Abstract
BACKGROUNDWeeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called multisystem inflammatory syndrome in children (MIS-C). Gastrointestinal (GI) symptoms are common in patients with MIS-C, and a severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not been identified to date.METHODSHere, we analyzed biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. Stools were assessed for SARS-CoV-2 by reverse transcription PCR (RT-PCR), and plasma was examined for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As a proof of concept, we treated a patient with MIS-C with larazotide, a zonulin antagonist, and monitored the effect on antigenemia and the patient’s clinical response.RESULTSWe showed that in children with MIS-C, a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The patient with MIS-C treated with larazotide had a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently available treatments.CONCLUSIONThese mechanistic data on MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.
Keywords: Antigen; COVID-19; Inflammation; Tight junctions.
【저자키워드】 COVID-19, Inflammation, Antigen, Tight junctions., 【초록키워드】 SARS-CoV-2, immune response, Biomarker, Pathogenesis, SARS-COV-2 infection, children, inflammatory markers, Symptom, RT-PCR, MIS-C, Antigen, antigenemia, immune responses, hyperinflammation, Patient, Gastrointestinal, Clinical improvement, plasma, target, Inflammatory marker, targets, SARS-CoV-2 antigen, antigen detection, reverse transcription PCR, disease, SARS-CoV-2 antigens, GI Tract, marker, mucosal, intestinal permeability, Inflammatory, tight junctions, Cardiac complications, proof of concept, larazotide, mucosal barrier, junctions, SARS-CoV-2 spike antigen, syndrome, bloodstream, life-threatening, biospecimens, stools, proof, acute COVID-19, diagnosing, breakdown, probe, Hyperinflammatory, controls, decrease, mechanistic data, analyzed, was used, develop, examined, the patient, subsequent, characterized, treated, increasingly, biospecimen, children with MIS-C, were assessed, 【제목키워드】 children, mucosal, Inflammatory, Gut, syndrome, driven by,