The complex landscape of immune dysregulation in multisystem inflammatory syndrome in children with COVID-19

Abstract

The immune responses following SARS-CoV-2 infection in children are still under investigation. While coronavirus disease 2019 (COVID-19) is usually mild in the paediatric population, some children develop severe clinical manifestations or multisystem inflammatory syndrome in children (MIS-C) after infection. MIS-C, typically emerging 2–6 weeks after SARS-CoV-2 exposure, is characterized by a hyperinflammatory response affecting multiple organs. This review aims to explore the complex landscape of immune dysregulation in MIS-C, focusing on innate, T cell-, and B cell-mediated immunity, and discusses the role of SARS-CoV-2 spike protein as a superantigen in MIS-C pathophysiology. Understanding these mechanisms is crucial for improving the management and outcomes for affected children.

Keywords

SARS-CoV-2 / multisystem inflammatory syndrome in children / immune dysregulation / superantigen / autoantibody

References

[1] Sharma A , Tiwari S , Deb MK , et al. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): a global pandemic and treatment strategies. Int J Antimicrob Agents 2020; 56: 106054.

[2] Fontanet A , Autran B , Lina B , et al. SARS-CoV-2 variants and ending the COVID-19 pandemic. Lancet 2021; 397: 952- 4.

[3] Ludvigsson JF . Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr 2020; 109: 1088- 95.

[4] Brodin P . Immune determinants of COVID-19 disease presentation and severity. Nat Med 2021; 27: 28- 33.

[5] Filippatos F , Tatsi EB , Michos A . Immunology of multisystem infammatory syndrome after COVID-19 in children: a review of the current evidence. Int J Mol Sci 2023; 24: 5711.

[6] Dufort EM , Koumans EH , Chow EJ , et al. Multisystem infammatory syndrome in children in New York state. N Engl J Med 2020; 383: 347- 58.

[7] Feldstein LR , Rose EB , Horwitz SM , et al. Multisystem infammatory syndrome in U.S. children and adolescents. N Engl J Med 2020; 383: 334- 46.

[8] Riphagen S , Gomez X , Gonzalez-Martinez C , et al. Hyperinfammatory shock in children during COVID-19 pandemic. Lancet 2020; 395: 1607- 8.

[9] 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: 1771- 8.

[10] Son MBF , Burns JC , Newburger JW . A new defnition for multisystem infammatory syndrome in children. Pediatrics 2023; 151: e2022060302.

[11] Patel JM . Multisystem infammatory syndrome in children (MIS-C). Curr Allergy Asthma Rep 2022; 22: 53- 60.

[12] Belhadjer Z , Méot M , Bajolle F , et al. Acute heart failure in multisystem infammatory syndrome in children in the context of global SARS-CoV-2 pandemic. Circulation 2020; 142: 429- 36.

[13] Toubiana J , Poirault C , Corsia A , et al. Kawasaki-like multisystem infammatory syndrome in children during the COVID-19 pandemic in Paris, France: prospective observational study. Br Med J 2020; 369: m2094.

[14] Wang WY , Wang Y-J , An C-X , et al. Multisystem infammatory syndrome (MIS-C) with SARS-CoV-2 omicron variant BA.2.38 in a four-year-old Chinese girl: a case report. Front Public Health 2022; 10: 1021200.

[15] Radia T , Williams N , Agrawal P , et al. Multi-system infammatory syndrome in children & adolescents (MIS-C): a systematic review of clinical features and presentation. Paediatr Respir Rev 2021; 38: 51- 7.

[16] Molloy EJ , Nakra N , Gale C , et al. Multisystem infammatory syndrome in children (MIS-C) and neonates (MIS-N) associated with COVID-19: optimizing defnition and management. Pediatr Res 2023; 93: 1499- 508.

[17] Godfred-Cato S , Tsang CA , Giovanni J , et al. Multisystem infammatory syndrome in infants <12 months of age, United States, May 2020-January 2021. Pediatr Infect Dis J 2021; 40: 601- 5.

[18] Jiang L , Tang K , Irfan O , et al. Epidemiology, clinical features, and outcomes of multisystem infammatory syndrome in children (MIS-C) and adolescents—a live systematic review and meta-analysis. Curr Pediatr Rep 2022; 10: 19- 30.

[19] Abrams JY , Oster ME , Godfred-Cato SE , et al. Factors linked to severe outcomes in multisystem infammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study. Lancet Child Adolesc Health 2021; 5: 323- 31.

