Comparative Study

. 2021 Jul 1;385(1):23-34.

doi: 10.1056/NEJMoa2102605. Epub 2021 Jun 16.

Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes

Mary Beth F Son¹, Nancy Murray¹, Kevin Friedman¹, Cameron C Young¹, Margaret M Newhams¹, Leora R Feldstein¹, Laura L Loftis¹, Keiko M Tarquinio¹, Aalok R Singh¹, Sabrina M Heidemann¹, Vijaya L Soma¹, Becky J Riggs¹, Julie C Fitzgerald¹, Michele Kong¹, Sule Doymaz¹, John S Giuliano Jr¹, Michael A Keenaghan¹, Janet R Hume¹, Charlotte V Hobbs¹, Jennifer E Schuster¹, Katharine N Clouser¹, Mark W Hall¹, Lincoln S Smith¹, Steven M Horwitz¹, Stephanie P Schwartz¹, Katherine Irby¹, Tamara T Bradford¹, Aline B Maddux¹, Christopher J Babbitt¹, Courtney M Rowan¹, Gwenn E McLaughlin¹, Phoebe H Yager¹, Mia Maamari¹, Elizabeth H Mack¹, Christopher L Carroll¹, Vicki L Montgomery¹, Natasha B Halasa¹, Natalie Z Cvijanovich¹, Bria M Coates¹, Charles E Rose¹, Jane W Newburger¹, Manish M Patel¹, Adrienne G Randolph¹; Overcoming COVID-19 Investigators

Collaborators, Affiliations

Collaborators

Overcoming COVID-19 Investigators:
Michele Kong, Mary Glas Gaspers, Katri V Typpo, Ronald C Sanders Jr, Katherine Irby, Adam J Schwarz, Christopher J Babbitt, Natalie Z Cvijanovich, Matt S Zinter, Aline B Maddux, Peter M Mourani, Christopher L Carroll, John S Giuliano Jr, Gwenn E McLaughlin, Keiko M Tarquinio, Kelly N Michelson, Bria M Coates, Courtney M Rowan, Kari Wellnitz, Guru Bhoojhawon, Janice E Sullivan, Vicki L Montgomery, Kevin M Havlin, Tamara T Bradford, Becky J Riggs, Melania M Bembea, Ana Lia Graciano, Susan V Lipton, Kimberly L Marohn, Adrienne G Randolph, Margaret M Newhams, Sabrina R Chen, Cameron C Young, Suden Kucukak, Katherine Kester, Jane W Newburger, Kevin G Friedman, Mary Beth F Son, Janet Chou, Ryan W Carroll, Phoebe H Yager, Neil D Fernandes, Sabrina M Heidemann, Heidi R Flori, Janet R Hume, Emily R Levy, Charlotte V Hobbs, Jennifer E Schuster, Philip C Spinella, Melissa L Cullimore, Russell J McCulloh, Katharine N Clouser, Rowan F Walsh, Lawrence C Kleinman, Simon Li, Steven M Horwitz, Shira J Gertz, Kate G Ackerman, Jill M Cholette, Michael A Keenaghan, Aalok R Singh, Sheemon P Zackai, Jennifer K Gillen, Adam J Ratner, Heda Dapul, Vijaya L Soma, Ilana Harwayne-Gidansky, Saul R Hymes, Sule Doymaz, Stephanie P Schwartz, Tracie C Walker, Steven L Shein, Amanda N Lansell, Mark W Hall, Mary A Staat, Julie C Fitzgerald, Jenny L Bush, Ryan H Burnett, Neal J Thomas, Monica L Koncicki, Ericka L Fink, Joseph A Carcillo, Elizabeth H Mack, Laura Smallcomb, Natasha B Halasa, Dai Kimura, Laura L Loftis, Alvaro Coronado Munoz, Mia Maamari, Cindy Bowens, Hillary Crandall, Lincoln S Smith, John K McGuire, Manish M Patel, Leora R Feldstein, Mark W Tenforde, Ashley M Jackson, Nancy Murray, Charles E Rose

