{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T21:26:52Z","timestamp":1793914012219,"version":"4.8.0"},"reference-count":55,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T00:00:00Z","timestamp":1593561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in the multisystem inflammatory syndrome in children (MIS-C). The clinical presentation of MIS-C includes fever, severe illness, and the involvement of two or more organ systems, in combination with laboratory evidence of inflammation and laboratory or epidemiologic evidence of SARS-CoV-2 infection. Some features of MIS-C resemble Kawasaki Disease, toxic shock syndrome, and secondary hemophagocytic lymphohistiocytosis\/macrophage activation syndrome. The relationship of MIS-C to SARS-CoV-2 infection suggests that the pathogenesis involves post-infectious immune dysregulation. Patients with MIS-C should ideally be managed in a pediatric intensive care environment since rapid clinical deterioration may occur. Specific immunomodulatory therapy depends on the clinical presentation. The relationship between the immune response to SARS-CoV-2 vaccines in development and MIS-C requires further study.<\/jats:p>","DOI":"10.3390\/children7070069","type":"journal-article","created":{"date-parts":[[2020,7,2]],"date-time":"2020-07-02T02:44:25Z","timestamp":1593657865000},"page":"69","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":292,"title":["Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management"],"prefix":"10.3390","volume":"7","author":[{"given":"Natasha","family":"Nakra","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Blumberg","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Herrera-Guerra","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6098-2155","authenticated-orcid":false,"given":"Satyan","family":"Lakshminrusimha","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatology, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"CDC COVID-19 Response Team (2020). Coronavirus disease 2019 in children\u2014United States, February 12\u2013April 2, 2020. Morb. Mortal. Wkly. Rep., 69, 422\u2013426.","DOI":"10.15585\/mmwr.mm6914e4"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Parri, N., Lenge, M., and Buonsenso, D. (2020). Children with Covid-19 in Pediatric Emergency Departments in Italy. N. Engl. J. Med.","DOI":"10.1056\/NEJMc2007617"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Riphagen, S., Gomez, X., Gonzalez-Martinez, C., Wilkinson, N., and Theocharis, P. (2020). Hyperinflammatory shock in children during COVID-19 pandemic. Lancet.","DOI":"10.1016\/S0140-6736(20)31094-1"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Verdoni, L., Mazza, A., Gervasoni, A., Martelli, L., Ruggeri, M., Ciuffreda, M., Bonanomi, E., and D\u2019Antiga, L. (2020). An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: An observational cohort study. Lancet.","DOI":"10.1016\/S0140-6736(20)31103-X"},{"key":"ref_5","unstructured":"CDC Health Alert Network (2020, May 23). Mulitsystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19), Available online: https:\/\/emergency.cdc.gov\/han\/2020\/han00432.asp."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Belhadjer, Z., Meot, M., Bajolle, F., Khraiche, D., Legendre, A., Abakka, S., Auriau, J., Grimaud, M., Oualha, M., and Beghetti, M. (2020). Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation.","DOI":"10.1161\/CIRCULATIONAHA.120.048360"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Toubiana, J.P.C., Corsia, A., Bajolle, F., Fourgeaud, J., Angoulvant, F., Debray, A., Basmaci, R., Salvador, E., Biscardi, S., and Frange, P. (2020, May 25). Outbreak of Kawasaki Disease in Children during COVID-19 Pandemic: A Prospective Observational Study in Paris, France. Pre-Print. Available online: https:\/\/doi.org\/10.1101\/2020.05.10.20097394.","DOI":"10.1101\/2020.05.10.20097394"},{"key":"ref_8","unstructured":"Belluck, P. (New York Times, 2020). New inflammatory condition in children probably linked to coronavirus, study finds, New York Times."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Jones, V.G., Mills, M., Suarez, D., Hogan, C.A., Yeh, D., Bradley Segal, J., Nguyen, E.L., Barsh, G.R., Maskatia, S., and Mathew, R. (2020). COVID-19 and Kawasaki disease: Novel virus and novel case. Hosp. Pediatr.","DOI":"10.1542\/hpeds.2020-0123"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jpeds.2015.11.021","article-title":"Clinical and virologic characteristics may aid distinction of acute adenovirus disease from Kawasaki disease with incidental adenovirus detection","volume":"170","author":"Song","year":"2016","journal-title":"J. Pediatr."},{"key":"ref_11","unstructured":"(2020, May 13). Health Advisory: Pediatric Multi-System Inflammatory Syndrome Temporally Associated with COVID-19 Interim Case Definition in New York State, Available online: https:\/\/health.ny.gov\/press\/releases\/2020\/docs\/2020-05-13_health_advisory.pdf."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rawat, M., Chandrasekharan, P., Hicar, M.D., and Lakshminrusimha, S. (2020). COVID-19 in newborns and infants-low risk of severe disease: Silver lining or dark cloud?. Am. J. Perinatol.","DOI":"10.1055\/s-0040-1710512"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bunyavanich, S., Do, A., and Vicencio, A. (2020). Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA.","DOI":"10.1001\/jama.2020.8707"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Giamarellos-Bourboulis, E.J., Netea, M.G., Rovina, N., Akinosoglou, K., Antoniadou, A., Antonakos, N., Damoraki, G., Gkavogianni, T., Adami, M.E., and Katsaounou, P. (2020). Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe.","DOI":"10.1016\/j.chom.2020.04.009"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.cyto.2014.07.003","article-title":"Decreased levels of inflammatory cytokines in immunoglobulin-resistant Kawasaki disease after plasma exchange","volume":"70","author":"Fujimaru","year":"2014","journal-title":"Cytokine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e927","DOI":"10.1161\/CIR.0000000000000484","article-title":"Diagnosis, treatment, and long-term management of Kawasaki disease: A scientific statement for health professionals from the American Heart Association","volume":"135","author":"McCrindle","year":"2017","journal-title":"Circulation"},{"key":"ref_17","unstructured":"Shulman, S.T. (2020). Pediatric COVID-associated Multi-system Inflammatory Syndrome (PMIS). J. Pediatr. Infect. Dis. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"374","DOI":"10.3389\/fped.2018.00374","article-title":"The epidemiology and pathogenesis of Kawasaki disease","volume":"6","author":"Rowley","year":"2018","journal-title":"Front. Pediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1086\/428291","article-title":"Association between a novel human coronavirus and Kawasaki disease","volume":"191","author":"Esper","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1586\/1744666X.2015.1044980","article-title":"The immunomodulatory effects of intravenous immunoglobulin therapy in Kawasaki disease","volume":"11","author":"Burns","year":"2015","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e783","DOI":"10.1542\/peds.2008-1871","article-title":"Recognition of a Kawasaki disease shock syndrome","volume":"123","author":"Kanegaye","year":"2009","journal-title":"Pediatrics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1007\/s00134-012-2473-8","article-title":"Kawasaki disease: An unexpected etiology of shock and multiple organ dysfunction syndrome","volume":"38","author":"Gatterre","year":"2012","journal-title":"Intensive Care Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1111\/ped.13614","article-title":"Kawasaki disease shock syndrome: Unique and severe subtype of Kawasaki disease","volume":"60","year":"2018","journal-title":"Pediatr. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1089\/vim.2004.17.528","article-title":"Structure-based preliminary analysis of immunity and virulence of SARS coronavirus","volume":"17","author":"Li","year":"2004","journal-title":"Viral Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2165\/00148581-200507010-00002","article-title":"Toxic shock syndrome in children: Epidemiology, pathogenesis, and management","volume":"7","author":"Chuang","year":"2005","journal-title":"Paediatr. Drugs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1093\/cid\/ciy401","article-title":"Polyspecific intravenous immunoglobulin in clindamycin-treated patients with streptococcal toxic shock syndrome: A systematic review and meta-analysis","volume":"67","author":"Parks","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1097\/INF.0000000000000852","article-title":"Early differentiation of Kawasaki disease shock syndrome and toxic shock syndrome in a pediatric intensive care unit","volume":"34","author":"Lin","year":"2015","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Henderson, L.A., Canna, S.W., Schulert, G.S., Volpi, S., Lee, P.Y., Kernan, K.F., Caricchio, R., Mahmud, S., Hazen, M.M., and Halyabar, O. (2020). On the alert for cytokine storm: Immunopathology in COVID-19. Arthritis Rheumatol.","DOI":"10.1002\/art.41285"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nrrheum.2015.179","article-title":"Macrophage activation syndrome in the era of biologic therapy","volume":"12","author":"Grom","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.jpeds.2019.06.033","article-title":"DNA viremia is associated with hyperferritinemia in pediatric sepsis","volume":"213","author":"Simon","year":"2019","journal-title":"J. Pediatr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e54","DOI":"10.1097\/INF.0000000000002248","article-title":"Hemophagocytic lymphohistiocytosis and infections: An update","volume":"38","author":"Chesshyre","year":"2019","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1097\/MPH.0b013e3181dccbf4","article-title":"Macrophage activation syndrome in the acute phase of Kawasaki disease","volume":"32","author":"Latino","year":"2010","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1093\/rheumatology\/kep418","article-title":"Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis","volume":"49","author":"Vastert","year":"2010","journal-title":"Rheumatolology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12969-019-0309-6","article-title":"Calm in the midst of cytokine storm: A collaborative approach to the diagnosis and treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome","volume":"17","author":"Halyabar","year":"2019","journal-title":"Pediatr. Rheumatol. Online J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1182\/blood-2014-10-602607","article-title":"Marked hyperferritinemia does not predict for HLH in the adult