[20] Rafferty MS , Burrows H , Joseph JP , et al. Multisystem infammatory syndrome in children (MIS-C) and the coronavirus pandemic: current knowledge and implications for public health. J Infect Public Health 2021; 14: 484- 94.

[21] Rajamanickam A , Kumar NP , Venkataraman A , et al. Sex-specifc differences in systemic immune responses in MIS-C children. Sci Rep 2024; 14: 1720.

[22] Payne AB , Gilani Z , Godfred-Cato S , et al. Incidence of multisystem infammatory syndrome in children among US persons infected with SARS-CoV-2. JAMA Netw Open 2021; 4: e2116420.

[23] Cloete J , Kruger A , Masha M , et al. Paediatric hospitalisations due to COVID-19 during the frst SARS-CoV-2 omicron (B.1.1.529) variant wave in South Africa: a multicentre observational study. Lancet Child Adolesc Health 2022; 6: 294- 302.

[24] Miller AD , Zambrano LD , Yousaf AR , et al. Multisystem infammatory syndrome in children-United States, February 2020-July 2021. Clin Infect Dis 2022; 75: e1165- 75.

[25] Eleftheriou I , Maritsi D , Lampidi S , et al. Decreasing incidence of the multisystem infammatory syndrome in children over 3 pandemic waves. Pediatr Infect Dis J 2023; 42: 122- 4.

[26] Levy N , Koppel JH , Kaplan O , et al. Severity and incidence of multisystem infammatory syndrome in children during 3 SARS-CoV-2 pandemic waves in Israel. JAMA 2022; 327: 2452- 4.

[27] Arifuddin MS , Hazari MAH . Multisystem infammatory syndrome in children (MIS-C) of Asian countries: a mini-literature review on its clinical characteristics and outcomes. Medical Research Archives 2023; 11.

[28] Li W , Tang Y , Shi Y , et al. Why multisystem infammatory syndrome in children has been less commonly described in Asia? Transl Pediatr 2020; 9: 873- 5.

[29] Javalkar K , Robson VK , Gaffney L , et al. Socioeconomic and racial and/or ethnic disparities in multisystem infammatory syndrome. Pediatrics 2021; 147: e2020039933.

[30] Asghar Z , Sharaf K , Butt FA , et al. A global review of racial, ethnic and socio-economic disparities in multisystem infammatory syndrome in children related to COVID-19. Front Public Health 2022; 10: 996311.

[31] Zambrano LD , Newhams MM , Olson SM , et al. BNT162b2 mRNA vaccination against coronavirus disease 2019 is associated with a decreased likelihood of multisystem infammatory syndrome in children aged 5-18 years-United States, July 2021-April 2022. Clin Infect Dis 2023; 76: e90- e100.

[32] Levy M , Recher M , Hubert H , et al. Multisystem infammatory syndrome in children by COVID-19 vaccination status of adolescents in France. JAMA 2022; 327: 281- 3.

[33] Zambrano LD , Newhams MM , Olson SM , et al. Effectiveness of BNT162b2 (Pfzer-BioNTech) mRNA vaccination against multisystem infammatory syndrome in children among persons aged 12-18 years - United States, July-December 2021. MMWR Morb Mortal Wkly Rep 2022; 71: 52- 8.

[34] Nygaard U , Holm M , Hartling UB , et al. Incidence and clinical phenotype of multisystem infammatory syndrome in children after infection with the SARS-CoV-2 delta variant by vaccination status: a Danish nationwide prospective cohort study. Lancet Child Adolesc Health 2022; 6: 459- 65.

[35] Sharma C , Ganigara M , Galeotti C , et al. Multisystem infammatory syndrome in children and Kawasaki disease: a critical comparison. Nat Rev Rheumatol 2021; 17: 731- 48.

[36] Kawasaki T . Acute febrile mucocutaneous syndrome with lymphoid involvement with specifc desquamation of the fngers and toes in children. Arerugi 1967; 16: 178- 222.

[37] Burns JC , Shimizu C , Gonzalez E , et al. Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease. J Infect Dis 2005; 192: 344- 9.

[38] Burgner D , Davila S , Breunis WB , et al. A genome-wide association study identifes novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet 2009; 5: e1000319.

[39] Burgner D , Harnden A . Kawasaki disease: what is the epidemiology telling us about the etiology? Int J Infect Dis 2005; 9: 185- 94.

[40] Son MBF , Newburger JW . Kawasaki disease. Pediatr Rev 2018; 39: 78- 90.

[41] Burns JC . The riddle of Kawasaki disease. N Engl J Med 2007; 356: 659- 61.

