//Background//---
Time
passes over 1.5 years after SARS-CoV-2 pandemic. Fortunately, the young persons
including the children and the neonates relatively have milder symptom than the
adult. However, as a rare symptom, MIS-C(multisystem inflammatory syndrome in
children) appeared(3-6). MIS-C typical symptoms is related to cardiovascular
system, such as shock, decreased function confirmed by echocardiographic
measurement, coronary-artery aneurysms(1). This symptom is similar to
Kawasaki’s disease, so the standard treatment for this disease, which is
intravenous immunoglobulin(IVIG)(7), is the first choice. However, there are
both clinical and immunophenotypic differences between MIS-C by SARS-CoV-2 and
Kawasaki’s disease(8-10). Therefore, we need to modify the standard treatment of
Kawasaki’s diseases in order to provide a proper treatment for the child
patients with MIS-C due to SARS infection. Glucocorticoids uses the treatment
for the adult with SARS infection especially in severe symptom and some
clinical benefits are confirmed(11). Therefore, Glucocorticoids plus IVIG
immunotherapy was adopted in some hospitals. Hence, evaluating superiority of
this combination therapy for the IVIG only treatment is crucial.
M.B.F.
Son, N. Murray et al.(1) and A.J. McArdle, O. Vito, H. Patel, E.G. Seaby et
al.(2) evaluate the clinical effect of these two therapies (Glucocorticoids+IVIG
and IVIG only) in a comparative manner(1,2).
//MIS-C criteria(1,12)//---
*Serious illness leading to hospitalization
*An age of less than 21 years, fever (body
temperature, >38.0°C) or report of subjective fever
lasting at least 24 hours,
*Laboratory evidence of inflammation
*Multisystem organ involvement (i.e.,
involving at least two organ systems),
*Laboratory-confirmed SARS-CoV-2 infection
(positive SARS-CoV-2 real-time reverse-transcriptasepolymerase-chain-reaction
[RT-PCR] or antibody test during hospitalization)
*An epidemiologic link to a person with
suspected or confirmed Covid-19 within 4 weeks before the onset of MIS-C
symptoms.
//Period, number and place(1,2)//---
(Ref.(1))
March 15 to October 31, 2020 / 518 patients /
58 U.S. hospitals
(Ref.(2))
June 20, 2020 to February 24, 2021 / 614 patients / 81 hospitals in 34
countries
//Age condition(1,2)//---
(Ref.(1))
Median Age(IQR) 8.9(4.4-12.1) / 7.0 (3.6-11.5)
-- Combination / IVIG only
(Ref.(2))
Median Age(IQR) 8.8(4.6-12.0) / 7.0 (3.7-11.0)
-- Combination / IVIG only
//Clinical outcomes(1)(See Figure 3)//---
Glucocorticoids+IVIG
--- IVIG alone (%)
Risk ratio left condition / right one (95% CI)
*Cardiovascular dysfunction 18/103(17%) ---
32/103 (31%)
Risk ratio 0.56 (0.34-0.94)
*Left ventricular dysfunction 6/75(8%) ---
13/75 (17%)
Risk ratio 0.46 (0.19-1.15)
*Shock resulting in vasopressor use 13/102(13%)
--- 24/102(24%)
Risk ratio 0.54 (0.29-1.00)
*Adjunctive immunomodulatory therapy
36/106(34%) --- 74/106(70%)
Risk ratio 0.49 (0.36-0.65)
* Persistent or recurrent fever 31/101(31%)
--- 40/101 (40%)
Risk ratio 0.78 (0.53-1.13)
//Clinical outcomes(2)(See Figure 2A)//---
Risk
ratio (IVIG plus Glucocorticoids versus IVIG Alone)
(Primary analyses)
*Respiratory support by day 2 or later or
death --- 0.77 (0.33–1.82)
*Severity-score reduction by day 2 --- 0.90
(0.48–1.69)
(Secondary analyses)
*Inotropic support by day 2 or later --- 1.43
(0.57–3.62)
*Mechanical ventilation by day 2 or later
--- 1.10 (0.39–3.09)
*Treatment escalation --- 0.18 (0.10–0.33)
*Treatment escalation on day 0 or day 1 ---
0.33 (0.16–0.71)
*Fever by day 2 or later --- 0.60 (0.31–1.17)
*Death --- 0.32 (0.05–1.86)
*Any deterioration --- 1.22 (0.55–2.71)
*Aneurysm --- 0.32 (0.03–3.21)
//Discussion and conclusion//---
From
two important clinical reports (M.B.F. Son et al.(1) and A.J. McArdle et
al.(2)), cardiovascular symptom of the child patients with MIS-C due to
SARS-CoV-2 infection is improved by the combination immunotherapy(Glucocorticoids+IVIG)
for IVIG only(1,2), but respiratory function typically confirmed in the
manifestation of SARS-CoV infection is not improved by the combination therapy.
This is due to IVIG therapy may not have specific clinical benefit to
SARS-CoV-2 respiratory symptom. If the antibody used in IVIG is specific to
SARS-CoV-2, the clinical result could be change also for the respiratory
symptom. Therefore, the choice of antibody in IVIG therapy may be important for
the future MIS-C clinical treatment in SARS-CoV-2 infection.
