Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children

Study Overview
=================
Brief Summary
-----------------
Multi-system Inflammatory Syndrome in Children (MIS-C) is a new condition related to COVID-19, the study investigators are still learning about its causes, effects, and long-term impact. Long-Term Outcomes after the Multisystem Inflammatory Syndrome In Children, the Coronavirus MUSIC Study, is a research study funded by NIH and the National Heart, Lung, and Blood Institute. The study investigators hope to enroll at least 900 young people with MIS-C at children's medical centers in the U.S. and Canada. This research study will help us learn more about MIS-C and its effects on the long-term health of children.

Detailed Description
-----------------
This study is an observational cohort study that will use routinely collected clinical and cardiac (EKG, echocardiogram, Cardiac MRI, exercise testing) data to assess the association between MIS-C and cardiac outcomes within the first year after hospital discharge. Research funding will be available for EKGs, echocardiograms and MRIs in protocol windows that are not ordered by primary caregivers. The principal goal is to determine the spectrum and early time course of coronary artery involvement, LV systolic function, and arrhythmias or conduction system abnormalities, and, using these data, to define associated clinical and laboratory factors. The study investigators planned to include all eligible patients, including retrospective cases beginning January 1, 2020, with follow-up (in-person or telehealth) to up within one year and annual medical history forms until up to 5 years have elapsed since illness onset. Because many patients will have been identified by retrospective review, the study team will obtain consent at different times in their illness course. For this reason, it may be hard to reach some patients and their families. Waiver of consent will be obtained after three attempts have been made to locate the patient and family without success, as well as for the rare child who dies before informed consent can be obtained. The study investigators will include a HIPAA-compliant cryptographic algorithm to create a sharable hashed identifier from patient information. If blood work for research purposes is added on to usual clinically indicated blood work during follow-up visits, this will be covered by other informed consent forms.

Official Title
-----------------
Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children

Conditions
-----------------
Multisystem Inflammatory Syndrome in Children (MIS-C)

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age <21 years. Fever ≥38°C for ≥24 hours, or report of subjective fever lasting ≥24 hours. Laboratory evidence of inflammation, including, but not limited to, one or more of the following: an elevated CRP, ESR, fibrinogen, procalcitonin, d-dimer, ferritin, LDH, or IL-6, elevated neutrophils, reduced lymphocytes and low albumin. Evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement, based on clinical judgment from record review, discharge diagnosis, laboratory or diagnostic tests. Organ system involvement includes but is not limited to cardiac, renal, respiratory, hematologic including coagulopathy, gastrointestinal including liver, dermatologic or neurological. Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms Exclusion Criteria: No plausible alternative diagnosis, such as bacterial sepsis, murine typhus, staphylococcal or streptococcal shock syndromes