Affiliation

¹ From the Division of Immunology (M.B.F.S.), and the Departments of Cardiology (K.F., J.W.N.) and Anesthesiology, Critical Care, and Pain Medicine (C.C.Y., M.M.N., A.G.R.), Boston Children's Hospital, the Division of Pediatric Critical Care Medicine, MassGeneral Hospital for Children (P.H.Y.), and the Departments of Anesthesia (A.G.R.) and Pediatrics (M.B.F.S., K.F., P.H.Y., J.W.N., A.G.R.), Harvard Medical School - all in Boston; the COVID-19 Response Team, Centers for Disease Control and Prevention (N.M., L.R.F., C.E.R., M.M.P.), and the Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta (K.M.T.) - both in Atlanta; the Commissioned Corps of the U.S. Public Health Service, Rockville (L.R.F., M.M.P.), and the Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore (B.J.R.) - both in Maryland; the Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston (L.L.L.); the Department of Pediatrics, Division of Critical Care Medicine, University of Texas Southwestern, Children's Medical Center of Dallas, Dallas (M.M.); the Pediatric Critical Care Division, Maria Fareri Children's Hospital at Westchester Medical Center and New York Medical College, Valhalla (A.R.S.), the Division of Pediatric Infectious Diseases, Department of Pediatrics, New York University Grossman School of Medicine, New York (V.L.S.), and the Division of Pediatric Critical Care, Department of Pediatrics, State University of New York Downstate Health Sciences University (S.D.), and Pediatric Critical Care, New York City Health and Hospitals, Kings County Hospital (M.A.K.), Brooklyn - all in New York; the Department of Pediatrics, Division of Pediatric Critical Care Medicine, Central Michigan University, Detroit (S.M. Heidemann); the Division of Critical Care, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia (J.C.F.); the Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham (M.K.); the Department of Pediatrics, Division of Critical Care, Yale University School of Medicine, New Haven (J.S.G.), and the Division of Critical Care, Connecticut Children's, Hartford (C.L.C.) - both in Connecticut; the Division of Pediatric Critical Care, M Health Fairview University of Minnesota Masonic Children's Hospital, Minneapolis (J.R.H.); the Department of Pediatrics, Department of Microbiology, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson (C.V.H.); the Division of Pediatric Infectious Diseases, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO (J.E.S.); the Department of Pediatrics, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center, Hackensack (K.N.C.), and the Department of Pediatrics, Division of Pediatric Critical Care, Bristol-Myers Squibb Children's Hospital at Robert Wood Johnson Medical School, Rutger's University, New Brunswick (S.M. Horwitz) - both in New Jersey; the Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH (M.W.H.); the Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Washington, Seattle (L.S.S.); the Department of Pediatrics, University of North Carolina Children's Hospital, Chapel Hill (S.P.S.); the Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children's Hospital, Little Rock (K.I.); the Department of Pediatrics, Division of Cardiology, Louisiana State University Health Sciences Center and Children's Hospital of New Orleans, New Orleans (T.T.B.); the Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora (A.B.M.); the Division of Pediatric Critical Care, Miller Children's and Women's Hospital of Long Beach, Long Beach (C.J.B.), and the Division of Critical Care Medicine, University of California San Francisco Benioff Children's Hospital Oakland, Oakland (N.Z.C.) - both in California; the Division of Pediatric Critical Care Medicine, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis (C.M.R.); the Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Miami Miller School of Medicine, Miami (G.E.M.); the Division of Pediatric Critical Care Medicine, Medical University of South Carolina, Charleston (E.H.M.); the Department of Pediatrics, University of Louisville and Norton Children's Hospital, Louisville, KY (V.L.M.); the Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville (N.B.H.); and the Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago (B.M.C.).

PMID: 34133855
PMCID: PMC8220972
DOI: 10.1056/NEJMoa2102605

Comparative Study

Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes

Mary Beth F Son et al. N Engl J Med. 2021.

. 2021 Jul 1;385(1):23-34.

doi: 10.1056/NEJMoa2102605. Epub 2021 Jun 16.

