Noninvasive low-level tragus stimulation attenuates inflammation and oxidative stress in acute heart failure.

PURPOSE: Acute decompensated heart failure (ADHF) is associated with inflammation, oxidative stress, and excess sympathetic drive. It is unknown whether neuromodulation would improve inflammation and oxidative stress in acute heart failure. We, therefore, performed this proof-of-concept study to evaluate the effects of neuromodulation using noninvasive low-level tragus stimulation on inflammation and oxidative stress in ADHF. METHODS: Nineteen patients with ejection fraction < 40% were randomized to neuromodulation 4 h twice daily (6-10 a.m. and 6-10 p.m.) (n = 8) or sham stimulation (n = 11) during hospital admission. All patients received standard-of-care treatment. Blood samples were collected at admission and discharge. Serum cytokines were assayed using standard immunosorbent techniques. Reactive oxygen species inducibility from cultured coronary endothelial cells exposed to patient sera was determined using a dihydrodichlorofluorescein probe test (expressed as fluorescein units). RESULTS: Compared to sham stimulation, neuromodulation was associated with a significant reduction of circulating serum interleukin-6 levels (-78% vs. -9%; p = 0.012). Similarly, neuromodulation led to a reduction of endothelial cell oxidative stress in the neuromodulation group (1363 units to 978 units, p = 0.003) compared to sham stimulation (1146 units to 1083 units, p = 0.094). No significant differences in heart rate, blood pressure, or renal function were noted between the two groups. CONCLUSION: In this proof-of-concept pilot study, in acute decompensated heart failure, neuromodulation was feasible and safe and was associated with a reduction in systemic inflammation and attenuation of coronary endothelial cellular oxidative stress. CLINICAL TRIAL REGISTRATION: NCT02898181.

Research priorities for the secondary prevention and management of acute rheumatic fever and rheumatic heart disease: a National Heart, Lung, and Blood Institute workshop report.

Secondary prevention of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) involves continuous antimicrobial prophylaxis among affected individuals and is recognised as a cornerstone of public health programmes that address these conditions. However, several important scientific issues around the secondary prevention paradigm remain unresolved. This report details research priorities for secondary prevention that were developed as part of a workshop convened by the US National Heart, Lung, and Blood Institute in November 2021. These span basic, translational, clinical and population science research disciplines and are built on four pillars. First, we need a better understanding of RHD epidemiology to guide programmes, policies, and clinical and public health practice. Second, we need better strategies to find and diagnose people affected by ARF and RHD. Third, we urgently need better tools to manage acute RF and slow the progression of RHD. Fourth, new and existing technologies for these conditions need to be better integrated into healthcare systems. We intend for this document to be a reference point for research organisations and research sponsors interested in contributing to the growing scientific community focused on RHD prevention and control.

Tertiary prevention and treatment of rheumatic heart disease: a National Heart, Lung, and Blood Institute working group summary.

Although entirely preventable, rheumatic heart disease (RHD), a disease of poverty and social disadvantage resulting in high morbidity and mortality, remains an ever-present burden in low-income and middle-income countries (LMICs) and rural, remote, marginalised and disenfranchised populations within high-income countries. In late 2021, the National Heart, Lung, and Blood Institute convened a workshop to explore the current state of science, to identify basic science and clinical research priorities to support RHD eradication efforts worldwide. This was done through the inclusion of multidisciplinary global experts, including cardiovascular and non-cardiovascular specialists as well as health policy and health economics experts, many of whom also represented or closely worked with patient-family organisations and local governments. This report summarises findings from one of the four working groups, the Tertiary Prevention Working Group, that was charged with assessing the management of late complications of RHD, including surgical interventions for patients with RHD. Due to the high prevalence of RHD in LMICs, particular emphasis was made on gaining a better understanding of needs in the field from the perspectives of the patient, community, provider, health system and policy-maker. We outline priorities to support the development, and implementation of accessible, affordable and sustainable interventions in low-resource settings to manage RHD and related complications. These priorities and other interventions need to be adapted to and driven by local contexts and integrated into health systems to best meet the needs of local communities.

Noninvasive low-level tragus stimulation attenuates inflammation and oxidative stress in acute heart failure.