[42] Green MS . The male predominance in the incidence of infectious diseases in children: a postulated explanation for disparities in the literature. Int J Epidemiol 1992; 21: 381- 6.

[43] Uehara R , Belay ED . Epidemiology of Kawasaki disease in Asia, Europe, and the United States. J Epidemiol 2012; 22: 79- 85.

[44] Choe YJ , Choi EH , Choi JW , et al. Surveillance of COVID-19-associated multisystem infammatory syndrome in children, South Korea. Emerg Infect Dis 2021; 27: 1196- 200.

[45] Belay ED , Abrams J , Oster ME , et al. Trends in geographic and temporal distribution of US children with multisystem infammatory syndrome during the COVID-19 pandemic. JAMA Pediatr 2021; 175: 837- 45.

[46] Rowley AH . Is Kawasaki disease an infectious disorder? Int J Rheum Dis 2018; 21: 20- 5.

[47] Perez-Toledo M , Faustini SE , Jossi SE , et al. SARS-CoV-2-specifc IgG1/IgG3 but not IgM in children with pediatric infammatory multi-system syndrome. Pediatr Allergy Immunol 2021; 32: 1125- 9.

[48] Gruber CN , Patel RS , Trachtman R , et al. Mapping systemic infammation and antibody responses in multisystem infammatory syndrome in children (MIS-C). Cell 2020; 183: 982- 995.e14.

[49] Rostad CA , Chahroudi A , Mantus G , et al. Quantitative SARS-CoV-2 serology in children with multisystem infammatory syndrome (MIS-C). Pediatrics 2020; 146: e2020018242.

[50] Weisberg SP , Connors TJ , Zhu Y , et al. Distinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum. Nat Immunol 2021; 22: 25- 31.

[51] Anderson EM , Diorio C , Goodwin EC , et al. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibody responses in children with multisystem infammatory syndrome in children (MIS-C) and mild and severe coronavirus disease 2019 (COVID-19). J. Pediatric Infect. Dis. Soc. 2021; 10: 669- 73.

[52] Bartsch YC , Wang C , Zohar T , et al. Humoral signatures of protective and pathological SARS-CoV-2 infection in children. Nat Med 2021; 27: 454- 62.

[53] Porritt RA , Binek A , Paschold L , et al. HLA class I-associated expansion of TRBV11-2 T cells in multisystem infammatory syndrome in children. J Clin Invest 2021; 131: e151520.

[54] Hoste L , Roels L , Naesens L , et al. TIM3+ TRBV11-2 T cells and IFN gamma signature in patrolling monocytes and CD16+ NK cells delineate MIS-C. J Exp Med 2022; 219: e20211381.

[55] Porritt RA , Binek A , Paschold L , et al. The autoimmune signature of hyperinfammatory multisystem infammatory syndrome in children. J Clin Invest 2021; 131: e151520.

[56] Pietra BA , De Inocencio J , Giannini EH , et al. TCR V beta family repertoire and T cell activation markers in Kawasaki disease. J Immunol 1994; 153: 1881- 8.

[57] Mancia L , Wahlström J , Schiller B , et al. Characterization of the T-cell receptor V-beta repertoire in Kawasaki disease. Scand J Immunol 1998; 48: 443- 9.

[58] Esteve-Sole A , Anton J , Pino-Ramirez RM , et al. Similarities and differences between the immunopathogenesis of COVID-19-related pediatric multisystem infammatory syndrome and Kawasaki disease. J Clin Invest 2021; 131: e144554.

[59] Consiglio CR , Cotugno N , Sardh F , et al. The immunology of multisystem infammatory syndrome in children with COVID-19. Cell 2020; 183: 968- 81.e7.

[60] McCrindle BW , Rowley AH , Newburger JW , et al. Diagnosis, treatment, and long-term management of Kawasaki Disease: a scientifc statement for health professionals from the American Heart Association. Circulation 2017; 135: e927- 99.

[61] Gamez-Gonzalez LB , Moribe-Quintero I , Cisneros-Castolo M , et al. Kawasaki disease shock syndrome: unique and severe subtype of Kawasaki disease. Pediatr Int 2018; 60: 781- 90.

[62] McArdle AJ , Vito O , Patel H , et al. Treatment of multisystem infammatory syndrome in children. N Engl J Med 2021; 385: 11- 22.

[63] Sacco K , Castagnoli R , Vakkilainen S , et al. Immunopathological signatures in multisystem infammatory syndrome in children and pediatric COVID-19. Nat Med 2022; 28: 1050- 62.

