¹COVID-19 Response Team, Centers for Disease Control and Prevention, Atlanta, Georgia
²Public Health Service Commissioned Corps, Rockville, Maryland
³Department of Cardiology, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
⁴Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts
⁵Division of Pediatric Critical Care Medicine, Department of Pediatrics, New York University Grossman School of Medicine, New York
⁶Division of Pediatric Infectious Diseases, Department of Pediatrics, New York University Grossman School of Medicine, New York
⁷Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora
⁸Division of Critical Care Medicine, Department of Pediatrics, University of Texas Southwestern, Children’s Medical Center Dallas, Dallas
⁹Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio
¹⁰Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
¹¹Division of Critical Care, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut
¹²Pediatric Critical Care Division, Maria Fareri Children’s Hospital at Westchester Medical Center and New York Medical College, Valhalla
¹³Department of Pediatrics, Division of Pediatric Critical Care, Bristol-Myers Squibb Children’s Hospital, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
¹⁴Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham
¹⁵Division of Pediatric Infectious Disease, Department of Pediatrics, Children’s Mercy Kansas City, Kansas City, Missouri
¹⁶Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida
¹⁷Department of Pediatrics, University of North Carolina at Chapel Hill Children’s Hospital
¹⁸Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
¹⁹Division of Infectious Diseases, Department of Pediatrics, Department of Microbiology, University of Mississippi Medical Center, Jackson
²⁰Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
²¹Division of Pediatric Critical Care, Department of Pediatrics, SUNY Downstate Health Sciences University, Brooklyn, New York
²²Division of Pediatric Critical Care, Miller Children’s and Women’s Hospital of Long Beach, Long Beach, California
²³Division of Pediatric Critical Care, University of Minnesota Masonic Children’s Hospital, Minneapolis
²⁴Division of Pediatric Critical Care, Department of Pediatrics, Saint Barnabas Medical Center, Livingston, New Jersey
²⁵Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children’s Hospital, Little Rock
²⁶Division of Hospital Medicine, Department of Pediatrics, Hackensack University Medical Center, Hackensack, New Jersey
²⁷Division of Critical Care Medicine, UCSF Benioff Children’s Hospital Oakland, Oakland, California
²⁸Division of Cardiology, Department of Pediatrics, Louisiana State University Health Sciences Center and Children’s Hospital of New Orleans, New Orleans
²⁹Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington, Seattle
³⁰Division of Pediatric Critical Care Medicine, Department of Pediatrics, Central Michigan University, Detroit
³¹Pediatric Critical Care Medicine, Department of Pediatrics, Icahn School of Medicine at the Mount Sinai Kravis Children’s Hospital, New York, New York
³²Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City
³³Division of Critical Care Medicine, Department of Pediatrics, Akron Children’s Hospital, Akron, Ohio
³⁴Department of Pediatrics, Division of Critical Care, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
³⁵Division of Pediatric Critical Care Medicine, MassGeneral Hospital for Children, Harvard Medical School, Boston, Massachusetts
³⁶Division of Pediatric Critical Care Medicine, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis
³⁷Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia
³⁸Division of Pediatric Critical Care Medicine, Medical University of South Carolina, Charleston
³⁹Division of Critical Care, Department of Anesthesiology and Critical Care, The University of Pennsylvania Perelman School of Medicine, Philadelphia
⁴⁰Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
⁴¹Division of Immunology, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
⁴²Departments of Anesthesia and Pediatrics, Harvard Medical School, Boston, Massachusetts

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Original Investigation

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Elizabeth Whittaker, MD; Alasdair Bamford, MD; Julia Kenny, MD; Myrsini Kaforou, PhD; Christine E. Jones, MD; Priyen Shah, MD; Padmanabhan Ramnarayan, MD; Alain Fraisse, MD; Owen Miller, MD; Patrick Davies, MD; Filip Kucera, MD; Joe Brierley, MD; Marilyn McDougall, MD; Michael Carter, MD; Adriana Tremoulet, MD; Chisato Shimizu, MD; Jethro Herberg, MD; Jane C. Burns, MD; Hermione Lyall, MD; Michael Levin, MD; for the PIMS-TS Study Group and EUCLIDS and PERFORM Consortia
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Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents

Eva W. Cheung, MD; Philip Zachariah, MD, MS; Mark Gorelik, MD; Alexis Boneparth, MD; Steven G. Kernie, MD; Jordan S. Orange, MD, PhD; Joshua D. Milner, MD
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Race/Ethnicity Among Children With COVID-19–Associated Multisystem Inflammatory Syndrome

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Association of IVIG Plus Methylprednisolone With Persistent or Recurrent Fever in Children With MIS-C

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Multisystem Inflammatory Syndrome in Children by COVID-19 Vaccination Status of Adolescents in France

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Multisystem Inflammatory Syndrome in Children During SARS-CoV-2 Pandemic Waves in Israel

Nitai Levy, MD; Jordanna H. Koppel, MD; Or Kaplan, MD; Hadas Yechiam, MD; Keren Shahar-Nissan, MD; Naama Kuchinski Cohen, MD; Itai Shavit, MD

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Key Points

Question How do the characteristics and outcomes of children and adolescents with multisystem inflammatory syndrome in children (MIS-C) compare with severe coronavirus disease 2019 (COVID-19)?

Findings In this case series that included 539 patients with MIS-C and 577 patients with severe COVID-19, patients with MIS-C were more likely than those with severe COVID-19 to be 6 to 12 years old, be non-Hispanic Black, and have severe cardiovascular or mucocutaneous involvement and more extreme inflammation.