Purpose: Acute decompensated heart failure is associated with inflammation, oxidative stress, and excess sympathetic drive. It is unknown if neuromodulation would improve inflammation and oxidative stress in acute heart failure. We, therefore, performed this proof-of-concept study to evaluate the effects of neuromodulation using noninvasive low-level Tragus stimulation on inflammation and oxidative stress in ADHF. Methods: 19 patients with ejection fraction < 40% were randomized to neuromodulation- 4 hours twice daily (6 AM-10 AM and 6 PM-10 PM) (n = 8) or sham stimulation (n = 11) during hospital admission. All patients received standard-of-care treatment. Blood samples were collected at admission and discharge. Serum cytokines were assayed using standard immunosorbent techniques. Reactive oxygen species inducibility from cultured coronary endothelial cells exposed to patient sera was determined using dihydrodichlorofluorescein probe test (expressed as fluorescein units). Results: Compared to sham stimulation, neuromodulation was associated with a significant reduction of circulating serum Interleukin-6 levels (-78% vs -9%; p = 0.012). Similarly, neuromodulation led to reduction of endothelial cell oxidative stress, in the neuromodulation group (1363 units to 978 units, p = 0.003) compared to sham stimulation (1146 units to 1083 units, p = 0.094). No significant difference in heart rate, blood pressure or renal function were noted between the two groups. Conclusion: In this proof-of-concept pilot study, in acute systolic heart failure, neuromodulation was feasible and safe and was associated with a reduction in systemic inflammation and attenuation of cellular oxidative stress. Clinical trial: NCT02898181.

Group A Streptococcus Vaccine Targeting the Erythrogenic Toxins SpeA and SpeB Is Safe and Immunogenic in Rabbits and Does Not Induce Antibodies Associated with Autoimmunity.

Group A streptococcus (GAS) is a global pathogen associated with significant morbidity and mortality for which there is currently no licensed vaccine. Vaccine development has been slow, mostly due to safety concerns regarding streptococcal antigens associated with autoimmunity and related complications. For a GAS vaccine to be safe, it must be ensured that the antigens used in the vaccine do not elicit an antibody response that can cross-react with host tissues. In this study, we evaluated the safety of our GAS vaccine candidate called VaxiStrep in New Zealand White rabbits. VaxiStrep is a recombinant fusion protein comprised of streptococcal pyrogenic exotoxin A (SpeA) and exotoxin B (SpeB), also known as erythrogenic toxins, adsorbed to an aluminum adjuvant. The vaccine elicited a robust immune response against the two toxins in the rabbits without any adverse events or toxicity. No signs of autoimmune pathology were detected in the rabbits' brains, hearts, and kidneys via immunohistochemistry, and serum antibodies did not cross-react with cardiac or neuronal tissue proteins associated with rheumatic heart disease or Sydenham chorea (SC). This study further confirms that VaxiStrep does not elicit autoantibodies and is safe to be tested in a first-in-human trial.

Corrigendum: IgG2 rules: N-acetyl-ß-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.

[This corrects the article DOI: 10.3389/fcvm.2022.919700.].

Research opportunities for the primordial prevention of rheumatic fever and rheumatic heart disease-streptococcal vaccine development: a national heart, lung and blood institute workshop report.

Streptococcus pyogenes, also known as group A streptococcus (StrepA), is a bacterium that causes a range of human diseases, including pharyngitis, impetigo, invasive infections, and post-infection immune sequelae such as rheumatic fever and rheumatic heart disease. StrepA infections cause some of the highest burden of disease and death in mostly young populations in low-resource settings. Despite decades of effort, there is still no licensed StrepA vaccine, which if developed, could be a cost-effective way to reduce the incidence of disease. Several challenges, including technical and regulatory hurdles, safety concerns and a lack of investment have hindered StrepA vaccine development. Barriers to developing a StrepA vaccine must be overcome in the future by prioritising key areas of research including greater understanding of StrepA immunobiology and autoimmunity risk, better animal models that mimic human disease, expanding the StrepA vaccine pipeline and supporting vaccine clinical trials. The development of a StrepA vaccine is a complex and challenging process that requires significant resources and investment. Given the global burden of StrepA infections and the potential for a vaccine to save lives and livelihoods, StrepA vaccine development is an area of research that deserves considerable support. This report summarises the findings of the Primordial Prevention Working Group-VAX, which was convened in November 2021 by the National Heart, Lung, and Blood Institute. The focus of this report is to identify research gaps within the current StrepA vaccine landscape and find opportunities and develop priorities to promote the rapid and successful advancement of StrepA vaccines.

Meeting the Challenges of Myocarditis: New Opportunities for Prevention, Detection, and Intervention-A Report from the 2021 National Heart, Lung, and Blood Institute Workshop.