//Additional note(1)//---
From
April to October, the main choice for the treatment changes, and Glucocorticoids+IVIG
becomes dominant later.(See Figure 2A)
//Support(1,2)//---
Supported
by the Centers for Disease Control and Prevention under a contract with Boston
Children’s Hospital(1).
Supported
by the European Union’s Horizon 2020 Program under grants (848196 DIAMONDS and
668303 PERFORM, to Dr. Levin), by the Imperial Biomedical Research Centre (BRC)
of the National Institute for Health Research (NIHR) for the enrollment of
patients in London, by a grant (to Dr. McArdle) from the Lee Family Foundation,
a grant (203928/Z/16/Z, to Dr. Wilson) from the Wellcome Trust, a grant (RDA02,
to Dr. Broderick) from the Wellcome Trust and the BRC, grants (206508/Z/17/Z
and MRF-160-0008-ELP-KAFO-C0801, to Dr. Kaforou) from the Wellcome Trust and
the Medical Research Foundation, a grant (ACL-2018-021-007, to Dr. Nijman) from
the NIHR, and a grant (GA5R01AI128765, to Dr. Levin) from the National
Institutes of Health(2).
(Reference)
(1)
Mary Beth F. Son, M.D., Nancy Murray,
M.Sc., Kevin Friedman, M.D., Cameron C. Young, Margaret M. Newhams, M.P.H.,
Leora R. Feldstein, Ph.D., Laura L. Loftis, M.D., Keiko M. Tarquinio, M.D.,
Aalok R. Singh, M.D., Sabrina M. Heidemann, M.D., Vijaya L. Soma, M.D., Becky
J. Riggs, M.D., Julie C. Fitzgerald, M.D., Michele Kong, M.D., Sule Doymaz, M.D.,
John S. Giuliano, Jr., M.D., Michael A. Keenaghan, M.D., Janet R. Hume, M.D.,
Charlotte V. Hobbs, M.D., Jennifer E. Schuster, M.D., Katharine N. Clouser,
M.D., Mark W. Hall, M.D., Lincoln S. Smith, M.D., Steven M. Horwitz, M.D.,
Stephanie P. Schwartz, M.D., Katherine Irby, M.D., Tamara T. Bradford, M.D.,
Aline B. Maddux, M.D., Christopher J. Babbitt, M.D., Courtney M. Rowan, M.D.,
Gwenn E. McLaughlin, M.D., Phoebe H. Yager, M.D., Mia Maamari, M.D., Elizabeth
H. Mack, M.D., Christopher L. Carroll, M.D., Vicki L. Montgomery, M.D., Natasha
B. Halasa, M.D., Natalie Z. Cvijanovich, M.D., Bria M. Coates, M.D., Charles E.
Rose, Ph.D., Jane W. Newburger, M.D., M.P.H., Manish M. Patel, M.D., and
Adrienne G. Randolph, M.D. for the Overcoming COVID-19 Investigators*
Multisystem Inflammatory Syndrome in
Children — Initial Therapy and Outcomes
The New England Journal of Medicine 2021;
385:23-34
---
Author Affiliations
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.).
(2)
Andrew J. McArdle, M.B., B.Chir., Ortensia
Vito, M.Sc., Harsita Patel, M.B., B.S., Eleanor G. Seaby, B.M., B.S., Priyen
Shah, M.B., B.S., Clare Wilson, M.B., B.Chir., Claire Broderick, M.B., B.S.,
Ruud Nijman, M.D., Ph.D., Adriana H. Tremoulet, M.D., Daniel Munblit, M.D.,
Ph.D., Rolando Ulloa-Gutierrez, M.D., Michael J. Carter, B.M., B.Ch., D.Phil.,
Tisham De, Ph.D., Clive Hoggart, Ph.D., Elizabeth Whittaker, M.B., B.A.O.,
B.Ch., Ph.D., Jethro A. Herberg, Ph.D., Myrsini Kaforou, Ph.D., Aubrey J.
Cunnington, B.M., B.Ch., Ph.D., and Michael Levin, F.Med.Sci. for the BATS
Consortium*
Treatment of Multisystem Inflammatory
Syndrome in Children
The New England Journal of Medicine 2021;
385:11-22
---
Author Affiliations
From the Department of Infectious Disease,
Section of Pediatric Infectious Disease (A.J.M., O.V., H.P., E.G.S., P.S.,
C.W., C.B., R.N., T.D., E.W., J.A.H., M.K., A.J.C., M.L.), and the
Inflammation, Repair, and Development Section, National Heart and Lung
Institute, Faculty of Medicine (D.M.), Imperial College London, the Department
of Pediatrics, Imperial College Healthcare NHS Trust (R.N., E.W., J.A.H.,
A.J.C., M.L.), and the Department of Women and Children’s Health, School of
Life Course Sciences, King’s College London, St. Thomas’ Hospital (M.J.C.),
London, and the Genomic Informatics Group, University of Southampton,
Southampton (E.G.S.) — all in the United Kingdom; the Translational Genomics
Group, Broad Institute of MIT and Harvard, Cambridge, MA (E.G.S.); the
Department of Pediatrics, University of California, San Diego, and Rady
Children’s Hospital, San Diego (A.H.T.); the Department of Pediatrics and
Pediatric Infectious Diseases, Sechenov University, Moscow (D.M.); Servicio de
Infectología, Hospital Nacional de Niños Dr. Carlos Sáenz Herrera, Centro de
Ciencias Médicas, Caja Costarricense de Seguro Social, San José, Costa Rica
(R.U.-G.); and the Department of Genetics and Genomic Sciences, Icahn School of
Medicine at Mount Sinai, New York (C.H.).
