Trial DesignsThe NHLBI Study on Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC): Design and Objectives
Section snippets
Cardiovascular involvement
Cardiovascular involvement occurs in approximately 80% of children with MIS-C,7,8 consisting of left ventricular (LV) dysfunction, shock, coronary artery dilation and/or aneurysms, valvulitis, pericardial effusions, arrhythmias, and conduction abnormalities.5,7., 8., 9.,15., 16., 17., 18., 19., 20., 21., 22. Few studies have characterized MIS-C-associated ventricular dysfunction or coronary artery anatomy using standardized assessments, and no data are available regarding long-term follow-up.
Non-cardiovascular organ system involvement
As implied by the syndrome name, multiple organ systems beyond the cardiovascular system have been involved in MIS-C. While any organ system is at risk, children with MIS-C most commonly present with gastrointestinal8,9 and mucocutaneous symptoms and/or laboratory abnormalities,8,9,36 including vomiting, diarrhea, abdominal pain, transaminitis, and gall bladder hydrops, as well as rash and conjunctivitis, respectively.37 Hematologic abnormalities have included pulmonary embolism38 and deep vein
Rationale for the study
To better understand this emerging illness and its sequelae, the Long-TerM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC) study was developed and will be the first to define long-term cardiovascular and other organ system health status in the largest population of children and adolescents with MIS-C to date. In addition, this study will contribute important new information on acute cardiac findings, including standardized measures of myocardial performance and coronary
Study design and methods
This multicenter observational cohort study, funded by the National Institutes of Health and the National Heart, Lung, and Blood Institute (NHLBI), will use routinely collected clinical and cardiac (electrocardiogram [ECG], echocardiogram, CMR, exercise testing) data to assess the association between MIS-C and cardiac and non-cardiac outcomes. The aims of this study are:
1. To characterize the frequency and course over time of LV dysfunction in MIS-C associated with COVID-19.
2. To characterize
Inclusion criteria
Eligibility criteria for the MUSIC study align with the current CDC definition for MIS-C4
- 1.
Age <21 years.
- 2.
Fever ≥38°C for ≥24 hours, or report of subjective fever lasting ≥24 hours.
- 3.
Laboratory evidence of inflammation, including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactate dehydrogenase (LDH), interleukin-6 (IL-6) or neutrophils, reduced lymphocytes and low albumin.
Exclusion criterion
- 1.
A plausible alternative diagnosis, such as culture-positive bacterial sepsis, murine typhus, staphylococcal or streptococcal shock syndromes.
Recruitment and enrollment
As of March 31, 2021, 33 centers in North America have committed to participating in the MUSIC study: 10 PHN core centers and 23 auxiliary centers, which were chosen based on geographic variation, racial diversity and number of MIS-C cases (Supplement 1). We plan to enroll at least 600 participants in 2 years and will include all eligible patients who meet the CDC case definition of MIS-C starting from March 2020. Follow-up will be for up to 5 years. The MUSIC study launched in October 2020,
Outcome measures and schedule of measurements
Our principal goal is to determine the spectrum and early time course of LV systolic dysfunction, coronary artery involvement, and arrhythmias or conduction system abnormalities, and to define associated clinical and laboratory factors using these data. The primary and secondary cardiac outcomes are listed in Table I.
The secondary non-cardiac outcomes are listed in Table II.
The schedule of measurements is based on standard clinical follow-up in MIS-C patients (Table III), with study timepoints
Adjudication of MIS-C Diagnosis
The CDC case definition of MIS-C is broad and nonspecific, and confirmatory laboratory testing by serologic testing can be unreliable. Furthermore, as increasing seroprevalence from exposures or vaccination becomes more common, accurate diagnosis of MIS-C will become more complicated and inaccurate diagnoses may increase. An Adjudication Committee of three experts from pediatric rheumatology, pediatric infectious disease, and pediatric cardiology, will classify cases as definite, possible, or
Medical history and annual health assessment
Besides extensive data collection during the hospital period, including labs, treatment and medication, participants will undergo a medical history at each timepoint, including at the annual health assessment that will either occur in-person, or via virtual platform or telephone starting 1 year from MIS-C diagnosis for up to 5 years from diagnosis. The medical history includes a series of questions to better understand the participant's current health status. The broad range of questions covers
Echocardiographic core laboratory
The MUSIC study uses an echocardiographic imaging protocol for prospectively-performed imaging studies and an Echocardiographic Core Laboratory (Boston Children's Hospital) to ensure standardized echocardiographic assessment for the outcome measures. The Echocardiographic Core Laboratory will interpret all echocardiograms 1) performed at the study time points; 2) with the worst LVEF and worst-ever LAD or RCA z-score obtained outside of the study time points; 3) performed beyond the 6-month
CMR core laboratory
The CMR Core Laboratory (Cincinnati Children's Hospital) will ensure uniform assessment of CMR outcomes, measured according to standard established conventions.48., 49., 50. We anticipate that CMRs will be performed approximately 3 months (range 1-6 months) after illness onset in children who have at least moderately depressed LV function (i.e., LVEF <45%). Research funds will be available for CMR (unsedated and without a gadolinium-based contrast agent) if not ordered for clinical reasons in
Assessment of arrhythmias and conduction disturbances
To assess for arrhythmias and conduction disturbances, we will collect data from resting electrocardiograms (ECG) obtained during the hospitalization and follow-up of participants, with research funds available for ECGs if not ordered for clinical reasons at the study timepoints. Data will also be collected from any ambulatory monitoring, as well as any exercise stress testing performed for clinical purposes, both of which may be ordered as part of assessment prior to return to sports in those
Optional genetic testing and biorepository
Participants who consent for optional genetic testing will provide blood or saliva samples for future whole genome sequencing. Biological parents will also be approached for blood or saliva samples for optional genetic testing to better understand genetic variation within the MIS-C population. Samples will be stored at the PHN biorepository (University of Michigan). We will leverage the careful phenotyping of participants in the MUSIC study to provide an opportunity for future
Statistical considerations
In this observational study, we will exclude cases later adjudicated as “not MIS-C” from analyses of MIS-C outcomes, and will describe the alternative diagnoses. Coronary artery dimensions will be normalized for BSA as z-scores using the Boston Z-score system52 (primary, for consistency with the definition of coronary artery aneurysms in the AHA guideline), as well as the PHN53 (secondary). We will characterize the study population, treatment course, medical history, and study outcomes over
Importance of the knowledge to be gained
While MIS-C is a rare complication of COVID-19, the multiorgan involvement leads to critical illness in the majority of patients, many of whom had been previously healthy. The results of the MUSIC study will make an important contribution to our understanding of the cardiac and non-cardiac manifestations of MIS-C and its long-term effects through a systematic and standardized history and imaging assessment for up to 5 years across North American centers. Currently available practices and
Conclusions
The emergence of MIS-C during the COVID-19 pandemic has created a public health emergency that necessitates multicenter collaboration to better understand this new illness and its long-term outcomes. The MUSIC study will gather systematic follow-up data using standardized protocols for cardiac imaging, independent assessment in Echocardiographic and CMR Core Laboratories and surveillance for non-cardiac morbidities and global health in a large population of patients with MIS-C. Through
Acknowledgements
The study was supported by grants (HL135680, HL135685, HL135683, HL135689, HL135646, HL135665, HL135678, HL135682, HL135666, HL135691, HL068270) from the National Heart, Lung, and Blood Institute, NIH.
Disclosure
The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.
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Pediatric Heart Network Core Center