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of international experts to discuss new research opportunities for the prevention, detection, and intervention of myocarditis in May 2021. These experts reviewed the current state of science and identified key gaps and opportunities in basic, diagnostic, translational, and therapeutic frontiers to guide future research in myocarditis. In addition to addressing community-acquired myocarditis, the workshop also focused on emerging causes of myocarditis including immune checkpoint inhibitors and SARS-CoV-2 related myocardial injuries and considered the use of systems biology and artificial intelligence methodologies to define workflows to identify novel mechanisms of disease and new therapeutic targets. A new priority is the investigation of the relationship between social determinants of health (SDoH), including race and economic status, and inflammatory response and outcomes in myocarditis. The result is a proposal for the reclassification of myocarditis that integrates the latest knowledge of immunological pathogenesis to refine estimates of prognosis and target pathway-specific treatments.

Sex and age differences in sST2 in cardiovascular disease.

Aims: The goal of this study was to determine whether sex and age differences exist for soluble ST2 (sST2) for several cardiovascular diseases (CVDs). Methods: We examined sST2 levels using an ELISA kit for myocarditis (n = 303), cardiomyopathy (n = 293), coronary artery disease (CAD) (n = 239), myocardial infarct (MI) (n = 159), and congestive heart failure (CHF) (n = 286) and compared them to controls that did not have CVDs (n = 234). Results: Myocarditis occurred in this study in relatively young patients around age 40 while the other CVDs occurred more often in older individuals around age 60. We observed a sex difference in sST2 by age only in myocarditis patients (men aged 38, women 46, p = 0.0002), but not for other CVDs. Sera sST2 levels were significantly elevated compared to age-matched controls for all CVDs: myocarditis (p ≤ 0.0001), cardiomyopathy (p = 0.0009), CAD (p = 0.03), MI (p = 0.034), and CHF (p < 0.0001) driven by elevated sST2 levels in females for all CVDs except myocarditis, which was elevated in both females (p = 0.002) and males (p ≤ 0.0001). Sex differences in sST2 levels were found for myocarditis and cardiomyopathy but no other CVDs and were higher in males (myocarditis p = 0.0035; cardiomyopathy p = 0.0047). sST2 levels were higher in women with myocarditis over 50 years of age compared to men (p = 0.0004) or women under 50 years of age (p = 0.015). In cardiomyopathy and MI patients, men over 50 had significantly higher levels of sST2 than women (p = 0.012 and p = 0.043, respectively) but sex and age differences were not detected in other CVDs. However, women with cardiomyopathy that experienced early menopause had higher sST2 levels than those who underwent menopause at a natural age range (p = 0.02). Conclusion: We found that sex and age differences in sera sST2 exist for myocarditis, cardiomyopathy, and MI, but were not observed in other CVDs including CAD and CHF. These initial findings in patients with self-reported CVDs indicate that more research is needed into sex and age differences in sST2 levels in individual CVDs.

IgG2 rules: N-acetyl-ß-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-ß-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.

Autoantibody Biomarkers for Basal Ganglia Encephalitis in Sydenham Chorea and Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections.

Movement, behavioral, and neuropsychiatric disorders in children have been linked to infections and a group of anti-neuronal autoantibodies, implying dopamine receptor-mediated encephalitis within the basal ganglia. The purpose of this study was to determine if anti-neuronal biomarkers, when used as a group, confirmed the acute disease in Sydenham chorea (SC) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). IgG autoantibodies against four neuronal autoantigens (tubulin, lysoganglioside GM1, and dopamine receptors D1 and D2) were detected in SC sera (N=8), sera and/or cerebrospinal fluid (CSF) from two groups of PANDAS cases (N=25 first group and N=35 second group), sera from Tourette's syndrome (N=18), obsessive-compulsive disorder (N=25), attention deficit hyperactivity disorder (N=18), and healthy controls (N=28) by direct enzyme-linked immunosorbent assay (ELISA). IgG specific for neuronal autoantigens was significantly elevated during the acute symptomatic phase, and the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) pathway was significantly elevated in human neuronal cells. Five assays confirmed the disease in SC and in two groups of children with PANDAS. In 35 acute onset PANDAS patients, 32 sera (91.4%) were positive for one or more of the anti-neuronal autoantibodies compared with 9 of 28 healthy controls (32.1%, p<0.0001). Importantly, CSF of 32 (91.4%) PANDAS patients had one or more detectable anti-neuronal autoantibody titers and CaMKII activation. Among healthy control subjects with elevated serum autoantibody titers for individual antigens, none (0%) were positively associated with elevated positive CaMKII activation, which was a striking contrast to the sera of PANDAS subjects, who had 76-89% positive association with elevated individual autoantibody titers and positive CaMKII activity. At 6 months follow-up, symptoms improved for more than 80% of PANDAS subjects, and serum autoantibody titers also significantly decreased. Results reported herein and previously published studies in our laboratory suggest the antibody biomarkers may be a useful adjunct to clinical diagnosis of SC, PANDAS, and related disorders and are the first known group of autoantibodies detecting dopamine receptor-mediated encephalitis in children.