Meaning The study findings suggest patterns of clinical presentation and organ involvement that distinguish between patients with MIS-C and severe acute COVID-19.

Abstract

Importance Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes.

Objective To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19).

Setting, Design, and Participants Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase–polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement.

Exposure SARS-CoV-2.

Main Outcomes and Measures Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19.

Results Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×10³ cells/μL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days.

Conclusions and Relevance This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.

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Article Information

Corresponding Author: Adrienne G. Randolph, MD, Boston Children’s Hospital, 300 Longwood Ave, Bader 634, Boston, MA 02115 (adrienne.randolph@childrens.harvard.edu).

Accepted for Publication: February 8, 2021.

Published Online: February 24, 2021. doi:10.1001/jama.2021.2091

Author Contributions: Dr Patel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Feldstein, Tenforde, and Friedman contributed equally, as did Drs Patel, Newburger, and Randolph.

Concept and design: Feldstein, Li, Walker, Hobbs, Halasa, Doymaz, Horwitz, Patel, Randolph.

Acquisition, analysis, or interpretation of data: Feldstein, Tenforde, Friedman, Newhams, Rose, Dapul, Soma, Maddux, Mourani, Bowens, Maamari, Hall, Riggs, Giuliano, Singh, Li, Kong, Schuster, McLaughlin, Schwartz, Loftis, Hobbs, Halasa, Babbitt, Hume, Gertz, Irby, Clouser, Cvijanovich, Bradford, Smith, Heidemann, Zackai, Wellnitz, Nofziger, Horwitz, Carroll, Rowan, Tarquinio, Mack, Fitzgerald, Coates, Jackson, Young, Son, Patel, Newburger, Randolph.

Drafting of the manuscript: Feldstein, Tenforde, Friedman, Rose, Doymaz, Jackson, Young, Patel, Newburger, Randolph.

Critical revision of the manuscript for important intellectual content: Feldstein, Tenforde, Friedman, Newhams, Dapul, Soma, Maddux, Mourani, Bowens, Maamari, Hall, Riggs, Giuliano, Singh, Li, Kong, Schuster, McLaughlin, Schwartz, Walker, Loftis, Hobbs, Halasa, Doymaz, Babbitt, Hume, Gertz, Irby, Clouser, Cvijanovich, Bradford, Smith, Heidemann, Zackai, Wellnitz, Nofziger, Horwitz, Carroll, Rowan, Tarquinio, Mack, Fitzgerald, Coates, Son, Patel, Newburger, Randolph.

Statistical analysis: Feldstein, Tenforde, Rose, Giuliano, Zackai, Jackson, Young, Randolph.

Obtained funding: Patel, Randolph.

Administrative, technical, or material support: Feldstein, Tenforde, Newhams, Rose, Dapul, Maamari, Hall, Riggs, Kong, McLaughlin, Schwartz, Loftis, Hobbs, Doymaz, Babbitt, Hume, Gertz, Irby, Bradford, Zackai, Wellnitz, Carroll, Fitzgerald, Coates, Son, Randolph.

Supervision: Feldstein, Friedman, Newhams, Singh, Hobbs, Cvijanovich, Horwitz, Carroll, Coates, Patel, Randolph.

Conflict of Interest Disclosures: Dr Maddux reported receiving grants from National Institutes of Health (NIH) (K23HD096018) and Francis Family Foundation (Parker B. Francis Fellowship) during the conduct of the study. Dr Mourani reported receiving grants from the NIH. Dr Hall reported receiving personal fees from LaJolla Pharmaceuticals for service on a data safety and monitoring board outside the submitted work. Dr Schuster reported receiving grants from Merck outside the submitted work. Dr Halasa reported receiving grants from Sanofi, Quindell, and Quidel; personal fees from Genentech (educational grant); and hemagglutination inhibition and microneutralization testing and vaccine donation from Sanofi outside the submitted work. Dr Cvijanovich reported receiving grants from Cincinnati Children’s Hospital Medical Center outside the submitted work. Dr Rowan reported receiving grants from the National Heart, Lung, and Blood Institute (K23HL150244-01A1) outside the submitted work. Dr Fitzgerald reported receiving grants from an NIH career development award outside the submitted work. Dr Newburger reported serving as chair of events adjudication committee for a trial on apixaban in children for Pfizer and Bristol-Myers Squibb, as chair of events adjudication committee for a trial of Entresto in children for Novartis, and as a steering committee member for a trial of endoxaban for Daiichi-Sankyo outside the submitted work. Dr Randolph reported receiving royalties from UpToDate and personal fees from LaJolla Pharma Inc outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by the Centers for Disease Control and Prevention (CDC) under a contract to Boston Children’s Hospital.

Role of the Funder/Sponsor: The CDC designed and conducted the study; collected, managed, analyzed, and interpreted the data; prepared, reviewed, and approved the manuscript; and had a role in the decision to submit the manuscript for publication and journal choice, and had the right to veto publication.

Group Information: The Overcoming COVID-19 Investigators are listed in the eAppendix in the Supplement.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.

Additional Contributions: We appreciate and thank the many research coordinators at the Overcoming COVID-19 hospitals who assisted in data collection for this study. We thank the leadership of the Pediatric Acute Lung Injury and Sepsis Investigator’s (PALISI) Network for their ongoing support.

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