population","volume":"125","author":"Schram","year":"2015","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/pbc.21039","article-title":"HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis","volume":"48","author":"Henter","year":"2007","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1136\/annrheumdis-2015-208982","article-title":"2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: A European league against rheumatism\/American college of rheumatology\/paediatric rheumatology international trials organisation collaborative initiative","volume":"75","author":"Ravelli","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1002\/art.38769","article-title":"Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis","volume":"66","author":"Davi","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1093\/rheumatology\/key344","article-title":"European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease\u2014The SHARE initiative","volume":"58","author":"Groot","year":"2019","journal-title":"Rheumatology"},{"key":"ref_40","unstructured":"(2020, May 20). Clinicaltrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/results?cond=covid-19+tocilizumab&term=&cntry=&state=&city=&dist=&Search=Search."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.1161\/CIRCULATIONAHA.105.592865","article-title":"Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease","volume":"113","author":"Kobayashi","year":"2006","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1136\/heartjnl-2012-302126","article-title":"Intravenous immunoglobulin plus corticosteroid to prevent coronary artery abnormalities in Kawasaki disease: A meta-analysis","volume":"99","author":"Chen","year":"2013","journal-title":"Heart"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1016\/S0140-6736(11)61930-2","article-title":"Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): A randomised, open-label, blinded-endpoints trial","volume":"379","author":"Kobayashi","year":"2012","journal-title":"Lancet"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1017\/S1047951117002864","article-title":"Usefulness and safety of anakinra in refractory Kawasaki disease complicated by coronary artery aneurysm","volume":"28","author":"Guillaume","year":"2018","journal-title":"Cardiol. Young"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1056\/NEJMc1709609","article-title":"Coronary-artery aneurysm in tocilizumab-treated children with Kawasaki\u2019s disease","volume":"377","author":"Nozawa","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e000137","DOI":"10.1136\/rmdopen-2015-000137","article-title":"Long-term efficacy and safety of tocilizumab in giant cell arteritis and large vessel vasculitis","volume":"2","author":"Evans","year":"2016","journal-title":"RMD Open"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Antinori, S., Bonazzetti, C., Gubertini, G., Capetti, A., Pagani, C., Morena, V., Rimoldi, S., Galimberti, L., Sarzi-Puttini, P., and Ridolfo, A.L. (2020). Tocilizumab for cytokine storm syndrome in COVID-19 pneumonia: An increased risk for candidemia?. Autoimmun. Rev.","DOI":"10.1016\/j.autrev.2020.102564"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1097\/CCM.0000000000001402","article-title":"Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: Reanalysis of a prior phase III trial","volume":"44","author":"Shakoory","year":"2016","journal-title":"Crit. Care Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41422-020-0282-0","article-title":"Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro","volume":"30","author":"Wang","year":"2020","journal-title":"Cell Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/S0140-6736(20)31022-9","article-title":"Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bmb\/62.1.15","article-title":"Immunology of vaccination","volume":"62","author":"Beverley","year":"2002","journal-title":"Br. Med. Bull."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Jares Baglivo, S., and Polack, F.P. (2019). The long road to protect infants against severe RSV lower respiratory tract illness. F1000 Res., 8.","DOI":"10.12688\/f1000research.18749.1"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.immuni.2010.10.002","article-title":"Vaccine adjuvants: Putting innate immunity to work","volume":"33","author":"Coffman","year":"2010","journal-title":"Immunity"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Korber, B., Fischer, W.M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., Foley, B., Giorgi, E.E., Bhattacharya, T., and Parker, M.D. (2020, May 26). Spike Mutation Pipeline Reveals the Emergence of a More Transmissible Form of SARS-CoV-2. Available online: https:\/\/doi.org\/10.1101\/2020.04.29.069054.","DOI":"10.1101\/2020.04.29.069054"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"S80","DOI":"10.1016\/j.ijid.2019.01.029","article-title":"Dengue vaccine development: Global and Indian scenarios","volume":"84S","author":"Swaminathan","year":"2019","journal-title":"Int. J. Infect. Dis."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/7\/7\/69\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:45:47Z","timestamp":1760175947000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/7\/7\/69"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,1]]},"references-count":55,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["children7070069"],"URL":"https:\/\/doi.org\/10.3390\/children7070069","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,1]]}}}