[64] Dove ML , Jaggi P , Kelleman M , et al. Multisystem infammatory syndrome in children: survey of protocols for early hospital evaluation and management. J Pediatr 2021; 229: 33- 40.

[65] Jonat B , Gorelik M , Boneparth A , et al. Multisystem infammatory 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.

[66] Vella LA , Giles JR , Baxter AE , et al. Deep immune profling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19. Sci Immunol 2021; 6: eabf7570.

[67] Fraser R , Orta-Resendiz A , Dockrell D , et al. Severe COVID-19 versus multisystem infammatory syndrome: comparing two critical outcomes of SARS-CoV-2 infection. Eur Respir Rev 2023; 32: 220197.

[68] Kabeerdoss J , Pilania RK , Karkhele R , et al. Severe COVID-19, multisystem infammatory syndrome in children, and Kawasaki disease: immunological mechanisms, clinical manifestations and management. Rheumatol Int 2021; 41: 19- 32.

[69] Kunal S , Ish P , Sakthivel P , et al. The emerging threat of multisystem infammatory syndrome in adults (MIS-A) in COVID-19: a systematic review. Heart Lung 2022; 54: 7- 18.

[70] Patel P , DeCuir J , Abrams J , et al. Clinical characteristics of multisystem infammatory syndrome in adults: a systematic review. JAMA Netw Open 2021; 4: e2126456.

[71] Carter MJ , Fish M , Jennings A , et al. Peripheral immunophenotypes in children with multisystem infammatory syndrome associated with SARS-CoV-2 infection. Nat Med 2020; 26: 1701- 7.

[72] AboAlEla HH , Ali AY , Al-Sharif GA , et al. Clinical and epidemiological features and severity markers in children admitted with multisystem inflammatory syndrome in children (MISC) in a tertiary care center in the United Arab Emirates. Pediatr Pulmonol 2023; 58: 2930- 40.

[73] Whitworth H , Sartain SE , Kumar R , et al. Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C. Blood 2021; 138: 190- 8.

[74] Lee PY , Day-Lewis M , Henderson LA , et al. Distinct clinical and immunological features of SARS-CoV-2-induced multisystem infammatory syndrome in children. J Clin Invest 2020; 130: 5942- 50.

[75] Ramaswamy A , Brodsky NN , Sumida TS , et al. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem infammatory syndrome in children. Immunity 2021; 54: 1083- 95.e7.

[76] Diorio C , Henrickson SE , Vella LA , et al. Multisystem infammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2. J Clin Invest 2020; 130: 5967- 75.

[77] Caldarale F , Giacomelli M , Garrafa E , et al. Plasmacytoid dendritic cells depletion and elevation of IFN-gamma dependent chemokines CXCL9 and CXCL10 in children with multisystem infammatory syndrome. Front Immunol 2021; 12: 654587.

[78] Pierce CA , Preston-Hurlburt P , Dai Y , et al. Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients. Sci Transl Med 2020; 12: eabd5487.

[79] Moreews M , Le Gouge K , Khaldi-Plassart S , et al. Polyclonal expansion of TCR V beta 21.3(+) CD4(+) and CD8(+) T cells is a hallmark of multisystem infammatory syndrome in children. Sci Immunol 2021; 6: eabh1516.

[80] Peart Akindele N , Kouo T , Karaba AH , et al. Distinct cytokine and chemokine dysregulation in hospitalized children with acute coronavirus disease 2019 and multisystem infammatory syndrome with similar levels of nasopharyngeal severe acute respiratory syndrome coronavirus 2 shedding. J Infect Dis 2021; 224: 606- 15.

[81] Nathan C . Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 2006; 6: 173- 82.

[82] LaSalle TJ , Gonye ALK , Freeman SS , et al. Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients. Cell Rep Med 2022; 3: 100779.

[83] Schulte-Schrepping J , Reusch N , Paclik D , et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell 2020; 182: 1419- 40 e23.

[84] Seery V , Raiden SC , Algieri SC , et al. Blood neutrophils from children with COVID-19 exhibit both infammatory and anti-infammatory markers. eBioMedicine 2021; 67: 103357.

[85] Boribong BP , LaSalle TJ , Bartsch YC , et al. Neutrophil profles of pediatric COVID-19 and multisystem infammatory syndrome in children. Cell Rep Med 2022; 3: 100848.

[86] Wang Y , Jonsson F . Expression, role, and regulation of neutrophil fc gamma receptors. Front Immunol 2019; 10: 1958.

