Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.
Lael M. Yonker,Tal Gilboa,Tal Gilboa,Tal Gilboa,Alana F. Ogata,Alana F. Ogata,Alana F. Ogata,Yasmeen Senussi,Roey Lazarovits,Roey Lazarovits,Brittany P. Boribong,Yannic C. Bartsch,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 Mahajan,Vinay Mahajan,Soroush Hajizadeh,Xcanda Ixchel Herrera Lopez,Johannes Kreuzer,Robert Morris,Enid E. Martinez,Enid E. Martinez,Isaac Han,Isaac Han,Kettner Griswold,Kettner Griswold,Nicholas C. Barry,Nicholas C. Barry,David B. Thompson,David B. Thompson,George M. Church,George M. Church,Andrea G. Edlow,Wilhelm Haas,Shiv Pillai,Shiv Pillai,Moshe Arditi,Galit Alter,Galit Alter,David R. Walt,David R. Walt,David R. Walt,Alessio Fasano +49 more
TLDR
In this paper, the authors showed that a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability.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.read more
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Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19
Keith Sacco,Riccardo Castagnoli,Svetlana Vakkilainen,Chien-Liang Liu,Ottavia M. Delmonte,Cihan Oguz,Ian Kaplan,Sara Alehashemi,Peter D. Burbelo,Farzana Bhuyan,Adriana Almeida de Jesus,Kerry Dobbs,Lindsey B. Rosen,A. Chen,Elana Shaw,Mikko S. Vakkilainen,Francesca Pala,Justin B. Lack,Yu Zhang,Danielle Fink,Vasilis Oikonomou,Andrew L. Snow,Clifton L. Dalgard,Jinguo Chen,Brian Sellers,Gina A. Montealegre Sanchez,Karyl S. Barron,Emma Rey-Jurado,Cecilia Vial,M. Cecilia Poli,Amelia Licari,Daniela Montagna,Gian Luigi Marseglia,Francesco Licciardi,Ugo Ramenghi,Valentina Discepolo,Andrea Lo Vecchio,Alfredo Guarino,Eli M. Eisenstein,Luisa Imberti,Alessandra Sottini,Andrea Biondi,Sayonara Pérez Mato,Dana Gerstbacher,M. Truong,Michael Stack,Mary Magliocco,Marita Bosticardo,Tomoki Kawai,Jeffrey Danielson,Tyler W. Hulett,Manor Askenazi,Shaohui Hu,Jeffrey I. Cohen,Helen C. Su,Douglas B. Kuhns,Michail S. Lionakis,Thomas M. Snyder,Steven M. Holland,Raphaela Goldbach-Mansky,John S. Tsang,Luigi D. Notarangelo +61 more
TL;DR: In this article , a longitudinal multi-institutional study was conducted to identify distinct immunopathological signatures in COVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.
Journal ArticleDOI
Unraveling the Mystery Surrounding Post-Acute Sequelae of COVID-19.
Rakhee K. Ramakrishnan,Tarek Kashour,Qutayba Hamid,Qutayba Hamid,Rabih Halwani,Rabih Halwani,Imad M. Tleyjeh +6 more
TL;DR: In this paper, the authors hypothesize potential immunological mechanisms underlying these persistent and prolonged effects, and describe the multi-organ long-term manifestations of COVID-19, and hypothesize that the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely responsible for the appearance of these lasting symptoms, possibly through facilitating an ongoing inflammatory process.
Journal ArticleDOI
Persistent Circulating Severe Acute Respiratory Syndrome Coronavirus 2 Spike Is Associated With Post-acute Coronavirus Disease 2019 Sequelae
TL;DR: In this article , the authors identify biomarkers associated with postacute sequelae of coronavirus disease 2019 (PASC) poses an ongoing medical challenge, and they detect severe acute respiratory syndrome coronavirus 2 spike predominantly in PASC patients up to 12 months after diagnosis.
Journal ArticleDOI
Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison.
Chetan Sharma,Madhusudan Ganigara,Caroline Galeotti,Joseph Burns,Fernando Molina Berganza,Denise A. Hayes,Davinder Singh-Grewal,Suman Bharath,Sujata Sajjan,Jagadeesh Bayry,Jagadeesh Bayry +10 more
TL;DR: In this article, a multisystem inflammatory syndrome in children (MIS-C) has been found to overlap with myocarditis, toxic-shock syndrome and Kawasaki disease.
Journal ArticleDOI
The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children.
Rebecca A. Porritt,Aleksandra Binek,Lisa Paschold,Magali Noval Rivas,Angela McArdle,Lael M. Yonker,Galit Alter,Galit Alter,Harsha K. Chandnani,Merrick Lopez,Alessio Fasano,Jennifer E. Van Eyk,Mascha Binder,Moshe Arditi +13 more
TL;DR: In this article, the authors used 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.
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