Characterization of Multisystem Inflammatory Syndrome in Children (MIS-C) and Its Relationship to Kawasaki Disease

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Brief Title

Characterization of Multisystem Inflammatory Syndrome in Children (MIS-C) and Its Relationship to Kawasaki Disease

Official Title

Characterization of Multisystem Inflammatory Syndrome in Children (MIS-C) and Its Relationship to Kawasaki Disease

Brief Summary

      Beginning in mid-March 2020, pediatricians in communities in Western Europe, the UK, and the
      Eastern U.S. that had been severely affected by the Covid-19 pandemic noted an increased
      number of children presenting with fever and evidence of severe inflammation who required
      admission to intensive care. The syndrome was branded by the CDC in the U.S. as Multisystem
      Inflammatory Syndrome in Children (MIS-C). The most severely affected children presented with
      heart failure leading to shock and the absence of significant pulmonary disease. The clinical
      presentation in these patients shared many features with Kawasaki disease (KD), a
      self-limited pediatric vasculitis that can result in coronary artery aneurysms.The
      inflammatory markers, however, were much higher even than KD shock syndrome, a variant of KD
      presenting with distributive shock and requiring inotropic and vasoactive support in the ICU.
      Some patients were polymerase chain reaction (PCR)+ for SARS-CoV-2 while most were
      virus-negative but had detectable antibody suggesting that MIS-C was an immune-mediated
      reaction to antecedent exposure to the virus. While patients were being diagnosed with shock
      and MIS-C, children with a milder version of MIS-C that shared many features of KD were being
      diagnosed in these same regions.
    

Detailed Description

      Clinical characterization (Burns, Tremoulet, Sivilay, Roberts, Jain): Over the 8 months of
      enrollment funded by this supplement, 30 sites will collect data on KD and MIS-C patients
      using the detailed case report form in our REDCap database. This includes data on patient
      demographics, clinical presentation, laboratory data, treatments, clinical outcomes, and
      cardiovascular outcomes on all KD and MIS-C patients so that the investigators can develop a
      systematic picture of the different patient groups (see details below).

      Parent observations (Kim): To learn about signs and symptoms in the patient and family
      members leading up to acute presentation a parent questionnaire will be devised and analyzed
      by Dr. Katherine Kim with the Patient and Parent Advisory Board. The investigators will
      collect known signs and symptoms as well as those that may not have been previously reported
      in the literature and record presence/absence, location in the body, and severity level by
      day. The questionnaire will be available as a mobile/web application and via paper. With
      these data, the investigators will conduct an exploratory analysis to characterize symptom
      phenotypes and the relationships of these profiles with demographic features and clinical
      characteristics. In addition, the investigators will assess whether we can detect differences
      between the symptom phenotypes of KD and MIS-C. The investigators will conduct cluster
      analysis to identify symptom phenotypes from aggregate symptom observations blinded as to
      presumed or verified diagnosis (n=100 with each sign/symptom on each day as a distinct data
      point). Phenotypes may include characteristics such as symptoms that co-occur or are
      independent, and symptom burden index (e.g., number symptoms present). The investigators will
      use Ward's hierarchical cluster analysis to estimate the number of likely clusters.3 The
      investigators will apply K-means nonhierarchical cluster analysis repeated 100 times in a
      leave-one out validation model to assure repeatability and stability within the model. The
      investigators will create score indices analyzed with logistic regression, principal
      component analysis, factor analysis and correlation analysis. The investigators will then
      assess whether clusters are related to verified diagnosis and/or sociodemographic
      characteristics such as age, race/ethnicity, geography. The investigators will use
      discriminant analysis techniques and more recent classification techniques such as CART to
      examine if symptom phenotypes of KD and MIS-C are dissimilar. If information in terms of
      symptom clusters at a point in time or a trajectory of a single symptom over time are
      insufficient to distinguish between the two conditions, this would provide support for the
      argument that the recorded symptoms are insufficient for discrimination or that the two
      disease entities are not symptomatically different. This exploratory analysis will provide
      important information that can be further developed for clinical guidance and parent
      education.

      Photography (Kim, Tremoulet): Patient photographs of the eye, mouth/tongue, and rash will be
      collected as a novel addition to the usual clinical data. These photographs obtained before
      treatment will document the presence or absence of conjunctival injection and perilimbal
      sparing, mucocutaneous changes in the oropharynx including changes in the vermillion border
      (erythema, fissuring) and the tongue (strawberry tongue), and the nature of the rash. The
      photographs will be subjected to analysis using facial recognition software and artificial
      intelligence approaches used by our collaborators at the University of Southern California
      Center for Artificial Intelligence in Society led by Hayden Shively and Lucas Hu to evaluate
      whether a computer algorithm can be created that can differentiate the clinical
      characteristics of MIS-C from photographs taken of children with acute KD and those with
      other pediatric febrile illnesses. Dr. Katherine Kim at UC Davis will compare the photos with
      the questionnaire responses to supplement the parent descriptions of signs and symptoms and
      validate the observations. This comparison can result in enhanced descriptions using the
      words of parents themselves. Photography is needed to document these physical findings as the
      investigators have learned over the years that physician description of these features is
      woefully inaccurate. The finding, for example, of a strawberry tongue is a specific injury
      pattern that involves sloughing of the cornified tips of the filiform papillae and has
      historically been associated with only 3 conditions: staphylococcal and streptococcal
      toxin-mediated disease and KD.
    


Study Type

Observational


Primary Outcome

Collection of clinical data and patient samples from children with MIS-C and KD to


Condition

Kawasaki Disease



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

100

Start Date

August 1, 2020

Completion Date

December 31, 2021

Primary Completion Date

August 1, 2021

Eligibility Criteria

        Inclusion criteria:

        The following patients (age 1 mos. through young adults) will be recruited for this study:

        Patients who meet the CDC definition for MIS-C:

          -  Patients presenting with fever (>38C for >24 h - also by subjective report),
             laboratory evidence of inflammation, and evidence of clinically severe illness
             requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal,
             respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND

          -  No alternative plausible diagnoses; AND Positive for current or recent SARS-CoV-2
             infection by RT-PCR, serology, or antigen test; or suspected COVID-19 exposure within
             the 4 weeks prior to the onset of symptoms

          -  Patients who meet the CDC definition for MIS-C and require care in the PICU

        Exclusion Criteria:

        • All patients with pre-existing major medical conditions will be excluded. This includes
        patients with known genetic disorders (e.g. trisomy 21, cystic fibrosis), conditions
        requiring continuous medication (e.g. seizure disorder, heart disease), or known immune
        disorder (e.g. hypogammaglobulinemia, complement deficiency). Patients with asthma or
        atopic dermatitis will not be excluded unless patients have received oral steroids in the
        previous week. Obesity is not an exclusion.
      

Gender

All

Ages

1 Month - N/A

Accepts Healthy Volunteers

No

Contacts

Jane C Burns, 858-246-0155, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04538495

Organization ID

CER-1602-34473


Responsible Party

Principal Investigator

Study Sponsor

University of California, San Diego


Study Sponsor

Jane C Burns, Principal Investigator, University of California, San Diego


Verification Date

November 2021