to start, many others remain unanswered. In infants, early initiation of ART greatly reduces mortality and disease progression. Treatment guidelines now recommend ART in all infants younger than 1 or 2 years of age depending on geographical setting. In children >1 year of age, US, European (Paediatric European Network for Treatment of AIDS; PENTA) and WHO guidelines differ and debate is ongoing. Recent data from an RCT in Thailand in children with moderate immune suppression indicate that it is safe to monitor asymptomatic children closely without initiating ART, although earlier treatment was associated with improved growth. Untreated HIV progression in children aged over 5 years is similar to that in adults, and traditionally adult treatment thresholds are applied. Recent adult observational and modeling studies showed a survival advantage and reduction of age-associated complications with early treatment. The current US guidelines have lowered CD4+ cell count thresholds for ART initiation for children aged >5 years to 500 cells/mm3. Co-infections influence the choice of drugs and the timing of starting ART. Drug interactions, overlapping toxicities and adherence problems secondary to increased pill burden are important issues. Rapid changes in the pharmacokinetics of antiretrovirals in the first years of life, limited pharmacokinetic data in children and genetic variation in metabolism of many antiretrovirals make correct dosing difficult. Adherence should always be addressed prior to starting ART or switching regimens. The initial ART regimen depends on previous exposure, including perinatal administration for prevention of mother to child transmission (PMTCT), adherence, co-infections, drug availability and licensing. A European cohort study in infants indicated that treatment with four drugs produced superior virologic suppression and immune recovery. Protease inhibitor (PI)-based ART has the advantage of a high barrier to viral resistance. A recent RCT conducted in several African countries showed PI-based ART to be advantageous in children aged <3 years compared with nevirapine-based ART irrespective of previous nevirapine exposure. Another trial in older children from resource rich settings showed both regimens were equally effective. Treatment interruption remains a controversial issue in children, but one study in Europe demonstrated no short-term detrimental effects. ART in children is a rapidly evolving area with many new antiretrovirals being developed and undergoing trials. The aim of ART has shifted from avoiding mortality and morbidity to achieving a normal life expectancy and quality of life, minimizing toxicities and preventing early cancers and age-related illnesses.

Optimising echocardiographic screening for rheumatic heart disease in New Zealand: not all valve disease is rheumatic.

AIMS: Echocardiography detects a greater prevalence of rheumatic heart disease than heart auscultation. Echocardiographic screening for rheumatic heart disease combined with secondary prophylaxis may potentially prevent severe rheumatic heart disease in high-risk populations. We aimed to determine the prevalence of rheumatic heart disease in children from an urban New Zealand population at high risk for acute rheumatic fever. METHODS AND RESULTS: To optimise accurate diagnosis of rheumatic heart disease, we utilised a two-step model. Portable echocardiography was conducted on 1142 predominantly Maori and Pacific children aged 10-13 years. Children with an abnormal screening echocardiogram underwent clinical assessment by a paediatric cardiologist together with hospital-based echocardiography. Rheumatic heart disease was then classified as definite, probable, or possible. Portable echocardiography identified changes suggestive of rheumatic heart disease in 95 (8.3%) of 1142 children, which reduced to 59 (5.2%) after cardiology assessment. The prevalence of definite and probable rheumatic heart disease was 26.0 of 1000, with 95% confidence intervals ranging from 12.6 to 39.4. Portable echocardiography overdiagnosed rheumatic heart disease with physiological valve regurgitation diagnosed in 28 children. A total of 30 children (2.6%) had non-rheumatic cardiac abnormalities, 11 of whom had minor congenital mitral valve anomalies. CONCLUSIONS: We found high rates of undetected rheumatic heart disease in this high-risk population. Rheumatic heart disease screening has resource implications with cardiology evaluation required for accurate diagnosis. Echocardiographic screening for rheumatic heart disease may overdiagnose rheumatic heart disease unless congenital mitral valve anomalies and physiological regurgitation are excluded.