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      Multisystem Inflammatory Syndrome in Children — Initial Therapy and Outcomes

      research-article
      , M.D., , M.Sc., , M.D., , , M.P.H., , Ph.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , Ph.D., , M.D., M.P.H., , M.D., , M.D. *
      The New England Journal of Medicine
      Massachusetts Medical Society
      Keyword part (code): 4Keyword part (keyword): PediatricsKeyword part (code): 4_1Keyword part (keyword): Pediatrics GeneralKeyword part (code): 4_3Keyword part (keyword): Childhood Diseases , 4, Pediatrics, Keyword part (code): 4_1Keyword part (keyword): Pediatrics GeneralKeyword part (code): 4_3Keyword part (keyword): Childhood Diseases , 4_1, Pediatrics General, 4_3, Childhood Diseases, Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_12Keyword part (keyword): Coronavirus , 18, Infectious Disease, Keyword part (code): 18_12Keyword part (keyword): Coronavirus, 18_12, Coronavirus, Keyword part (code): 19Keyword part (keyword): Allergy/ImmunologyKeyword part (code): 19_1Keyword part (keyword): Allergy/Immunology General , 19, Allergy/Immunology, Keyword part (code): 19_1Keyword part (keyword): Allergy/Immunology General, 19_1, Allergy/Immunology General

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          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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          Most cited references26

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          Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

          Abstract Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)
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            Sensitivity Analysis in Observational Research: Introducing the E-Value.

            Sensitivity analysis is useful in assessing how robust an association is to potential unmeasured or uncontrolled confounding. This article introduces a new measure called the "E-value," which is related to the evidence for causality in observational studies that are potentially subject to confounding. The E-value is defined as the minimum strength of association, on the risk ratio scale, that an unmeasured confounder would need to have with both the treatment and the outcome to fully explain away a specific treatment-outcome association, conditional on the measured covariates. A large E-value implies that considerable unmeasured confounding would be needed to explain away an effect estimate. A small E-value implies little unmeasured confounding would be needed to explain away an effect estimate. The authors propose that in all observational studies intended to produce evidence for causality, the E-value be reported or some other sensitivity analysis be used. They suggest calculating the E-value for both the observed association estimate (after adjustments for measured confounders) and the limit of the confidence interval closest to the null. If this were to become standard practice, the ability of the scientific community to assess evidence from observational studies would improve considerably, and ultimately, science would be strengthened.
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              Multisystem Inflammatory Syndrome in U.S. Children and Adolescents

              Abstract Background Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. Methods We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. Results We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease–like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). Conclusions Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.)
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                Author and article information

                Journal
                N Engl J Med
                N Engl J Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                16 June 2021
                : NEJMoa2102605
                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.).
                Author notes
                Address reprint requests to Dr. Randolph, Boston Children’s Hospital, 300 Longwood Ave., Bader 634, Boston, MA 02115, or at adrienne.randolph@ 123456childrens.harvard.edu .
                [*]

                A complete list of the Overcoming COVID-19 Investigators is provided in the Supplementary Appendix, available at NEJM.org.

                Drs. Newburger, Patel, and Randolph contributed equally to this article.

                Author information
                http://orcid.org/0000-0002-4430-6760
                http://orcid.org/0000-0002-4071-0280
                http://orcid.org/0000-0002-6957-1624
                Article
                NJ202106163850104
                10.1056/NEJMoa2102605
                8220972
                34133855
                29bcf0b0-e450-460b-80e3-25f940f9216f
                Copyright © 2021 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

                History
                Funding
                Funded by: Centers for Disease Control and Prevention, FundRef http://dx.doi.org/10.13039/100000030;
                Categories
                Original Article
                Custom metadata
                2021-06-16T17:00:00-04:00
                2021
                06
                16
                17
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