{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:26:57Z","timestamp":1793831217978,"version":"4.6.1"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Multisystem Inflammatory Syndrome in Children (MIS-C) is defined as a clinically serious condition requiring hospitalization with fever, multi-system organ disfunction, inflammatory biomarkers increase. The syndrome develops in the context of a probable or ascertained Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV2) infection, but other possible etiologies should be ruled out for definitive diagnosis. On the clinical side, along with the multi-system involvement, myocarditis with heart failure and shock is the most striking feature. Capillary leak is another fundamental feature of MIS-C. In fact, shock and hemodynamic compromise in MIS-C can occur also in the absence of laboratory evidence of myocardial inflammation, with preserved cardiac function and rapid reversibility. Since the first observations of MIS-C patients, it was evident that there is a delay between the peak of adult cases of Coronavirus disease 19 (COVID-19) and the MIS-C peak. Moreover, SARS-Cov2 isolation in children with MIS-C is not always possible, due to low viral load, while positive serology is far more commonly observed. These observations lead to the interpretation of MIS-C as a post-infectious disease. Although the exact pathogenesis of MIS-C is far from being elucidated, it is clear that it is a hyperinflammatory disease with a different inflammatory response as compared to what is seen in acute SARS-CoV-2 infection and that the disease shares some, but not all, immunological features with Macrophage Activation Syndrome (MAS), Kawasaki Disease (KD), Hemophagocytic Lymphohistiocytosis (HLH), and Toxic Shock Syndrome (TSS). Different mechanisms have been hypothesized as being responsible, from molecular mimicry to antibody dependent enhancement (ADE). Some evidence has also been collected on the immunological profile of patients with MIS-C and their difference from COVID-19. This review is focused on critical aspects of MIS-C clinical presentation and pathogenesis, and different immunological profiles. We propose a model where this hyperinflammatory disease represents one manifestation of the SARS-CoV2 spectrum in children, going from asymptomatic carriers to the post-infectious MIS-C, through symptomatic children, a low number of which may suffer from a severe infection with hyperinflammation (pediatric Hyper-COVID).<\/jats:p>","DOI":"10.3389\/fmed.2021.747190","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T06:23:32Z","timestamp":1635402212000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["The Spectrum of Manifestations of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV2) Infection in Children: What We Can Learn From Multisystem Inflammatory Syndrome in Children (MIS-C)"],"prefix":"10.3389","volume":"8","author":[{"given":"Salvatore","family":"Panaro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Cattalini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.ijid.2020.01.022","article-title":"Clinical features and short-term outcomes of elderly patients with COVID-19","volume":"97","author":"Li","year":"2020","journal-title":"Int J Infect Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1056\/NEJMc2007617","article-title":"Children with COVID-19 in pediatric emergency departments in Italy","volume":"383","author":"Parri","year":"2020","journal-title":"N Engl J Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1002\/jmv.25807","article-title":"COVID-19 epidemic: disease characteristics in children","volume":"92","author":"Jiatong","year":"2020","journal-title":"J Med Virol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e20201576","DOI":"10.1542\/peds.2020-1576","article-title":"COVID-19 in children and the dynamics of infection in families","volume":"146","author":"Posfay-Barbe","year":"2020","journal-title":"Pediatrics."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1056\/NEJMc2005073","article-title":"SARS-CoV-2 infection in children","volume":"382","author":"Lu","year":"2020","journal-title":"N Engl J Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1016\/S0140-6736(20)31103-X","article-title":"An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study","volume":"395","author":"Verdoni","year":"2020","journal-title":"Lancet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1016\/S0140-6736(20)31094-1","article-title":"Hyperinflammatory shock in children during COVID-19 pandemic","volume":"395","author":"Riphagen","year":"2020","journal-title":"Lancet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1056\/NEJMoa2021680","article-title":"Multisystem inflammatory syndrome in U.S. children and adolescents","volume":"383","author":"Feldstein","year":"2020","journal-title":"N Engl J Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1056\/NEJMoa2021756","article-title":"Multisystem inflammatory syndrome in children in New York State","volume":"383","author":"Dufort","year":"2020","journal-title":"N Engl J Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1001\/jama.2020.10369","article-title":"Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2","volume":"324","author":"Whittaker","year":"2020","journal-title":"JAMA."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.15585\/mmwr.mm6932e2","article-title":"COVID-19\u2013associated multisystem inflammatory syndrome in children \u2014 United States, March\u2013July 2020","volume":"69","author":"Godfred-Cato","year":"2020","journal-title":"MMWR Morb Mortal Wkly Rep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.15585\/mmwr.mm6940e1","article-title":"Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection - 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