Multisystem Inflammatory Syndrome in Children (MIS-C), a Post-viral Myocarditis and Systemic Vasculitis-A Critical Review of Its Pathogenesis and Treatment.

MIS-C is a newly defined post-viral myocarditis and inflammatory vasculopathy of children following COVID-19 infection. This review summarizes the literature on diagnosis, parameters of disease severity, and current treatment regimens. The clinical perspective was analyzed in light of potential immunopathogenesis and compared to other post-infectious and inflammatory illnesses of children affecting the heart. In this paradigm, the evidence supports the importance of endothelial injury and activation of the IL-1 pathway as a common determinant among MIS-C, Kawasaki disease, and Acute Rheumatic fever.

Anti-lysoganglioside and other anti-neuronal autoantibodies in post-treatment Lyme Disease and Erythema Migrans after repeat infection.

BACKGROUND: Molecular mimicry targeting neural tissue has been reported after Borrelia burgdorferi(Bb) infection. Herein, we investigate whether antineuronal autoantibodies are increased and whether antibody-mediated signaling of neuronal cells is elevated in a cohort of symptomatic adults with a history of Lyme Disease (LD). METHODS: Participants (n â€‹= â€‹179) included 24 with recent Erythema Migrans (EM) without prior LD, 8 with recent EM and prior LD (EM â€‹+ â€‹prior LD), 119 with persistent post-treatment LD symptoms (PTLS), and 28 seronegative endemic controls with no prior LD history. Antineuronal immunoglobulin G (IgG) titers were measured by standard ELISA and compared with mean titers of normal age-matched sera against lysoganglioside, tubulin, and dopamine receptors (D1R and D2R). Antibody-mediated signaling of calcium calmodulin dependent protein kinase II (CaMKII) activity in a human neuronal cell line (SK-N-SH) was identified in serum. RESULTS: EM â€‹+ â€‹prior LD cases had higher antibody titers than controls for anti-lysoganglioside GM1 (p â€‹= â€‹0.002), anti-tubulin (p â€‹= â€‹0.03), and anti-D1R (p â€‹= â€‹0.02), as well as higher expression in the functional antibody-mediated CaMKII Assay (p â€‹= â€‹0.03). The EM cases with no prior history showed no significant differences on any measures. The PTLS cases demonstrated significantly higher titers (p â€‹= â€‹0.01) than controls on anti-lysoganglioside GM1, but not for the other measures. CONCLUSION: The finding of elevated anti-neuronal autoantibodies in our small sample of those with a prior history of Lyme disease but not in those without prior Lyme disease, if replicated in a larger sample, suggests an immune priming effect of repeated infection; the CaMKII activation suggests that antineuronal antibodies have functional significance. The elevation of anti-lysoganglioside antibodies among those with PTLS is of particular interest given the established role of anti-ganglioside antibodies in peripheral and central neurologic diseases. Future prospective studies can determine whether these autoantibodies emerge after Bb infection and whether their emergence coincides with persistent neurologic or neuropsychiatric symptoms.

Molecular Mimicry, Autoimmunity, and Infection: The Cross-Reactive Antigens of Group A Streptococci and their Sequelae.

The group A streptococci are associated with a group of diseases affecting the heart, brain, and joints that are collectively referred to as acute rheumatic fever. The streptococcal immune-mediated sequelae, including acute rheumatic fever, are due to antibody and cellular immune responses that target antigens in the heart and brain as well as the group A streptococcal cross-reactive antigens as reviewed in this article. The pathogenesis of acute rheumatic fever, rheumatic heart disease, Sydenham chorea, and other autoimmune sequelae is related to autoantibodies that are characteristic of autoimmune diseases and result from the immune responses against group A streptococcal infection by the host. The sharing of host and streptococcal epitopes leads to molecular mimicry between the streptococcal and host antigens that are recognized by the autoantibodies during the host response. This article elaborates on the discoveries that led to a better understanding of the pathogenesis of disease and provides an overview of the history and the most current thought about the immune responses against the host and streptococcal cross-reactive antigens in group A streptococcal sequelae.

