Endothelial Cell and Cardiomyocyte Dysfunction in Children with Kawasaki disease-like SARS-CoV-2 Induced Immune Activation

  • Funded by National Institutes of Health (NIH)
  • Total publications:0 publications

Grant number: unknown

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Key facts

  • Disease

    COVID-19
  • Start & end year

    2018
    2021
  • Known Financial Commitments (USD)

    $727,650
  • Funder

    National Institutes of Health (NIH)
  • Principle Investigator

    Pending
  • Research Location

    United States of America, Americas
  • Lead Research Institution

    UNIVERSITY OF CALIFORNIA-SAN DIEGO
  • Research Category

    Pathogen: natural history, transmission and diagnostics

  • Research Subcategory

    Diagnostics

  • Special Interest Tags

    Gender

  • Study Subject

    Clinical

  • Clinical Trial Details

    Not applicable

  • Broad Policy Alignment

    Pending

  • Age Group

    Children (1 year to 12 years)

  • Vulnerable Population

    Unspecified

  • Occupations of Interest

    Unspecified

Abstract

Project SummaryIn the wake of COVID-19 pandemic, fever with severe systemic inflammation and shock, known as PediatricInflammatory Multisystem Syndrome (PIMS), has evolved as a new threat to children. PIMS was originallyreported in Western Europe and the number of cases is rapidly increasing in the U.S. A hallmark of PIMS hasbeen heart failure leading to shock and the absence of significant pulmonary disease. The clinical presentationin these patients shares many features with Kawasaki disease (KD), the most common cause of acquired heartdisease in children, which itself can present with distributive shock requiring inotropic and vasoactive support inthe intensive care unit. Several PIMS patients are either SARS-CoV-2 PCR positive or have developedantibodies against SARS-CoV-2, suggesting that PIMS is an immune-mediated reaction to antecedent exposureto the virus. Curiously, at the same time that patients are being diagnosed with PIMS, the numbers of childrenwith typical KD has increased dramatically in these same regions. The emergence of PIMS is so new and sorapidly evolving that there are literally no publications, treatment guidelines or clinical trials related to theseseriously affected pediatric patients. Through our network of 30 pediatric centers participating in KIDCARE, ourcomparative effectiveness trial for treatment-resistant KD funded by PCORI, we are collecting patient data andclinical samples to support the work proposed here. The goal of this administrative supplement is to analyzedemographic, clinical and laboratory data in conjunction with assays using patient cells and sera, whichwill allow us to study the relationships among SARS-CoV-2 infection, typical KD, and PIMS and to modeldifferent therapeutic strategies against PIMS. Three specific aims are proposed to achieve this goal. SpecificAim 1 will profile and compare clinical features of PIMS and typical KD. Demographic and clinical data and theneutrophil response to intravenous immunoglobulin (IVIG) will be compared between these two illnesses.Cytokine profiles and inflammatory markers in plasma from acute and subacute PIMS and typical KD will alsobe compared. Specific Aim 2 will elucidate molecular features of PIMS and compare with typical KD. We willuse RNA-seq, ELISA, and Western blot analyses to profile changes in levels of molecules related to inflammation(e.g., TIFA, NFkβ, NLRP3-inflammasome, IL-1, IL-6, TNFα) and cardiovascular health (KLF4, miR-483, ACE2)in endothelial cells and cardiomyocytes. Specific Aim 3 will test the efficacy of drug therapy for PIMS bycomparing the in vitro effects of intravenous immunoglobulin, steroids, and anakinra on inflammatory pathwaysand cardiovascular biomarkers in endothelial cells and cardiomyocytes treated with sera from acute PIMSpatients prior to therapy. The synergistic expertise of the investigative teams in this multi-PI supplement providesa unique opportunity to understand the clinical features, molecular basis, and efficacy of drug treatment of PIMSas compared to KD.