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------
What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| worst-ever LV ejection fraction | worst left ventricular (LV) ejection fraction from core lab echo read during MUSIC study | hospital admission through 5 years post-hospitalization | 
| worst-ever maximum z score of the proximal LAD or RCA | worst maximum z-score of the proximal left anterior descending coronary artery (LAD) or right coronary artery (RCA) from core lab echo read; z-scores to be calculated via Boston z-score calculator (primary) and Pediatric Heart Network z-score calculator (secondary); higher z-scores are worse | hospital admission through 5 years post-hospitalization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of a proximal LAD or RCA z score of ≥2.5 on any echocardiogram | proximal left anterior descending coronary artery (LAD) or right coronary artery (RCA) ≥2.5 from any core lab echo read | hospital admission through 5 years post-hospitalization | 
| Occurrence of aneurysms by Japanese Ministry of Health criteria | Occurrence of aneurysms by Japanese Ministry of Health criteria applied to core lab echo reads | hospital admission through 5 years post-hospitalization | 
| Individual z scores for LMCA, RCA and LAD | Individual z scores for left main coronary artery (LMCA), right coronary artery (RCA) and proximal left anterior descending coronary artery (LAD) as per core lab echo reads; higher z-scores are worse | hospital admission through 5 years post-hospitalization | 
| LVEDV z score | left ventricular (LV) size as measured by left ventricular end-diastolic volume (LVEDV) z score | hospital admission through 5 years post-hospitalization | 
| LVEF | left ventricular (LV) function as measured by left ventricular ejection fraction (LVEF) | hospital admission through 5 years post-hospitalization | 
| LVSF | left ventricular (LV) function as measured by left ventricular shortening fraction (LVSF) | hospital admission through 5 years post-hospitalization | 
| The percentage of patients who had LV ejection of <55%, and further categorization of 45-54% (i.e., mildly depressed systolic function), 35-44% (moderately depressed systolic function) and <35% (severely depressed systolic function) on any echocardiogram | The percentage of patients who had left ventricular (LV) ejection of <55%, and further categorization of 45-54% (i.e., mildly depressed systolic function), 35-44% (moderately depressed systolic function) and <35% (severely depressed systolic function) on any echocardiogram read by the core lab | hospital admission through 5 years post-hospitalization | 
| LV strain (global longitudinal strain from apical view and global circumferential strain from parasternal short-axis view) | left ventricular (LV) strain (global longitudinal strain from apical view and global circumferential strain from parasternal short-axis view) on core lab echo read | hospital admission through 5 years post-hospitalization | 
| Qualitative assessment of RV systolic function | Qualitative assessment of right ventricular (RV) systolic function on core lab echo read | hospital admission through 5 years post-hospitalization | 
| Qualitative assessment of RV global longitudinal strain | Qualitative assessment, if possible, of right ventricular (RV) global longitudinal strain on core lab echo read | hospital admission through 5 years post-hospitalization | 
| Presence and degree of mitral and aortic regurgitation | Presence and degree of mitral and aortic regurgitation on echo core lab read | hospital admission through 5 years post-hospitalization | 
| LV diastolic function, i.e., tissue Doppler imaging and mitral valve (MV) inflow | left ventricular (LV) diastolic function, i.e., tissue Doppler imaging and mitral valve (MV) inflow on echo core lab read | hospital admission through 5 years post-hospitalization | 
| Presence and size of pericardial effusion | Presence and size of pericardial effusion on echo core lab read | hospital admission through 5 years post-hospitalization | 
| The occurrence of arrhythmias and conduction system disturbances by in-hospital monitoring, electrocardiograms, and exercise testing at 3 months in those with a history of ≥moderate systolic dysfunction when age and maturity permit | The occurrence of arrhythmias and conduction system disturbances by in-hospital monitoring, electrocardiograms, and exercise testing at 3 months in those with a history of ≥moderate systolic dysfunction when age and maturity permit | 3 months post-discharge | 
| MRI LVEF | LVEF on MRI core lab read | hospital admission through 5 years post-hospitalization | 
| MRI RVEF | RVEF on MRI core lab read | hospital admission through 5 years post-hospitalization | 
| valvar regurgitation | valvar regurgitation on MRI core lab read | hospital admission through 5 years post-hospitalization | 
| myocardial late gadolinium enhancement (LGE) | percent with and distribution of myocardial late gadolinium enhancement (LGE) on MRI core lab read | hospital admission through 5 years post-hospitalization | 
| abnormal T2-weighted imaging | percent abnormal T2-weighted imaging on MRI core lab read | hospital admission through 5 years post-hospitalization | 
| elevated T2 | percent with elevated T2 on MRI core lab read | hospital admission through 5 years post-hospitalization | 
| elevated native T1 | percent with elevated native T1 on MRI core lab read | hospital admission through 5 years post-hospitalization | 
| elevated extracellular volume fraction | percent with elevated extracellular volume fraction on MRI core lab read | hospital admission through 5 years post-hospitalization | 
| coronary artery dilation | percent with coronary artery dilation on MRI core lab read | hospital admission through 5 years post-hospitalization | 
| CMR abnormal, equivocal, or negative | final interpretation of CMR as abnormal, equivocal, or negative (i.e., no abnormal or equivocal findings) on MRI core lab read | hospital admission through 5 years post-hospitalization | 
| Other organ abnormalities by medical history: Immunologic, rheumatologic, renal, pulmonary, hematologic, gastrointestinal, dermatologic or neurologic | percent with other organ abnormalities by medical history: Immunologic, rheumatologic, renal, pulmonary, hematologic, gastrointestinal, dermatologic or neurologic | hospital admission through 5 years post-hospitalization | 
| CRP | C-Reactive Protein (CRP) as a laboratory marker of inflammation | hospital admission through 5 years post-hospitalization | 
| Admission to ICU | percent with admission to ICU | hospital admission through 5 years post-hospitalization | 
| Maximal vasoactive inotrope score | Maximal vasoactive inotrope score | from MIS-C hospital admission to MIS-C hospital discharge | 
| Hospital length of stay | Hospital length of stay | from MIS-C hospital admission to MIS-C hospital discharge | 
| Symptom duration | Symptom duration | hospital admission through 5 years post-hospitalization | 
| Major medical events | percent with major medical events (e.g., stroke, need for extracorporeal therapies such as renal replacement therapy, plasma exchange, ECMO, VAD) | hospital admission through 5 years post-hospitalization | 
| Mortality | Percent mortality | hospital admission through 5 years post-hospitalization | 
| Global Health - FSS | Global Health as measured by Functional Status Score [FSS]: range 6-30, lower is better | hospital admission through 5 years post-hospitalization | 
| Global Health - PROMIS | Global Health as measured by Parent-Reported Outcomes Measurement Information Systems [PROMIS] Instrument: range 7-35, higher is better | hospital admission through 5 years post-hospitalization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID