Serologic and Cytokine Signatures in Children With Multisystem Inflammatory Syndrome and Coronavirus Disease 2019

Stacey A Lapp; Joseph Abrams; Austin T Lu; Laila Hussaini; Carol M Kao; David A Hunstad; Robert B Rosenberg; Marc J Zafferani; Kaleo C Ede; Wassim Ballan; Federico R Laham; Yajira Beltran; Hui-Mien Hsiao; Whitney Sherry; Elan Jenkins; Kaitlin Jones; Anna Horner; Alyssa Brooks; Bobbi Bryant; Lu Meng; Teresa A Hammett; Matthew E Oster; Sapna Bamrah-Morris; Shana Godfred-Cato; Ermias Belay; Ann Chahroudi; Evan J Anderson; Preeti Jaggi; Christina A Rostad

doi:10.1093/ofid/ofac070

Serologic and Cytokine Signatures in Children With Multisystem Inflammatory Syndrome and Coronavirus Disease 2019

Open Forum Infect Dis. 2022 Feb 24;9(3):ofac070. doi: 10.1093/ofid/ofac070. eCollection 2022 Mar.

Authors

Stacey A Lapp^{1

2}, Joseph Abrams³, Austin T Lu^{1

2}, Laila Hussaini^{1

2}, Carol M Kao⁴, David A Hunstad⁴, Robert B Rosenberg^{5

6}, Marc J Zafferani^{5

6}, Kaleo C Ede^{6

7}, Wassim Ballan^{6

8}, Federico R Laham⁹, Yajira Beltran⁹, Hui-Mien Hsiao^{1

2}, Whitney Sherry^{1

2}, Elan Jenkins^{1

2}, Kaitlin Jones², Anna Horner^{1

2}, Alyssa Brooks^{1

2}, Bobbi Bryant^{3

10}, Lu Meng^{3

11}, Teresa A Hammett³, Matthew E Oster^{1

2

3}, Sapna Bamrah-Morris³, Shana Godfred-Cato³, Ermias Belay³, Ann Chahroudi^{1

2}, Evan J Anderson^{1

2

12}, Preeti Jaggi^{1

2}, Christina A Rostad^{1

2}

Affiliations

¹ Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
² Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
³ COVID-19 Response Team, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
⁴ Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA.
⁵ Division of Pediatric Critical Care Medicine, Phoenix Children's Hospital, Phoenix, Arizona, USA.
⁶ Department of Child Health, University of Arizona, College of Medicine-Phoenix, Phoenix, Arizona, USA.
⁷ Division of Pediatric Rheumatology, Phoenix Children's Hospital, Phoenix, Arizona, USA.
⁸ Pediatric Infectious Diseases, Phoenix Children's Hospital, Phoenix, Arizona, USA.
⁹ Arnold Palmer Hospital for Children, Orlando, Florida, USA.
¹⁰ Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, USA.
¹¹ Apex Systems affiliated with General Dynamics Information Technology, Falls Church, Virginia, USA.
¹² Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

Abstract

Background: The serologic and cytokine responses of children hospitalized with multisystem inflammatory syndrome (MIS-C) vs coronavirus disease 2019 (COVID-19) are poorly understood.

Methods: We performed a prospective, multicenter, cross-sectional study of hospitalized children who met the Centers for Disease Control and Prevention case definition for MIS-C (n = 118), acute COVID-19 (n = 88), or contemporaneous healthy controls (n = 24). We measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) immunoglobulin G (IgG) titers and cytokine concentrations in patients and performed multivariable analysis to determine cytokine signatures associated with MIS-C. We also measured nucleocapsid IgG and convalescent RBD IgG in subsets of patients.

Results: Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG than children with acute COVID-19 (median, 2783 vs 146; P < .001), and titers correlated with nucleocapsid IgG. For patients with MIS-C, RBD IgG titers declined in convalescence (median, 2783 vs 1135; P = .010) in contrast to patients with COVID-19 (median, 146 vs 4795; P < .001). MIS-C was characterized by transient acute proinflammatory hypercytokinemia, including elevated levels of interleukin (IL) 6, IL-10, IL-17A, and interferon gamma (IFN-γ). Elevation of at least 3 of these cytokines was associated with significantly increased prevalence of prolonged hospitalization ≥8 days (prevalence ratio, 3.29 [95% CI, 1.17-9.23]).

Conclusions: MIS-C was associated with high titers of SARS-CoV-2 RBD IgG antibodies and acute hypercytokinemia with IL-6, IL-10, IL-17A, and IFN-γ.

Keywords: COVID-19; MIS-C; PIMS; SARS-CoV-2; children; cytokines; serology.