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BACKGROUND: Weeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called Multisystem Inflammatory Syndrome in Children (MIS-C). Gastrointestinal symptoms are common in MIS-C patients and severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not previously been identified.
METHODS: Here, we analyzed biospecimens from 100 children: 19 children with MIS-C, 26 with acute COVID-19, and 55 controls. Stool was assessed for SARS-CoV-2 by RT-PCR and plasma was assessed 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 proof of concept, we treated a MIS-C patient with larazotide, a zonulin antagonist, and monitored impact on antigenemia and clinical response.
RESULTS: We showed that in MIS-C, prolonged presence of SARS-CoV-2 in the GI tract leads to release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The MIS-C patient treated with larazotide displayed a coinciding decrease in plasma SARS-CoV-2 Spike antigen levels, inflammatory markers, and a resultant clinical improvement above that achieved with currently available treatments.
CONCLUSION: These mechanistic data of 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.
Lael M Yonker,Tal Gilboa,Alana F Ogata
David R Walt,Alessio Fasano
Lael M Yonker,Tal Gilboa,Alana F Ogata,Yasmeen Senussi,Roey Lazarovits,Brittany P Boribong,Yannic C Bartsch,Maggie Loiselle,Magali Noval Rivas,Rebecca A Porritt,Rosiane Lima,Jameson P Davis,Eva J Farkas,Madeleine D Burns,Nicola Young,Vinay S Mahajan,Soroush Hajizadeh,Xcanda I Herrera Lopez,Johannes Kreuzer,Robert Morris,Enid E Martinez,Isaac Han,Kettner Griswold,Nicholas C Barry,David B Thompson,George Church,Andrea G Edlow,Wilhelm Haas,Shiv Pillai,Moshe Arditi,Galit Alter,David R Walt,Alessio Fasano