Clinical-Serological Characterization and Treatment Outcome of a Large Cohort of Italian Children with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection and Pediatric Acute Neuropsychiatric Syndrome.

Objective: Pediatric autoimmune neuropsychiatric disorder associated with Streptococcus pyogenes infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS) are emerging immune-mediated encephalopathies characterized by sudden onset of seemingly inexplicable complex neuropsychiatric symptoms, including obsessions, compulsions, and heterogeneous tics, which occur in children. Main goal of this study was to report our experience in a large cohort of Italian children affected by either PANDAS or PANS and treated long term with an antibiotic regimen similar to that used for acute rheumatic fever. Patients and Methods: The clinical charts of a cohort of 371 consecutive Italian children, 345 with PANDAS (93.0%) and 26 with PANS (7.0%), were retrospectively evaluated. Antistreptococcal, antinuclear antibodies, and serologic evaluation for a group of common autoantibodies and microbial agents were also assessed. A strict differential diagnosis with other autoimmune diseases displaying neuropsychiatric manifestations was performed. Results: Antistreptolysin O and anti-DNase B antibody titers were tested and were positive in all PANDAS subjects, but negative in PANS. Anti-Mycoplasma pneumoniae antibodies and anti-Epstein-Barr virus Nuclear Antigen antibodies were found positive in 11 (42.3%) and 5 (19.2%) patients with PANS, respectively. Among PANDAS cases, a clear streptococcal infection was clinically evident at the onset of neurological symptoms in only 74 patients (21.4%), whereas the relationship with Streptococcus pyogenes was confirmed by serologic tests in the other 271 (78.6%). All patients fulfilling the diagnostic criteria for PANDAS (n = 345) received amoxicillin/clavulanic acid for 10-21 days at diagnosis, while those who were diagnosed with PANS (n = 26) received treatment according to the causative agent. Thereafter, all PANDAS/PANS patients received prophylaxis with benzathine benzylpenicillin for an overall period of at least 5 years to prevent subsequent potential streptococcal infections. To date, 75.0% of PANDAS patients (n = 258) have shown an improvement of neurologic symptoms, mainly observed within 3-5 months of treatment for PANDAS cases, while 88.4% of PANS patients (n = 23) have improved after 6-12 months. Infection-related relapses of neurologic manifestations were observed in both PANDAS and PANS patients (n = 167 out of 371; 45% of the total cohort) in the long term. Conclusions: Our study has confirmed the usefulness of the preliminary diagnostic criteria for PANDAS and PANS, revealing also the importance of early diagnosis to reduce the risk of evolution toward disabling chronic neurologic sequelae. Long-term antibiotic prophylaxis has resulted in a substantial benefit to reduce neurological symptoms for the majority of PANDAS and PANS patients over a 7-year period.

Elevated Sera sST2 Is Associated With Heart Failure in Men ≤50 Years Old With Myocarditis.

Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.

Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism.

The identification of brain-targeted autoantibodies in children with autism spectrum disorder (ASD) raises the possibility of autoimmune encephalopathy (AIE). Intravenous immunoglobulin (IVIG) is effective for AIE and for some children with ASD. Here, we present the largest case series of children with ASD treated with IVIG. Through an ASD clinic, we screened 82 children for AIE, 80 of them with ASD. IVIG was recommended for 49 (60%) with 31 (38%) receiving the treatment under our care team. The majority of parents (90%) reported some improvement with 71% reporting improvements in two or more symptoms. In a subset of patients, Aberrant Behavior Checklist (ABC) and/or Social Responsiveness Scale (SRS) were completed before and during IVIG treatment. Statistically significant improvement occurred in the SRS and ABC. The antidopamine D2L receptor antibody, the anti-tubulin antibody and the ratio of the antidopamine D2L to D1 receptor antibodies were related to changes in the ABC. The Cunningham Panel predicted SRS, ABC, parent-based treatment responses with good accuracy. Adverse effects were common (62%) but mostly limited to the infusion period. Only two (6%) patients discontinued IVIG because of adverse effects. Overall, our open-label case series provides support for the possibility that some children with ASD may benefit from IVIG. Given that adverse effects are not uncommon, IVIG treatment needs to be considered cautiously. We identified immune biomarkers in select IVIG responders but larger cohorts are needed to study immune biomarkers in more detail. Our small open-label exploratory trial provides evidence supporting a neuroimmune subgroup in patients with ASD.

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

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