(3)
Feldstein LR, Rose EB, Horwitz SM, et al.
Multisystem inflammatory syndrome in U.S.
children and adolescents.
N Engl J Med 2020; 383: 334-46.
(4)
Riphagen S, Gomez X, Gonzalez-Martinez C,
Wilkinson N, Theocharis P.
Hyperinflammatory shock in children during
COVID-19 pandemic.
Lancet
2020; 395: 1607-8.
(5)
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: 1771-8.
(6)
Dufort EM, Koumans EH, Chow EJ, et al.
Multisystem inflammatory syndrome in
children in New York State.
N Engl J Med 2020; 383: 347-58.
(7)
Feldstein LR, Tenforde MW, Friedman KG, et
al.
Characteristics and outcomes of US children
and adolescents with multisystem inflammatory syndrome in children (MIS-C)
compared with severe acute COVID-19.
JAMA 2021; 325: 1074-87.
(8)
Carter MJ, Fish M, Jennings A, et al.
Peripheral immunophenotypes in children
with multisystem inflammatory syndrome associated with
SARS-CoV-2 infection.
Nat Med 2020; 26: 1701-7.
(9)
Lee PY, Day-Lewis M, Henderson LA, et al.
Distinct clinical and immunological
features of SARS-CoV-2-induced multisys-tem inflammatory syndrome in children.
J Clin Invest 2020; 130: 5942-50.
(10)
Diorio C, Henrickson SE, Vella LA, et al.
Multisystem
inflammatory syndrome in children and COVID-19 are distinct
pre-sentations of SARS-CoV-2.
J Clin Invest 2020; 130: 5967-75.
(11)
The RECOVERY Collaborative Group*
Dexamethasone in Hospitalized Patients with
Covid-19
The New England Journal of Medicine 2021;
384:693-704
---
Author Affiliations
From the Nuffield Department of Medicine
(P.H.), Nuffield Department of Population Health (J.R.E., M.M., J.L.B., L.L.,
N.S., E.J., R.H., M.J.L.), and MRC Population Health Research Unit (J.R.E.,
N.S., R.H., M.J.L.), University of Oxford, the Oxford University Hospitals NHS
Foundation Trust (K.J.), and National Institute for Health Research (NIHR)
Oxford Biomedical Research Centre (M.J.L.), Oxford, the Respiratory Medicine
Department, Nottingham University Hospitals NHS Trust (W.S.L.), and the School
of Medicine, University of Nottingham (A.M.), Nottingham, the Institute for
Lung Health, Leicester NIHR Biomedical Research Centre, University of
Leicester, Leicester (C.B.), the Regional Infectious Diseases Unit, North
Manchester General Hospital and University of Manchester (A.U.), and the
University of Manchester and Manchester University NHS Foundation Trust (T.F.),
Manchester, the Research and Development Department, Northampton General
Hospital, Northampton (E.E.), the Department of Respiratory Medicine, North
Tees and Hartlepool NHS Foundation Trust, Stockton-on-Tees (B.P.), University
Hospitals Birmingham NHS Foundation Trust and Institute of Microbiology and
Infection, University of Birmingham, Birmingham (C.G.), the Centre for Clinical
Infection, James Cook University Hospital, Middlesbrough (D.C.), the North West
Anglia NHS Foundation Trust, Peterborough (K. Rege), the Department of Research
and Development, Cardiff and Vale University Health Board, Cardiff (C.F.), the
School of Life Course Sciences, King’s College London
(L.C.C.), and the Intensive Care National Audit and Research Centre (K. Rowan),
London, the NIHR Southampton Clinical Research Facility and Biomedical Research
Centre, University Hospital Southampton NHS Foundation Trust and University of
Southampton, Southampton (S.N.F.), the Department of Mathematics and
Statistics, Lancaster University, Lancaster (T.J.), the MRC Biostatistics Unit,
University of Cambridge, Cambridge (T.J.), and Roslin Institute, University of
Edinburgh, Edinburgh (J.K.B.) — all in the United Kingdom.
(12)
Centers for Disease Control and
Prevention. Multisystem inflammatory
syndrome in children (MIS-C) associated with coronavirus disease
2019 (COVID-19).
Emergency
preparedness and response: HAN00432. 2020 (https://emergency .
cdc .gov/ han/ 2020/
han00432 . asp).
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