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http://dx.doi.org/10.14776/piv.2021.28.e13

Multisystem Inflammatory Syndrome in Children (MIS-C)  

Lee, Joon Kee (Department of Pediatrics, Chungbuk National University Hospital)
Cho, Eun Young (Department of Pediatrics, Chungnam National University Hospital)
Lee, Hyunju (Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine)
Publication Information
Pediatric Infection and Vaccine / v.28, no.2, 2021 , pp. 66-81 More about this Journal
Abstract
The coronavirus disease 2019 pandemic has been continuously spreading throughout the world. As of July 15, 2021, there have been more than 188 million confirmed cases and more than 4.06 million deaths. Although the incidence of severe infections is relatively low in children and adolescents compared to adults, a complication called multisystem inflammatory syndrome in children (MIS-C) may occur in some cases at approximately 2-6 weeks after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. MIS-C can be seen in patients of various ages, from young infants to adolescents, and may present with diverse clinical manifestations. While fever present in a great majority of patients, symptoms suggesting the involvement of the digestive or nervous system and the skin and mucous membranes (Kawasaki disease-like symptoms) also appear in many cases. Cardiac involvement may also be observed, including left ventricular dysfunction, myocarditis, coronary artery dilatation, and coronary aneurysm. In some cases, hypotension or shock can occur, and mechanical ventilation or treatment in the intensive care unit may be necessary. Fortunately, recovery is generally reported after appropriate treatment. MIS-C is a rare but important complication of SARS-CoV-2 infection in children and adolescents. As such, it is important to recognize the clinical symptoms and provide appropriate treatment at an early stage. In this review, the epidemiology, clinical symptoms, suggested pathophysiology, diagnostic approach, and treatment of MIS-C will be discussed.
Keywords
COVID-19; Pediatric multisystem inflammatory disease, COVID-19 related; SARS-CoV-2; Child; Therapeutics;
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1 Levin M. Childhood multisystem inflammatory syndrome - a new challenge in the pandemic. N Engl J Med 2020;383:393-5.   DOI
2 Centers for Disease Control and Prevention (CDC). Information for healthcare providers about multisystem inflammatory syndrome in children (MIS-C) [Internet]. Atlanta: CDC; 2020 [cited 2021 Jul 1]. Available from: https://www.cdc.gov/mis/hcp/index.html.
3 Central Disaster Management Headquarters. Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) [press release, 2020.10.31]. Cheongju: Central Disaster Management Headquarters; 2020.
4 Han MS, Choi EH, Chang SH, Jin BL, Lee EJ, Kim BN, et al. Clinical characteristics and viral RNA detection in children with coronavirus disease 2019 in the Republic of Korea. JAMA Pediatr 2021;175:73-80.   DOI
5 Central Disaster Management Headquarters. Case of multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) was reported in the country [press release, 2020.10.5]. Cheongju: Central Disaster Management Headquarters; 2020.
6 Kim L, Whitaker M, O'Halloran A, Kambhampati A, Chai SJ, Reingold A, et al. Hospitalization rates and characteristics of children aged <18 years hospitalized with laboratory-confirmed COVID-19 - COVIDNET, 14 States, March 1-July 25, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1081-8.   DOI
7 Toubiana J, Poirault C, Corsia A, Bajolle F, Fourgeaud J, Angoulvant F, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ 2020;369:m2094.
8 Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 2020;383:334-46.   DOI
9 Ogata S, Ogihara Y, Honda T, Kon S, Akiyama K, Ishii M. Corticosteroid pulse combination therapy for refractory Kawasaki disease: a randomized trial. Pediatrics 2012;129:e17-23.   DOI
10 Kone-Paut I, Cimaz R, Herberg J, Bates O, Carbasse A, Saulnier JP, et al. The use of interleukin 1 receptor antagonist (anakinra) in Kawasaki disease: a retrospective cases series. Autoimmun Rev 2018;17:768-74.   DOI
11 Lind-Holst M, Hartling UB, Christensen AE. High-dose anakinra as treatment for macrophage activation syndrome caused by refractory Kawasaki disease in an infant. BMJ Case Rep 2019;12:e229708.   DOI
12 Guillaume MP, Reumaux H, Dubos F. Usefulness and safety of anakinra in refractory Kawasaki disease complicated by coronary artery aneurysm. Cardiol Young 2018;28:739-42.   DOI
13 Tsuda E, Tsujii N, Hayama Y. Stenotic lesions and the maximum diameter of coronary artery aneurysms in Kawasaki disease. J Pediatr 2018;194:165-170.e2.   DOI
14 Banka P, Robinson JD, Uppu SC, Harris MA, Hasbani K, Lai WW, et al. Cardiovascular magnetic resonance techniques and findings in children with myocarditis: a multicenter retrospective study. J Cardiovasc Magn Reson 2015;17:96.   DOI
15 Abdel-Haq N, Asmar BI, Deza Leon MP, McGrath EJ, Arora HS, Cashen K, et al. SARS-CoV-2-associated multisystem inflammatory syndrome in children: clinical manifestations and the role of infliximab treatment. Eur J Pediatr 2021;180:1581-91.   DOI
16 Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA 2020;324:259-69.   DOI
17 Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, et al. Multisystem inflammatory syndrome in children in New York state. N Engl J Med 2020;383:347-58.   DOI
18 Levin M, Cunnington AJ, Wilson C, Nadel S, Lang HJ, Ninis N, et al. Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial. Lancet Respir Med 2019;7:581-93.   DOI
19 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation 2017;135:e927-99.   DOI
20 Henderson LA, Canna SW, Friedman KG, Gorelik M, Lapidus SK, Bassiri H, et al. American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARSCoV-2 and hyperinflammation in pediatric COVID-19: version 2. Arthritis Rheumatol 2021;73:e13-29.
21 Godfred-Cato S, Bryant B, Leung J, Oster ME, Conklin L, Abrams J, et al. COVID-19-associated multisystem inflammatory syndrome in children - United States, March-July 2020. MMWR Morb Mortal Wkly Rep 2020;69:1074-80.   DOI
22 Henderson LA, Canna SW, Friedman KG, Gorelik M, Lapidus SK, Bassiri H, et al. American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARSCoV-2 and hyperinflammation in pediatric COVID-19: version 1. Arthritis Rheumatol 2020;72:1791-805.   DOI
23 Shaigany S, Gnirke M, Guttmann A, Chong H, Meehan S, Raabe V, et al. An adult with Kawasaki-like multisystem inflammatory syndrome associated with COVID-19. Lancet 2020;396:e8-10.   DOI
24 Chung H, Seo H, Park S, Kim H, Jung J, Chong YP, et al. The first case of multisystem inflammatory syndrome in adult after COVID-19 in Korea. J Korean Med Sci 2021;36:e181.   DOI
25 Hoste L, Van Paemel R, Haerynck F. Multisystem inflammatory syndrome in children related to COVID-19: a systematic review. Eur J Pediatr 2021;180:2019-34.   DOI
26 Belay ED, Abrams J, Oster ME, Giovanni J, Pierce T, Meng L, et al. Trends in geographic and temporal distribution of US children with multisystem inflammatory syndrome during the COVID-19 pandemic. JAMA Pediatr 2021;175:837-45.   DOI
27 Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 2020;395:1607-8.   DOI
28 Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet 2020;395:1771-8.   DOI
29 World Health Organization (WHO). Multisystem inflammatory syndrome in children and adolescents with COVID-19 (2020.5.15). Geneva: WHO; 2020.
30 Royal College of Paediatrics and Child Health (RCPCH). Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS) - guidance for clinicians 2020 [Internet]. London: RCPCH; c2021 [cited 2021 Jul 1]. Available from: https://www.rcpch.ac.uk/resources/guidance-paediatricmultisystem-inflammatory-syndrome-temporally-associated-covid-19-pims.
