Acute COVID-19 Infection in a Pediatric Patient with ROHHAD

The novel coronavirus (severe acute respiratory syndrome coronavirus-2) has led to a global pandemic. In the adult population, coronavirus disease 2019 (COVID-19) has been found to cause multiorgan system damage with predicted long-term sequelae. We present a case of a 10-year-old boy with a history of ROHHAD (rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation) who presented with hypoxia, emesis, and abdominal pain. Imaging found bilateral ground glass opacities in the lungs and a pericardial effusion. Laboratory evaluation was concerning for elevated inflammatory markers. Remdesivir, hydroxychloroquine, and anticoagulation (heparin and enoxaparin) were utilized. The patient's severe respiratory failure was managed with conventional mechanical ventilation, inhaled nitric oxide, and airway pressure release ventilation. We hope that this report provides insight into the course and management of the severe acute pediatric COVID-19 patient, specifically with underlying comorbidities such as ROHHAD. Clinical trial registration is none.

The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.

Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8+ T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C.

HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vß chains results in Vß skewing, whereby T cells with specific Vß chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCRß variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementarity-determining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the Vß chain encoded by TRBV11-2 (Vß21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.

Acute COVID-19 Infection in a Pediatric Patient with ROHHAD.

The novel coronavirus (severe acute respiratory syndrome coronavirus-2) has led to a global pandemic. In the adult population, coronavirus disease 2019 (COVID-19) has been found to cause multiorgan system damage with predicted long-term sequelae. We present a case of a 10-year-old boy with a history of ROHHAD (rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation) who presented with hypoxia, emesis, and abdominal pain. Imaging found bilateral ground glass opacities in the lungs and a pericardial effusion. Laboratory evaluation was concerning for elevated inflammatory markers. Remdesivir, hydroxychloroquine, and anticoagulation (heparin and enoxaparin) were utilized. The patient's severe respiratory failure was managed with conventional mechanical ventilation, inhaled nitric oxide, and airway pressure release ventilation. We hope that this report provides insight into the course and management of the severe acute pediatric COVID-19 patient, specifically with underlying comorbidities such as ROHHAD. Clinical trial registration is none.