Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C)

Initially, the global outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spared children from severe disease. However, after the initial wave of infections, clusters of a novel hyperinflammatory disease have been reported in regions with ongoing SARS-CoV-2 epidemics. While the characteristic clinical features are becoming clear, the pathophysiology remains unknown. Herein, we report on the immune profiles of eight Multisystem Inflammatory Syndrome in Children (MIS-C) cases. We document that all MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with normal isotype-switching and neutralization capability. We further profiled the secreted immune response by high-dimensional cytokine assays, which identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1) and mucosal immune dysregulation (IL-17A, CCL20, CCL28). Mass cytometry immunophenotyping of peripheral blood revealed reductions of mDC1 and non-classical monocytes, as well as both NK- and T- lymphocytes, suggesting extravasation to affected tissues. Markers of activated myeloid function were also evident, including upregulation of ICAM1 and FcR1 in neutrophil and non-classical monocytes, well-documented markers in autoinflammation and autoimmunity that indicate enhanced antigen presentation and Fc-mediated responses. Finally, to assess the role for autoimmunity secondary to infection, we profiled the auto-antigen reactivity of MIS-C plasma, which revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal and immune-cell antigens. All patients were treated with anti- IL6R antibody or IVIG, which led to rapid disease resolution tracking with normalization of inflammatory markers.

Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution.

ECMO support in SARS-CoV2 multisystem inflammatory syndrome in children in a child.

In this report, we describe the case of a 5-year-old male with SARS-CoV-2 associated MIS-C with progressive respiratory failure and vasoplegic shock requiring extracorporeal support. At presentation, reverse transcription-polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 was negative, however, SARS-CoV2 antibody testing was positive. Multiple inflammatory markers and cardiac biomarkers were elevated. Echocardiogram demonstrated mildly depressed left ventricular function and no coronary anomalies noted. The patient required mechanical ventilation, vasopressors, and eventually extracorporeal membrane oxygenation (ECMO) for profound circulatory shock and progressive respiratory failure. During his clinical course, recovery of cardiac function was demonstrated however, a middle cerebral artery infarct and left frontal subarachnoid hemorrhage was suffered which ultimately the patient succumbed to. To the best of our knowledge, this is the youngest previously healthy child who had multi-system hyperinflammatory syndrome requiring ECMO support and the first case of SARS-CoV-2 related pediatric stroke.Clinical Trial Registration: None.

Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).

Initially, the global outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spared children from severe disease. However, after the initial wave of infections, clusters of a novel hyperinflammatory disease have been reported in regions with ongoing SARS-CoV-2 epidemics. While the characteristic clinical features are becoming clear, the pathophysiology remains unknown. Herein, we report on the immune profiles of eight Multisystem Inflammatory Syndrome in Children (MIS-C) cases. We document that all MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with normal isotype-switching and neutralization capability. We further profiled the secreted immune response by high-dimensional cytokine assays, which identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1) and mucosal immune dysregulation (IL-17A, CCL20, CCL28). Mass cytometry immunophenotyping of peripheral blood revealed reductions of mDC1 and non-classical monocytes, as well as both NK- and T- lymphocytes, suggesting extravasation to affected tissues. Markers of activated myeloid function were also evident, including upregulation of ICAM1 and FcR1 in neutrophil and non-classical monocytes, well-documented markers in autoinflammation and autoimmunity that indicate enhanced antigen presentation and Fc-mediated responses. Finally, to assess the role for autoimmunity secondary to infection, we profiled the auto-antigen reactivity of MIS-C plasma, which revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal and immune-cell antigens. All patients were treated with anti- IL6R antibody or IVIG, which led to rapid disease resolution tracking with normalization of inflammatory markers.

Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection (MIS-C): A Multi-institutional Study from New York City.

OBJECTIVE: To assess clinical characteristics and outcomes of severe acute respiratory syndrome coronavirus 2-associated multisystem inflammatory syndrome in children (MIS-C). STUDY DESIGN: Children with MIS-C admitted to pediatric intensive care units in New York City between April 23 and May 23, 2020, were included. Demographic and clinical data were collected. RESULTS: Of 33 children with MIS-C, the median age was 10 years; 61% were male; 45% were Hispanic/Latino; and 39% were black. Comorbidities were present in 45%. Fever (93%) and vomiting (69%) were the most common presenting symptoms. Depressed left ventricular ejection fraction was found in 63% of patients with median ejection fraction of 46.6% (IQR, 39.5-52.8). C-reactive protein, procalcitonin, d-dimer, and pro-B-type natriuretic peptide levels were elevated in all patients. For treatment, intravenous immunoglobulin was used in 18 (54%), corticosteroids in 17 (51%), tocilizumab in 12 (36%), remdesivir in 7 (21%), vasopressors in 17 (51%), mechanical ventilation in 5 (15%), extracorporeal membrane oxygenation in 1 (3%), and intra-aortic balloon pump in 1 (3%). The left ventricular ejection fraction normalized in 95% of those with a depressed ejection fraction. All patients were discharged home with median duration of pediatric intensive care unit stay of 4.7 days (IQR, 4-8 days) and a hospital stay of 7.8 days (IQR, 6.0-10.1 days). One patient (3%) died after withdrawal of care secondary to stroke while on extracorporeal membrane oxygenation. CONCLUSIONS: Critically ill children with coronavirus disease-2019-associated MIS-C have a spectrum of severity broader than described previously but still require careful supportive intensive care. Rapid, complete clinical and myocardial recovery was almost universal.