Authors

Collaborators

Overcoming COVID-19 Investigators:
Michele Kong, Mary Glas Gaspers, Katri V Typpo, Ronald C Sanders Jr, Katherine Irby, Adam J Schwarz, Christopher J Babbitt, Natalie Z Cvijanovich, Matt S Zinter, Aline B Maddux, Peter M Mourani, Christopher L Carroll, John S Giuliano Jr, Gwenn E McLaughlin, Keiko M Tarquinio, Kelly N Michelson, Bria M Coates, Courtney M Rowan, Kari Wellnitz, Guru Bhoojhawon, Janice E Sullivan, Vicki L Montgomery, Kevin M Havlin, Tamara T Bradford, Becky J Riggs, Melania M Bembea, Ana Lia Graciano, Susan V Lipton, Kimberly L Marohn, Adrienne G Randolph, Margaret M Newhams, Sabrina R Chen, Cameron C Young, Suden Kucukak, Katherine Kester, Jane W Newburger, Kevin G Friedman, Mary Beth F Son, Janet Chou, Ryan W Carroll, Phoebe H Yager, Neil D Fernandes, Sabrina M Heidemann, Heidi R Flori, Janet R Hume, Emily R Levy, Charlotte V Hobbs, Jennifer E Schuster, Philip C Spinella, Melissa L Cullimore, Russell J McCulloh, Katharine N Clouser, Rowan F Walsh, Lawrence C Kleinman, Simon Li, Steven M Horwitz, Shira J Gertz, Kate G Ackerman, Jill M Cholette, Michael A Keenaghan, Aalok R Singh, Sheemon P Zackai, Jennifer K Gillen, Adam J Ratner, Heda Dapul, Vijaya L Soma, Ilana Harwayne-Gidansky, Saul R Hymes, Sule Doymaz, Stephanie P Schwartz, Tracie C Walker, Steven L Shein, Amanda N Lansell, Mark W Hall, Mary A Staat, Julie C Fitzgerald, Jenny L Bush, Ryan H Burnett, Neal J Thomas, Monica L Koncicki, Ericka L Fink, Joseph A Carcillo, Elizabeth H Mack, Laura Smallcomb, Natasha B Halasa, Dai Kimura, Laura L Loftis, Alvaro Coronado Munoz, Mia Maamari, Cindy Bowens, Hillary Crandall, Lincoln S Smith, John K McGuire, Manish M Patel, Leora R Feldstein, Mark W Tenforde, Ashley M Jackson, Nancy Murray, Charles E Rose

Affiliation

¹ From the Division of Immunology (M.B.F.S.), and the Departments of Cardiology (K.F., J.W.N.) and Anesthesiology, Critical Care, and Pain Medicine (C.C.Y., M.M.N., A.G.R.), Boston Children's Hospital, the Division of Pediatric Critical Care Medicine, MassGeneral Hospital for Children (P.H.Y.), and the Departments of Anesthesia (A.G.R.) and Pediatrics (M.B.F.S., K.F., P.H.Y., J.W.N., A.G.R.), Harvard Medical School - all in Boston; the COVID-19 Response Team, Centers for Disease Control and Prevention (N.M., L.R.F., C.E.R., M.M.P.), and the Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta (K.M.T.) - both in Atlanta; the Commissioned Corps of the U.S. Public Health Service, Rockville (L.R.F., M.M.P.), and the Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore (B.J.R.) - both in Maryland; the Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston (L.L.L.); the Department of Pediatrics, Division of Critical Care Medicine, University of Texas Southwestern, Children's Medical Center of Dallas, Dallas (M.M.); the Pediatric Critical Care Division, Maria Fareri Children's Hospital at Westchester Medical Center and New York Medical College, Valhalla (A.R.S.), the Division of Pediatric Infectious Diseases, Department of Pediatrics, New York University Grossman School of Medicine, New York (V.L.S.), and the Division of Pediatric Critical Care, Department of Pediatrics, State University of New York Downstate Health Sciences University (S.D.), and Pediatric Critical Care, New York City Health and Hospitals, Kings County Hospital (M.A.K.), Brooklyn - all in New York; the Department of Pediatrics, Division of Pediatric Critical Care Medicine, Central Michigan University, Detroit (S.M. Heidemann); the Division of Critical Care, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia (J.C.F.); the Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham (M.K.); the Department of Pediatrics, Division of Critical Care, Yale University School of Medicine, New Haven (J.S.G.), and the Division of Critical Care, Connecticut Children's, Hartford (C.L.C.) - both in Connecticut; the Division of Pediatric Critical Care, M Health Fairview University of Minnesota Masonic Children's Hospital, Minneapolis (J.R.H.); the Department of Pediatrics, Department of Microbiology, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson (C.V.H.); the Division of Pediatric Infectious Diseases, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO (J.E.S.); the Department of Pediatrics, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center, Hackensack (K.N.C.), and the Department of Pediatrics, Division of Pediatric Critical Care, Bristol-Myers Squibb Children's Hospital at Robert Wood Johnson Medical School, Rutger's University, New Brunswick (S.M. Horwitz) - both in New Jersey; the Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH (M.W.H.); the Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Washington, Seattle (L.S.S.); the Department of Pediatrics, University of North Carolina Children's Hospital, Chapel Hill (S.P.S.); the Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children's Hospital, Little Rock (K.I.); the Department of Pediatrics, Division of Cardiology, Louisiana State University Health Sciences Center and Children's Hospital of New Orleans, New Orleans (T.T.B.); the Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora (A.B.M.); the Division of Pediatric Critical Care, Miller Children's and Women's Hospital of Long Beach, Long Beach (C.J.B.), and the Division of Critical Care Medicine, University of California San Francisco Benioff Children's Hospital Oakland, Oakland (N.Z.C.) - both in California; the Division of Pediatric Critical Care Medicine, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis (C.M.R.); the Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Miami Miller School of Medicine, Miami (G.E.M.); the Division of Pediatric Critical Care Medicine, Medical University of South Carolina, Charleston (E.H.M.); the Department of Pediatrics, University of Louisville and Norton Children's Hospital, Louisville, KY (V.L.M.); the Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville (N.B.H.); and the Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago (B.M.C.).