31 Belhadjer Z, Meot M, Bajolle F, Khraiche D, Legendre A, Abakka S, et al. Acute heart failure in multisystem inflammatory syndrome in children in the context of global SARS-CoV-2 pandemic. Circulation 2020;142:429-36.   DOI
32 Newburger JW, Sleeper LA, McCrindle BW, Minich LL, Gersony W, Vetter VL, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med 2007;356:663-75.   DOI
33 Choi NH, Fremed M, Starc T, Weller R, Cheung E, Ferris A, et al. MIS-C and cardiac conduction abnormalities. Pediatrics 2020;146:e2020009738.   DOI
34 Ouldali N, Toubiana J, Antona D, Javouhey E, Madhi F, Lorrot M, et al. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA 2021;325:855-64.   DOI
35 Wardle AJ, Connolly GM, Seager MJ, Tulloh RM. Corticosteroids for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev 2017;1:CD011188.
36 Inoue Y, Okada Y, Shinohara M, Kobayashi T, Kobayashi T, Tomomasa T, et al. A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease: clinical course and coronary artery outcome. J Pediatr 2006;149:336-41.   DOI
37 Sperotto F, Friedman KG, Son MB, VanderPluym CJ, Newburger JW, Dionne A. Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach. Eur J Pediatr 2021;180:307-22.   DOI
38 Central Disaster Management Headquarters. Establishment & operation of surveillance for multisystem inflammatory syndrome in children (MIS-C) [press release, 2020.5.25]. Cheongju: Central Disaster Management Headquarters; 2020.
39 Tullie L, Ford K, Bisharat M, Watson T, Thakkar H, Mullassery D, et al. Gastrointestinal features in children with COVID-19: an observation of varied presentation in eight children. Lancet Child Adolesc Health 2020;4:e19-20.   DOI
40 Valverde I, Singh Y, Sanchez-de-Toledo J, Theocharis P, Chikermane A, Di Filippo S, et al. Acute cardiovascular manifestations in 286 children with multisystem inflammatory syndrome associated with COVID-19 infection in Europe. Circulation 2021;143:21-32.   DOI
41 Carter MJ, Fish M, Jennings A, Doores KJ, Wellman P, Seow J, et al. Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Nat Med 2020;26:1701-7.   DOI
42 Kobayashi T, Saji T, Otani T, Takeuchi K, Nakamura T, Arakawa H, et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet 2012;379:1613-20.   DOI
43 Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004;114:1708-33.   DOI
44 Kociol RD, Cooper LT, Fang JC, Moslehi JJ, Pang PS, Sabe MA, et al. Recognition and initial management of fulminant myocarditis: a scientific statement from the American Heart Association. Circulation 2020;141:e69-92.
45 Dennert R, Velthuis S, Schalla S, Eurlings L, van Suylen RJ, van Paassen P, et al. Intravenous immunoglobulin therapy for patients with idiopathic cardiomyopathy and endomyocardial biopsy-proven high PVB19 viral load. Antivir Ther 2010;15:193-201.   DOI
46 Yen CY, Hung MC, Wong YC, Chang CY, Lai CC, Wu KG. Role of intravenous immunoglobulin therapy in the survival rate of pediatric patients with acute myocarditis: a systematic review and meta-analysis. Sci Rep 2019;9:10459.   DOI
47 Hu H, Ma F, Wei X, Fang Y. Coronavirus fulminant myocarditis treated with glucocorticoid and human immunoglobulin. Eur Heart J 2021;42:206.   DOI
48 Belhadjer Z, Auriau J, Meot M, Oualha M, Renolleau S, Houyel L, et al. Addition of corticosteroids to immunoglobulins is associated with recovery of cardiac function in multi-inflammatory syndrome in children. Circulation 2020;142:2282-4.   DOI
49 Deza Leon MP, Redzepi A, McGrath E, Abdel-Haq N, Shawaqfeh A, Sethuraman U, et al. COVID-19- associated pediatric multisystem inflammatory syndrome. J Pediatric Infect Dis Soc 2020;9:407-8.   DOI
