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      Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: immunological mechanisms, clinical manifestations and management

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          Abstract

          Multisystem inflammatory syndrome (MIS-C) is a pediatric hyperinflammation disorder caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It has now been reported from several countries the world over. Some of the clinical manifestations of MIS-C mimic Kawasaki disease (KD) shock syndrome. MIS-C develops 4–6 weeks following SARS-CoV-2 infection, and is presumably initiated by adaptive immune response. Though it has multisystem involvement, it is the cardiovascular manifestations that are most prominent. High titres of anti-SARS-CoV-2 antibodies are seen in these patients. As this is a new disease entity, its immunopathogenesis is not fully elucidated. Whether it has some overlap with KD is still unclear. Current treatment guidelines recommend use of intravenous immunoglobulin and high-dose corticosteroids as first-line treatment. Mortality rates of MIS-C are lower compared to adult forms of severe COVID-19 disease.

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          The online version of this article (10.1007/s00296-020-04749-4) contains supplementary material, which is available to authorized users.

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)
          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
          Article 0 comments Cited 9909 times – based on 0 reviews     Review now
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            Antibody responses to SARS-CoV-2 in patients with COVID-19

            Quan-Xin Long, Bai-Zhong Liu, Hai-Jun Deng … (2020)
            We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.
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              Multisystem Inflammatory Syndrome in U.S. Children and Adolescents

              Leora Feldstein, Erica Rose, Steven M. Horwitz … (2020)
              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

                Contributors
                Debashish Danda:
                ORCID: http://orcid.org/0000-0002-2121-0942
                debashisdandacmc@hotmail.com
                Surjit Singh:
                ORCID: http://orcid.org/0000-0002-6716-1883
                surjitsinghpgi@rediffmail.com
                Journal
                Journal ID (nlm-ta): Rheumatol Int
                Journal ID (iso-abbrev): Rheumatol Int
                Title: Rheumatology International
                Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )
                ISSN (Print): 0172-8172
                ISSN (Electronic): 1437-160X
                Publication date (Electronic): 21 November 2020
                Pages: 1-14
                Affiliations
                [1 ]GRID grid.11586.3b, ISNI 0000 0004 1767 8969, Department of Clinical Immunology and Rheumatology, , Christian Medical College and Hospital, ; Vellore, Tamil Nadu 632004 India
                [2 ]GRID grid.415131.3, ISNI 0000 0004 1767 2903, Allergy Immunology Unit, Department of Pediatrics and Chief, Advanced Pediatrics Centre, , Post Graduate Institute of Medical Education and Research (PGIMER), ; Chandigarh, 160012 India
                [3 ]GRID grid.460934.c, ISNI 0000 0004 1770 5787, MGM Medical College and Hospital, ; Navi Mumbai, Maharashtra India
                [4 ]GRID grid.11586.3b, ISNI 0000 0004 1767 8969, Department of Child Health, , Christian Medical College, ; Vellore, India
                Author information
                http://orcid.org/0000-0002-7852-6657
                http://orcid.org/0000-0002-9015-1704
                http://orcid.org/0000-0002-3405-5996
                http://orcid.org/0000-0003-2137-7475
                http://orcid.org/0000-0002-2121-0942
                http://orcid.org/0000-0002-6716-1883
                Article
                Publisher ID: 4749
                DOI: 10.1007/s00296-020-04749-4
                PMC ID: 7680080
                PubMed ID: 33219837
                SO-VID: f9b1403f-73d9-4763-9fc2-43ed26d5f708
                Copyright © © Springer-Verlag GmbH Germany, part of Springer Nature 2020
                License:

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 13 September 2020
                Date accepted : 3 November 2020
                Categories
                Subject: Review

                ScienceOpen disciplines: Rheumatology
                Keywords: multisystem inflammatory syndrome (mis-c),kawasaki disease (kd),hyperinflammation,coronavirus disease 2019,kawasaki-like disease
                Data availability:
                ScienceOpen disciplines: Rheumatology
                Keywords: multisystem inflammatory syndrome (mis-c), kawasaki disease (kd), hyperinflammation, coronavirus disease 2019, kawasaki-like disease

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