PMID: 34133855
PMCID: PMC8220972
DOI: 10.1056/NEJMoa2102605

Abstract

Background: The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy.

Methods: We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2.

Results: A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis.

Conclusions: Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.).

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Figures

**Figure 1. Patients with MIS-C Treated with Immunomodulatory Therapies in the Overcoming COVID-19 Surveillance Registry.**
Among the 65 patients who received initial treatment with intravenous immune globulin (IVIG) plus glucocorticoids, followed by adjunctive treatment on or after day 1, adjunctive treatment consisted of a second dose of IVIG in 35 patients, a biologic alone in 16 patients, and a second dose of IVIG plus a biologic in 14 patients. Among the 121 patients who received initial treatment with IVIG alone, followed by adjunctive treatment on or after day 1, adjunctive treatment consisted of glucocorticoids alone in 63 patients; a second dose of IVIG in 15 patients; a biologic alone in 8 patients; glucocorticoids and a second dose of IVIG in 19 patients; glucocorticoids, a second dose of IVIG, and a biologic in 14 patients; and a second dose of IVIG and a biologic in 2 patients. MIS-C denotes multisystem inflammatory syndrome in children.

**Figure 2. Immunomodulatory Treatments Received during Hospitalization and Indicators of Clinical Severity.**
Panel A shows the extent of variability in immunomodulatory treatment that patients with MIS-C received during hospitalization. Panel B shows the distribution of patients whose hospital course included indicators of clinical severity of illness, according to immunomodulatory treatments received during hospitalization. Left ventricular ejection fraction (LVEF) was measured by means of echocardiography. ICU denotes intensive care unit.

**Figure 3. Associations between Initial Treatment with IVIG plus Glucocorticoids, or with IVIG Alone, and Clinical Outcomes.**
Cardiovascular dysfunction was based on a composite of left ventricular dysfunction or shock that resulted in the use of vasopressors on or after day 2 after initial treatment. Left ventricular dysfunction was defined as an LVEF below 55%. Medications that met the study criterion of vasopressor use were dobutamine, dopamine, epinephrine, norepinephrine, or a combination of these. Adjunctive immunomodulatory therapy included a second dose of IVIG, glucocorticoids, or biologic treatment on or after day 1. Persistent or recurrent fever was defined as a body temperature of higher than 38.0°C on or after day 2.

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Comment in

Immunotherapy for MIS-C - IVIG, Glucocorticoids, and Biologics.
DeBiasi RL. DeBiasi RL. N Engl J Med. 2021 Jul 1;385(1):74-75. doi: 10.1056/NEJMe2108276. Epub 2021 Jun 16. N Engl J Med. 2021. PMID: 34133878 Free PMC article. No abstract available.
Therapy for Multisystem Inflammatory Syndrome in Children.
Harley JB. Harley JB. N Engl J Med. 2021 Sep 23;385(13):e42. doi: 10.1056/NEJMc2111096. Epub 2021 Aug 11. N Engl J Med. 2021. PMID: 34379918 No abstract available.
Therapy for Multisystem Inflammatory Syndrome in Children.
Ouldali N, Belot A, Angoulvant F. Ouldali N, et al. N Engl J Med. 2021 Sep 23;385(13):e42. doi: 10.1056/NEJMc2111096. Epub 2021 Aug 11. N Engl J Med. 2021. PMID: 34379919 No abstract available.

References

1. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 2020;383:334-346. - PMC - PubMed
1. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 2020;395:1607-1608. - PMC - PubMed
1. 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;395:1771-1778. - PMC - PubMed
1. Valverde I, Singh Y, Sanchez-de-Toledo J, et al. Acute cardiovascular manifestations in 286 children with multisystem inflammatory syndrome associated with COVID-19 infection in Europe. Circulation 2021;143:21-32. - PubMed
1. Kanegaye JT, Wilder MS, Molkara D, et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics 2009;123(5):e783-e789. - PMC - PubMed

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Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes

Collaborators

Affiliation

Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes

Authors

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Affiliation

Abstract

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Comment in

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Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical