J Pediatr Infect Dis 2021; 16(04): 137-147
DOI: 10.1055/s-0041-1729182
Review Article

Multisystem Inflammatory Syndrome in Children Associated with COVID-19: An Interim Review

Jyoti R. Behera
1   Department of Pediatrics, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
,
1   Department of Pediatrics, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
,
1   Department of Pediatrics, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
,
1   Department of Pediatrics, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
› Author Affiliations

Abstract

The pediatric population is relatively less affected by novel coronavirus disease 2019 (COVID-19) compared with adults, both in numbers and severity. However, evolution of a new entity, named multisystem inflammatory syndrome in children (MIS-C), has led to significant number of children being admitted to hospital, especially to intensive care units. Case definitions of MIS-C have been defined by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) separately. Autoantibodies and antibody-dependent enhancement (ADE) are the key factors proposed in pathogenesis, leading to immune dysregulation, and cytokine storm. Three distinct clinical types are observed as follows: (1) fever and elevated inflammatory markers with no end-organ damage; (2) shock with severe myocardial dysfunction similar to toxic shock syndrome (TSS); and (3) with mucocutaneous features like Kawasaki's disease (KD). Cardiovascular and gastrointestinal symptoms are the predominant presentations. Inflammatory markers like C-reactive protein (CRP), ferritin, and interleukin (IL)-6 are raised along with high D-dimer and lactate dehydrogenase (LDH). Echocardiography may demonstrate low left ventricular ejection fraction (<50%) and/or coronary aneurysms. Reverse-transcription polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is usually negative, with most having antibodies against the virus. KD, KD shock syndrome (KDSS), and toxic shock syndrome (TSS) are the important differential diagnoses to be considered. Immunomodulatory therapy is the cornerstone of the management. Intravenous immunoglobulin (IVIg) is preferred, the next option being steroids. Supportive care, antiplatelet, and anticoagulation medications, when indicated, are also vital aspects of treatment plan. The prognosis is favorable with low mortality but meticulous cardiac monitoring and follow-up by a multidisciplinary team is very important. Being an evolving disease, future research may reveal different manifestations, newer diagnostic modalities, and better treatment options.