[87] Auffray C , Sieweke MH , Geissmann F . Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 2009; 27: 669- 92.

[88] Banchereau J , Briere F , Caux C , et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767- 811.

[89] de Cevins C , Luka M , Smith N , et al. A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem infammatory syndrome in children with severe myocarditis. Med 2021; 2: 1072- 92.e7.

[90] Bjorkstrom NK , Strunz B , Ljunggren HG . Natural killer cells in antiviral immunity. Nat Rev Immunol 2022; 22: 112- 23.

[91] Jaxybayeva I , Boranbayeva R , Bulegenova M , et al. Clinical and immunological features in children with multisystem infammatory syndrome associated with SARS-CoV-2. Acta Biomed 2023; 94: e2023016.

[92] Beckmann ND , Comella PH , Cheng E , et al. Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem infammatory syndrome in children. Nat Commun 2021; 12: 4854.

[93] Diorio C , Shraim R , Vella LA , et al. Proteomic profling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction. Nat Commun 2021; 12: 7222.

[94] Zheng J , Liu Y , Lau Y-L , et al. Gammadelta-T cells: an unpolished sword in human anti-infection immunity. Cell Mol Immunol 2013; 10: 50- 7.

[95] Chiotos K , Bassiri H , Behrens EM , et al. Multisystem infammatory syndrome in children during the coronavirus 2019 pandemic: a case series. J. Pediatric Infect. Dis. Soc. 2020; 9: 393- 8.

[96] Fernandes DM , Oliveira CR , Guerguis S , et al. Severe acute respiratory syndrome coronavirus 2 clinical syndromes and predictors of disease severity in hospitalized children and youth. J Pediatr 2021; 230: 23- 31.e10.

[97] Hsieh LE , Song J , Grifoni A , et al. T cells in multisystem infammatory syndrome in children (MIS-C) have a predominant CD4+ T helper response to SARS-CoV-2 peptides and numerous virus-specifc CD4-CD8-double-negative T cells. Int J Mol Sci 2022; 23: 7219.

[98] Martinez OM , Bridges ND , Goldmuntz E , et al. The immune roadmap for understanding multi-system infammatory syndrome in children: opportunities and challenges. Nat Med 2020; 26: 1819- 24.

[99] Habtezion A , Nguyen LP , Hadeiba H , et al. Leukocyte trafficking to the small intestine and colon. Gastroenterology 2016; 150: 340- 54.

[100] Low DE . Toxic shock syndrome: major advances in pathogenesis, but not treatment. Crit Care Clin 2013; 29: 651- 75.

[101] Krakauer T . Staphylococcal superantigens: pyrogenic toxins induce toxic shock. Toxins (Basel) 2019; 11: 178.

[102] Li H , Llera A , Malchiodi EL , et al. The structural basis of T cell activation by superantigens. Annu Rev Immunol 1999; 17: 435- 66.

[103] Cheng MH , Zhang S , Porritt RA , et al. Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinfammation. Proc Natl Acad Sci U S A 2020; 117: 25254- 62.

[104] Rybkina K , Bell JN , Bradley MC , et al. SARS-CoV-2 infection and recovery in children: distinct T cell responses in MIS-C compared to COVID-19. J Exp Med 2023; 220: e20221518.

[105] Noval Rivas M , Porritt RA , Cheng MH , et al. Multisystem infammatory syndrome in children and long COVID: the SARS-CoV-2 viral superantigen hypothesis. Front Immunol 2022; 13: 941009.

[106] Alipoor SD , Mortaz E , Jamaati H , et al. COVID-19: molecular and cellular response. Front Cell Infect Microbiol 2021; 11: 563085.

[107] Hoffman W , Lakkis FG , Chalasani G . B cells, antibodies, and more. Clin J Am Soc Nephrol 2016; 11: 137- 54.

[108] Choi NH , Fremed M , Starc T , et al. MIS-C and cardiac conduction abnormalities. Pediatrics 2020; 146: e2020009738.

[109] Pfeifer J , Thurner B , Kessel C , et al. Autoantibodies against interleukin-1 receptor antagonist in multisystem infammatory syndrome in children: a multicentre, retrospective, cohort study. Lancet Rheumatol 2022; 4: e329- 37.

[110] Burbelo PD , Castagnoli R , Shimizu C , et al. Autoantibodies against proteins previously associated with autoimmunity in adult and pediatric patients with COVID-19 and children with MIS-C. Front Immunol 2022; 13: 841126.

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