50 Jonat B, Gorelik M, Boneparth A, Geneslaw AS, Zachariah P, Shah A, et al. Multisystem inflammatory syndrome in children associated with coronavirus disease 2019 in a children's hospital in New York city: patient characteristics and an institutional protocol for evaluation, management, and follow-up. Pediatr Crit Care Med 2021;22:e178-91.   DOI
51 Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020;26:1017-32.   DOI
52 Choe YJ, Choi EH, Choi JW, Eun BW, Eun LY, Kim YJ, et al. Surveillance of COVID-19-associated multisystem inflammatory syndrome in children, South Korea. Emerg Infect Dis 2021;27:1196-200.   DOI
53 Chiotos K, Bassiri H, Behrens EM, Blatz AM, Chang J, Diorio C, et al. Multisystem inflammatory syndrome in children during the coronavirus 2019 pandemic: a case series. J Pediatric Infect Dis Soc 2020;9:393-8.   DOI
54 Greene AG, Saleh M, Roseman E, Sinert R. Toxic shock-like syndrome and COVID-19: multisystem inflammatory syndrome in children (MIS-C). Am J Emerg Med 2020;38:2492.e5-6.   DOI
55 Grimaud M, Starck J, Levy M, Marais C, Chareyre J, Khraiche D, et al. Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children. Ann Intensive Care 2020;10:69.   DOI
56 Abrams JY, Godfred-Cato SE, Oster ME, Chow EJ, Koumans EH, Bryant B, et al. Multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2: a systematic review. J Pediatr 2020;226:45-54.e1.   DOI
57 Morris SB, Schwartz NG, Patel P, Abbo L, Beauchamps L, Balan S, et al. Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection - United Kingdom and United States, March-August 2020. MMWR Morb Mortal Wkly Rep 2020;69:1450-6.   DOI
58 Kaushik A, Gupta S, Sood M, Sharma S, Verma S. A systematic review of multisystem inflammatory syndrome in children associated with SARS-CoV-2 infection. Pediatr Infect Dis J 2020;39:e340-6.   DOI
59 Ahmed M, Advani S, Moreira A, Zoretic S, Martinez J, Chorath K, et al. Multisystem inflammatory syndrome in children: a systematic review. EClinicalMedicine 2020;26:100527.   DOI
60 Centers for Disease Control and Prevention (CDC). Health Department-reported cases of multisystem inflammatory syndrome in children (MIS-C) in the United States 2021 [Internet]. Atlanta: CDC; c2021 [cited 2021 Jun 28]. Available from: https://www.cdc.gov/mis/cases/index.html.
61 Nakamura Y, Yashiro M, Uehara R, Sadakane A, Chihara I, Aoyama Y, et al. Epidemiologic features of Kawasaki disease in Japan: results of the 2007-2008 nationwide survey. J Epidemiol 2010;20:302-7.   DOI
62 Goland S, Czer LS, Siegel RJ, Tabak S, Jordan S, Luthringer D, et al. Intravenous immunoglobulin treatment for acute fulminant inflammatory cardiomyopathy: series of six patients and review of literature. Can J Cardiol 2008;24:571-4.   DOI
63 Rowley AH, Shulman ST, Arditi M. Immune pathogenesis of COVID-19-related multisystem inflammatory syndrome in children. J Clin Invest 2020;130:5619-21.   DOI
64 Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis 2020;20:e276-88.   DOI
65 Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 2017;135:e146-603.   DOI
66 Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS, et al. Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York city. JAMA 2020;324:294-6.   DOI
67 Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986;315:341-7.   DOI
68 Furusho K, Kamiya T, Nakano H, Kiyosawa N, Shinomiya K, Hayashidera T, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 1984;2:1055-8.
69 Kanegaye JT, Wilder MS, Molkara D, Frazer JR, Pancheri J, Tremoulet AH, et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics 2009;123:e783-9.   DOI