MIS-C multisystem inflammatory syndrome in children; SARS-CoV-2; antibody response; commensals; common coronavirus; functional antibody; Antibodies, Viral; Blood Group Antigens; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Humans; Child; Antibody Formation; COVID-19; Connective Tissue Diseases; Immunology and Allergy; Immunology
Abstract :
[en] [en] OBJECTIVES: To comprehensively analyze the quality of the antibody response between children with Multisystem inflammatory syndrome (MIS-C) and age-matched controls at one month after SARS-CoV-2 exposure, and infected in the same time-period.
METHODS: Serum from 20 MIS-C children at admission, and 14 control children were analyzed. Antigen specific antibody isotypes and subclasses directed against various antigens of SARS-CoV-2 as well as against human common coronavirus (HCoVs) and commensal or pathogenic microorganisms were assessed by a bead-based multiplexed serological assay and by ELISA. The functionality of these antibodies was also assessed using a plaque reduction neutralization test, a RBD-specific avidity assay, a complement deposition assay and an antibody-dependent neutrophil phagocytosis (ADNP) assay.
RESULTS: Children with MIS-C developed a stronger IgA antibody response in comparison to children with uncomplicated COVID-19, while IgG and IgM responses are largely similar in both groups. We found a typical class-switched antibody profile with high level of IgG and IgA titers and a measurable low IgM due to relatively recent SARS-CoV-2 infection (one month). SARS-CoV-2-specific IgG antibodies of MIS-C children had higher functional properties (higher neutralization activity, avidity and complement binding) as compared to children with uncomplicated COVID-19. There was no difference in the response to common endemic coronaviruses between both groups. However, MIS-C children had a moderate increase against mucosal commensal and pathogenic strains, reflecting a potential association between a disruption of the mucosal barrier with the disease.
CONCLUSION: Even if it is still unclear why some children develop a MIS-C, we show here that MIS-C children produce higher titers of IgA antibodies, and IgG antibodies with higher functionality, which could reflect the local gastro-intestinal mucosal inflammation potentially induced by a sustained SARS-CoV-2 gut infection leading to continuous release of SARS-CoV-2 antigens.
Disciplines :
Immunology & infectious disease
Author, co-author :
Thiriard, Anaïs; Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium
Meyer, Benjamin; Centre for Vaccinology, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Eberhardt, Christiane S; Centre for Vaccinology, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Loevy, Natasha; Pediatric Platform for Clinical Research, Department of Woman, Child and Adolescent Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
Grazioli, Serge; Division of Neonatal and Pediatric Intensive Care, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
Adouan, Wafae; Centre for Vaccinology, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Fontannaz, Paola; Centre for Vaccinology, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Marechal, Fabienne; Pediatric Platform for Clinical Research, Department of Woman, Child and Adolescent Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
L'Huillier, Arnaud G; Pediatric Infectious Diseases Unit, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
Siegrist, Claire-Anne; Centre for Vaccinology, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Georges, Daphnée ; Université de Liège - ULiège > Integrative Biological Sciences (InBioS) ; Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium
Putignano, Antonella; Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium
Marchant, Arnaud; Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium
Didierlaurent, Arnaud M; Centre for Vaccinology, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Blanchard-Rohner, Geraldine; Centre for Vaccinology, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland ; Pediatric Immunology and Vaccinology Unit, Children's Hospital of Geneva, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
Cui X Zhang T Zheng J Zhang J Si P Xu Y et al. Children with coronavirus disease 2019: A review of demographic, clinical, laboratory, and imaging features in pediatric patients. J Med Virol (2020) 92(9):1501–10. doi: 10.1002/jmv.26023
Cui X Zhao Z Zhang T Guo W Guo W Zheng J et al. A systematic review and meta-analysis of children with coronavirus disease 2019 (COVID-19). J Med Virol (2021) 93(2):1057–69. doi: 10.1002/jmv.26398
Lu X Zhang L Du H Zhang J Li YY Qu J et al. SARS-CoV-2 infection in children. N Engl J Med (2020) 382(17):1663–5. doi: 10.1056/NEJMc2005073
Posfay-Barbe KM Wagner N Gauthey M Moussaoui D Loevy N Diana A et al. COVID-19 in children and the dynamics of infection in families. Pediatrics (2020) 146(2):e20201576. doi: 10.1542/peds.2020-1576
Riphagen S. Understanding covid and the associated post-infectious hyper-inflammatory state (PIMS-TS) in children. Med Hypotheses (2020) 144:110029. doi: 10.1016/j.mehy.2020.110029
Grazioli S Tavaglione F Torriani G Wagner N Rohr M L'Huillier AG et al. Immunological assessment of pediatric multisystem inflammatory syndrome related to coronavirus disease 2019. J Pediatr Infect Dis Soc (2021) 10(6):706–13. doi: 10.1093/jpids/piaa142
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(10239):1771–8. doi: 10.1016/S0140-6736(20)31103-X
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(3):259–69. doi: 10.1001/jama.2020.10369
Payne AB Gilani Z Godfred-Cato S Belay ED Feldstein LR Patel MM et al. Incidence of multisystem inflammatory syndrome in children among US persons infected with SARS-CoV-2. JAMA Netw Open (2021) 4(6):e2116420. doi: 10.1001/jamanetworkopen.2021.16420
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: 10.1016/j.eclinm.2020.100527
Dufort EM Koumans EH Chow EJ Rosenthal EM Muse A Rowlands J et al. Multisystem inflammatory syndrome in children in new York state. New Engl J Med (2020) 383(4):347–58. doi: 10.1056/NEJMoa2021756
Feldstein LR Rose EB Horwitz SM Collins JP Newhams MM Son MBF et al. Multisystem inflammatory syndrome in U.S. children and adolescents. New Engl J Med (2020) 383(4):334–46. doi: 10.1056/NEJMoa2021680
Young TK Shaw KS Shah JK Noor A Alperin RA Ratner AJ et al. Mucocutaneous manifestations of multisystem inflammatory syndrome in children during the COVID-19 pandemic. JAMA Dermatol (2021) 157(2):207–12. doi: 10.1001/jamadermatol.2020.4779
Zhao Y Yin L Patel J Tang L Huang Y. The inflammatory markers of multisystem inflammatory syndrome in children (MIS-c) and adolescents associated with COVID-19: A meta-analysis. J Med Virol (2021) 93(7):4358–69. doi: 10.1002/jmv.26951
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(1):21–32. doi: 10.1161/CIRCULATIONAHA.120.050065
Alsaied T Tremoulet AH Burns JC Saidi A Dionne A Lang SM et al. Review of cardiac involvement in multisystem inflammatory syndrome in children. Circulation (2021) 143(1):78–88. doi: 10.1161/CIRCULATIONAHA.120.049836
Consiglio CR Cotugno N Sardh F Pou C Amodio D Rodriguez L et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell (2020) 183(4):968–81 e7. doi: 10.1016/j.cell.2020.09.016
Gruber CN Patel RS Trachtman R Lepow L Amanat F Krammer F et al. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-c). Cell (2020) 183(4):982–95 e14. doi: 10.1016/j.cell.2020.09.034
Lamers MM Beumer J van der Vaart J Knoops K Puschhof J Breugem TI et al. SARS-CoV-2 productively infects human gut enterocytes. Science (2020) 369(6499):50–4. doi: 10.1126/science.abc1669
Anderson EM Diorio C Goodwin EC McNerney KO Weirick ME Gouma S et al. SARS-CoV-2 antibody responses in children with MIS-C and mild and severe COVID-19. J Pediatr Infect Dis Soc (2021) 10(5):669–73. doi: 10.1101/2020.08.17.20176552
Rostad CA Chahroudi A Mantus G Lapp SA Teherani M Macoy L et al. Quantitative SARS-CoV-2 serology in children with multisystem inflammatory syndrome (MIS-c). Pediatrics (2020) 146(6):e2020018242. doi: 10.1542/peds.2020-018242
Weisberg SP Connors TJ Zhu Y Baldwin MR Lin WH Wontakal S et al. Distinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum. Nat Immunol (2021) 22(1):25–31. doi: 10.1038/s41590-020-00826-9
Vono M Huttner A Lemeille S Martinez-Murillo P Meyer B Baggio S et al. Robust innate responses to SARS-CoV-2 in children resolve faster than in adults without compromising adaptive immunity. Cell Rep (2021) 37(1):109773. doi: 10.1016/j.celrep.2021.109773
Tamboli CP Neut C Desreumaux P Colombel JF. Dysbiosis in inflammatory bowel disease. Gut (2004) 53(1):1–4. doi: 10.1136/gut.53.1.1
Trebicka J Macnaughtan J Schnabl B Shawcross DL Bajaj JS. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol (2021) 75 Suppl 1(Suppl 1):S67–81. doi: 10.1016/j.jhep.2020.11.013
Bajaj JS Heuman DM Hylemon PB Sanyal AJ White MB Monteith P et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol (2014) 60(5):940–7. doi: 10.1016/j.jhep.2013.12.019
Kolata J Bode LG Holtfreter S Steil L Kusch H Holtfreter B et al. Distinctive patterns in the human antibody response to staphylococcus aureus bacteremia in carriers and non-carriers. Proteomics (2011) 11(19):3914–27. doi: 10.1002/pmic.201000760
Lodes MJ Cong Y Elson CO Mohamath R Landers CJ Targan SR et al. Bacterial flagellin is a dominant antigen in crohn disease. J Clin Invest (2004) 113(9):1296–306. doi: 10.1172/JCI200420295
Yonker LM Gilboa T Ogata AF Senussi Y Lazarovits R Boribong BP et al. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. J Clin Invest (2021) 131(14):e149633. doi: 10.1172/JCI149633
Miller J Cantor A Zachariah P Ahn D Martinez M Margolis K. Gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children (MIS-c) that is related to COVID-19: a single center experience of 44 cases. Gastroenterology (2020) 159(4):P1571–4.E2. doi: 10.1093/jpids/piaa161
Morparia K Park MJ Kalyanaraman M McQueen D Bergel M Phatak T. Abdominal imaging findings in critically ill children with multisystem inflammatory syndrome associated with COVID-19. Pediatr Infect Dis J (2021) 40(2):e82–e3. doi: 10.1097/INF.0000000000002967
Sahn B Eze OP Edelman MC Chougar CE Thomas RM Schleien CL et al. Features of intestinal disease associated with COVID-related multisystem inflammatory syndrome in children. J Pediatr Gastroenterol Nutr (2021) 72(3):384–7. doi: 10.1097/MPG.0000000000002953
Xing YH Ni W Wu Q Li WJ Li GJ Wang WD et al. Prolonged viral shedding in feces of pediatric patients with coronavirus disease 2019. J Microbiol Immunol Infect (2020) 53(3):473–80. doi: 10.1016/j.jmii.2020.03.021
Matthai J Shanmugam N Sobhan P Indian Society of Pediatric Gastroenterology H, Nutrition, and Pediatric Gastroenterology Chapter of Indian Academy of P. Coronavirus disease (COVID-19) and the gastrointestinal system in children. Indian Pediatr (2020) 57(6):533–5. doi: 10.1007/s13312-020-1851-5
Xu Y Li X Zhu B Liang H Fang C Gong Y et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med (2020) 26(4):502–5. doi: 10.1038/s41591-020-0817-4
Gaebler C Wang Z Lorenzi JCC Muecksch F Finkin S Tokuyama M et al. Evolution of antibody immunity to SARS-CoV-2. Nature (2021) 591(7851):639–44. doi: 10.1038/s41586-021-03207-w
Veraldi N Vives RR Blanchard-Rohner G L'Huillier AG Wagner N Rohr M et al. Endothelial glycocalyx degradation in multisystem inflammatory syndrome in children related to COVID-19. J Mol Med (Berl) (2022) 100(5):735–46. doi: 10.1007/s00109-022-02190-7
Noval Rivas M Porritt RA Cheng MH Bahar I Arditi M. Multisystem inflammatory syndrome in children and long COVID: The SARS-CoV-2 viral superantigen hypothesis. Front Immunol (2022) 13:941009. doi: 10.3389/fimmu.2022.941009
Swank Z Senussi Y Manickas-Hill Z Yu XG Li JZ Alter G et al. Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clin Infect Dis (2023) 76(3):e487–e90. doi: 10.1093/cid/ciac722
Sterlin D Mathian A Miyara M Mohr A Anna F Claer L et al. IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci Transl Med (2021) 13(577). doi: 10.1126/scitranslmed.abd2223