Publication History

Received: 19 September 2020

Accepted: 12 March 2021

Article published online:
11 June 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Jiang L, Tang K, Levin M. et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis 2020; 20 (11) e276-e288
  • 2 World Health Organization. Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19. Accessed April 7, 2021 at: https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19
  • 3 Serrau G, Bassareo PP, Neroni P, Fanos V, Marcialis MA. Children's heart and COVID-19: up-to-date evidence in the form of a systematic review. Eur J Pediatr 2020; 179 (07) 1079-1087
  • 4 Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 2020; 395 (10237): 1607-1608
  • 5 Jones VG, Mills M, Suarez D. et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr 2020; 10 (06) 537-540
  • 6 Royal College of Pediatrics and Child Health. Pediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS) – guidance for clinicians. Accessed September 15, 2020 from: https://www.rcpch.ac.uk/resources/paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pims-guidance
  • 7 Whittaker E, Bamford A, Kenny J. et al; PIMS-TS Study Group and EUCLIDS and PERFORM Consortia. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA 2020; 324 (03) 259-269
  • 8 Wang SF, Tseng SP, Yen CH. et al. Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins. Biochem Biophys Res Commun 2014; 451 (02) 208-214
  • 9 Hoepel W, Chen HJ, Allahverdiyeva S. et al. Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses. bioRxiv 2020; DOI: 10.1101/2020.07.13.190140.
  • 10 Gruber C, Patel R, Trachman R. et al. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-C). Cell 2020; 183 (04) 982-995
  • 11 Menikou S, Langford PR, Levin M. Kawasaki disease: the role of immune complexes revisited. Front Immunol 2019; 10: 1156
  • 12 Ono S, Onimaru T, Kawakami K, Hokonohara M, Miyata K. Impaired granulocyte chemotaxis and increased circulating immune complexes in Kawasaki disease. J Pediatr 1985; 106 (04) 567-570
  • 13 Park A, Iwasaki A. Type I and type III interferons - induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe 2020; 27 (06) 870-878
  • 14 Weisberg SP, Connors T, Zhu Y. et al. Antibody responses to SARS-CoV2 are distinct in children with MIS-C compared to adults with COVID-19. medRxiv. 2020 Jan 1
  • 15 Mozzini C, Girelli D. The role of neutrophil extracellular traps in Covid-19: only an hypothesis or a potential new field of research?. Thromb Res 2020; 191: 26-27
  • 16 Consiglio CR, Cotugno N, Sardh F. et al; CACTUS Study Team. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 2020; 183 (04) 968-981.e7
  • 17 Davies P, Evans C, Kanthimathinathan HK. et al. Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study. Lancet Child Adolesc Health 2020; 4 (09) 669-677
  • 18 Verdoni L, Mazza A, Gervasoni A. 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 (10239): 1771-1778
  • 19 Belhadjer Z, Méot M, Bajolle F. et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation 2020; 142 (05) 429-436
  • 20 Godfred-Cato S, Bryant B, Leung J. et al; California MIS-C Response Team. COVID-19–associated multisystem inflammatory syndrome in children—United States, March–July 2020. MMWR Morb Mortal Wkly Rep 2020; 69 (32) 1074-1080
  • 21 Dhanalakshmi K, Venkataraman A, Balasubramanian S. et al. Epidemiological and clinical profile of pediatric inflammatory multisystem syndrome - temporally associated with SARS-CoV-2 (PIMS-TS) in Indian children. Indian Pediatr 2020; 57 (11) 1010-1014
  • 22 Jain S, Sen S, Lakshmivenkateshiah S. et al. Multisystem inflammatory syndrome in children with COVID-19 in Mumbai, India. Indian Pediatr 2020; 57 (11) 1015-1019
  • 23 Sadiq M, Aziz OA, Kazmi U. et al. Multisystem inflammatory syndrome associated with COVID-19 in children in Pakistan. Lancet Child Adolesc Health 2020; 4 (10) e36-e37
  • 24 Centers for Disease Control and Prevention. Emergency preparedness and response. Accessed April 7, 2021 from: https://emergency.cdc.gov/
  • 25 Xu S, Chen M, Weng J. COVID-19 and Kawasaki disease in children. Pharmacol Res 2020; 159: 104951
  • 26 Kanegaye JT, Wilder MS, Molkara D. et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics 2009; 123 (05) e783-e789
  • 27 Matsubara K, Fukaya T. The role of superantigens of group A Streptococcus and Staphylococcus aureus in Kawasaki disease. Curr Opin Infect Dis 2007; 20 (03) 298-303
  • 28 Gatterre P, Oualha M, Dupic L. et al. Kawasaki disease: an unexpected etiology of shock and multiple organ dysfunction syndrome. Intensive Care Med 2012; 38 (05) 872-878
  • 29 Nagata S, Yamashiro Y, Ohtsuka Y. et al. Heat shock proteins and superantigenic properties of bacteria from the gastrointestinal tract of patients with Kawasaki disease. Immunology 2009; 128 (04) 511-520
  • 30 Gaensbauer JT, Todd JK. Staphylococcus. In: Kliegman RM, St Geme J, Blum NJ. et al, eds. Nelson Textbook of Pediatrics. 21st ed.. Philadelphia, PA: Elsevier; 2019
  • 31 Diorio C, Henrickson SE, Vella LA. et al. Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2. J Clin Invest 2020; 130 (11) 5967-5975
  • 32 Centers for Disease Control and Prevention. Multisystem inflammatory syndrome (MIS-C). Accessed April 7, 2021 at: https://www.cdc.gov/mis-c/#:~:text=Multisystem%20inflammatory%20syndrome%20in%20children%20(MIS%2DC)%20is%20a,%2C%20eyes%2C%20or%20gastrointestinal%20organs
  • 33 Henderson LA, Canna SW, Friedman KG. et al. American College of Rheumatology Clinical Guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19. Version 1. Arthritis Rheumatol 2020; 72 (11) 1791-1805
  • 34 Levin M, Cunnington AJ, Wilson C. et al. Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial. Lancet Respir Med 2019; 7 (07) 581-593
  • 35 Alhazzani W, Møller MH, Arabi YM. et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID19). Crit Care Med 2020; 48 (06) e440-e469
  • 36 Harwood R, Allin B, Jones CE. et al. PIMS-TS National Consensus Management Study Group. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process. Lancet Child Adolesc Health 2021; 5 (02) 133-141
  • 37 Hennon TR, Penque MD, Abdul-Aziz R. et al. COVID-19 associated multisystem inflammatory syndrome in children (MIS-C) guidelines; a Western New York approach. Prog Pediatr Cardiol 2020; 101232
  • 38 McCrindle BW, Rowley AH, Newburger JW. et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation 2017; 135 (17) e927-e999
  • 39 Burns JC, Franco A. The immunomodulatory effects of intravenous immunoglobulin therapy in Kawasaki disease. Expert Rev Clin Immunol 2015; 11 (07) 819-825
  • 40 Kobayashi T, Saji T, Otani T. et al; RAISE study group investigators. 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 (9826): 1613-1620
  • 41 Jain MK, Sahu SK, Behera JR, Patnaik S. Multisystem inflammatory syndrome in children associated with COVID19 treated with oral steroids. Indian J Pediatr 2021; 88 (01) 106
  • 42 Bhat CS, Gupta L, Balasubramanian S, Singh S, Ramanan AV. Hyperinflammatory syndrome in children associated with COVID-19: need for awareness. Indian Pediatr 2020; 57 (10) 929-935
  • 43 Balasubramanian S, Nagendran TM, Ramachandran B, Ramanan AV. Hyper-inflammatory syndrome in a child with COVID-19 treated successfully with intravenous immunoglobulin and tocilizumab. Indian Pediatr 2020; 57 (07) 681-683
  • 44 Feldstein LR, Rose EB, Horwitz SM. et al; Overcoming COVID-19 Investigators, CDC COVID-19 Response Team. Multisystem inflammatory syndrome in US children and adolescents. N Engl J Med 2020; 383 (04) 334-346
  • 45 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 (02) 307-322
  • 46 Ahmed M, Advani S, Moreira A. et al. Multisystem inflammatory syndrome in children: a systematic review. EClinicalMedicine 2020; 26: 100527