EClinicalMedicine (Oct 2021)
Data-driven clustering identifies features distinguishing multisystem inflammatory syndrome from acute COVID-19 in children and adolescents
- Alon Geva,
- Manish M. Patel,
- Margaret M. Newhams,
- Cameron C. Young,
- Mary Beth F. Son,
- Michele Kong,
- Aline B. Maddux,
- Mark W. Hall,
- Becky J. Riggs,
- Aalok R. Singh,
- John S. Giuliano,
- Charlotte V. Hobbs,
- Laura L. Loftis,
- Gwenn E. McLaughlin,
- Stephanie P. Schwartz,
- Jennifer E. Schuster,
- Christopher J. Babbitt,
- Natasha B. Halasa,
- Shira J. Gertz,
- Sule Doymaz,
- Janet R. Hume,
- Tamara T. Bradford,
- Katherine Irby,
- Christopher L. Carroll,
- John K. McGuire,
- Keiko M. Tarquinio,
- Courtney M. Rowan,
- Elizabeth H. Mack,
- Natalie Z. Cvijanovich,
- Julie C. Fitzgerald,
- Philip C. Spinella,
- Mary A. Staat,
- Katharine N. Clouser,
- Vijaya L. Soma,
- Heda Dapul,
- Mia Maamari,
- Cindy Bowens,
- Kevin M. Havlin,
- Peter M. Mourani,
- Sabrina M. Heidemann,
- Steven M. Horwitz,
- Leora R. Feldstein,
- Mark W. Tenforde,
- Jane W. Newburger,
- Kenneth D. Mandl,
- Adrienne G. Randolph
Affiliations
- Alon Geva
- Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital, Boston,1 These authors contributed equally to this work.2 A complete list of members and affiliations is provided in the Supplementary Appendix. MA, USA; Computational Health Informatics Program, Boston Children's Hospital, Boston, MA; Department of Anaesthesia, Harvard Medical School, Boston, MA, USA
- Manish M. Patel
- COVID-19 Response, Centers for Disease Control and Prevention, Atlanta, GA, USA; Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, USA
- Margaret M. Newhams
- Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital, Boston,1 These authors contributed equally to this work.2 A complete list of members and affiliations is provided in the Supplementary Appendix. MA, USA
- Cameron C. Young
- Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital, Boston,1 These authors contributed equally to this work.2 A complete list of members and affiliations is provided in the Supplementary Appendix. MA, USA
- Mary Beth F. Son
- Department of Pediatrics, Division of Immunology, Boston Children's Hospital, Boston, MA, USA
- Michele Kong
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
- Aline B. Maddux
- Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA
- Mark W. Hall
- Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA
- Becky J. Riggs
- Department of Anesthesiology and Critical Care Medicine; Division of Pediatric Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Aalok R. Singh
- Pediatric Critical Care Division, Maria Fareri Children's Hospital at Westchester Medical Center and New York Medical College, Valhalla, NY, USA
- John S. Giuliano
- Department of Pediatrics, Division of Critical Care, Yale University School of Medicine, New Haven, CT, USA
- Charlotte V. Hobbs
- Department of Pediatrics, Division of Disease; Microbiology; University of Mississippi Medical Center, Jackson, MS, USA
- Laura L. Loftis
- Section of Critical Care Medicine, Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
- Gwenn E. McLaughlin
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA
- Stephanie P. Schwartz
- Department of Pediatrics, University of North Carolina at Chapel Hill Children's Hospital, Chapel Hill, NC, USA
- Jennifer E. Schuster
- Division of Pediatric Infectious Disease, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA
- Christopher J. Babbitt
- Miller Children's and Women's Hospital of Long Beach, Long Beach, CA, USA
- Natasha B. Halasa
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
- Shira J. Gertz
- Division of Pediatric Critical Care, Department of Pediatrics, Saint Barnabas Medical Center, Livingston, NJ, USA
- Sule Doymaz
- Division of Pediatric Critical Care, Department of Pediatrics, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
- Janet R. Hume
- Division of Pediatric Critical Care, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA
- Tamara T. Bradford
- Department of Pediatrics, Division of Cardiology, Louisiana State University Health Sciences Center and Children's Hospital of New Orleans, New Orleans, LA, USA
- Katherine Irby
- Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children's Hospital, Little Rock, AR, USA
- Christopher L. Carroll
- Division of Critical Care, Connecticut Children's, Hartford, CT, USA
- John K. McGuire
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, Seattle Children's Hospital and the University of Washington, Seattle, WA, USA
- Keiko M. Tarquinio
- Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA, USA
- Courtney M. Rowan
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA
- Elizabeth H. Mack
- Division of Pediatric Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USA
- Natalie Z. Cvijanovich
- Division of Critical Care Medicine, UCSF Benioff Children's Hospital Oakland, CA, USA
- Julie C. Fitzgerald
- Division of Critical Care, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Philip C. Spinella
- Division of Critical Care, Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis, MO, USA
- Mary A. Staat
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Katharine N. Clouser
- Department of Pediatrics, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
- Vijaya L. Soma
- Department of Pediatrics, Division of Infectious Diseases, New York University Grossman School of Medicine and Hassenfeld Children's Hospital, New York, NY, USA
- Heda Dapul
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, New York University Grossman School of Medicine and Hassenfeld Children's Hospital, New York, NY, USA
- Mia Maamari
- Department of Pediatrics, Division of Critical Care Medicine, University of Texas Southwestern, Children's Health Medical Center Dallas, TX, USA
- Cindy Bowens
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Louisville, and Norton Children's Hospital, Louisville, KY, USA
- Kevin M. Havlin
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, Central Michigan University, Detroit, MI, USA
- Peter M. Mourani
- Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA
- Sabrina M. Heidemann
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, Central Michigan University, Detroit, MI, USA
- Steven M. Horwitz
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Leora R. Feldstein
- COVID-19 Response, Centers for Disease Control and Prevention, Atlanta, GA, USA; Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, USA
- Mark W. Tenforde
- COVID-19 Response, Centers for Disease Control and Prevention, Atlanta, GA, USA; Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, USA
- Jane W. Newburger
- Department of Cardiology, Boston Children's Hospital, Boston, MA, USA
- Kenneth D. Mandl
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA; Departments of Biomedical Informatics and Pediatrics, Harvard Medical School, Boston, MA, USA
- Adrienne G. Randolph
- Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital, Boston,1 These authors contributed equally to this work.2 A complete list of members and affiliations is provided in the Supplementary Appendix. MA, USA; Departments of Anaesthesia and Pediatrics, Harvard Medical School, Boston, MA, USA; Corresponding author at: Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital, Bader 634, 300 Longwood Avenue, Boston, MA 02115, USA.
- Journal volume & issue
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Vol. 40
p. 101112
Abstract
Background: Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia. Methods: We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians) <21 years old hospitalized with COVID-19-related illness admitted between 15 March 2020 and 31 December 2020. We compared prevalence of assigned MIS-C labels and clinical features among clusters, followed by recursive feature elimination to identify characteristics of potentially misclassified MIS-C-labeled patients. Findings: Of 94 clinical features tested, 46 were retained for clustering. Cluster 1 patients (N = 498; 92% labeled MIS-C) were mostly previously healthy (71%), with mean age 7·2 ± 0·4 years, predominant cardiovascular (77%) and/or mucocutaneous (82%) involvement, high inflammatory biomarkers, and mostly SARS-CoV-2 PCR negative (60%). Cluster 2 patients (N = 445; 27% labeled MIS-C) frequently had pre-existing conditions (79%, with 39% respiratory), were similarly 7·4 ± 2·1 years old, and commonly had chest radiograph infiltrates (79%) and positive PCR testing (90%). Cluster 3 patients (N = 583; 19% labeled MIS-C) were younger (2·8 ± 2·0 y), PCR positive (86%), with less inflammation. Radiographic findings of pulmonary infiltrates and positive SARS-CoV-2 PCR accurately distinguished cluster 2 MIS-C labeled patients from cluster 1 patients. Interpretation: Using a data driven, unsupervised approach, we identified features that cluster patients into a group with high likelihood of having MIS-C. Other features identified a cluster of patients more likely to have acute severe COVID-19 pulmonary disease, and patients in this cluster labeled by clinicians as MIS-C may be misclassified. These data driven phenotypes may help refine the diagnosis of MIS-C.
