This cohort study evaluates the 6-month cardiovascular and noncardiovascular outcomes in individuals younger than 21 years diagnosed with multisystem inflammatory syndrome associated with COVID-19 infection.
Key Points
Question
What are the cardiovascular and noncardiovascular outcomes through 6 months in persons younger than 21 years diagnosed with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 infection?
Findings
In this cohort study including 1204 participants, by 6 months after hospital discharge, 99% had normalization of left ventricular systolic function, and 92.3% had normalization of coronary artery dimensions. Over 95% reported being more than 90% back to baseline health status, and comparison of Patient-Reported Outcomes Measurement Information Systems Global Health scores with prepandemic population normative values were at least equivalent.
Meaning
Results suggest that, although many patients with MIS-C in this cohort were very sick, most had excellent cardiovascular and overall health outcomes by 6 months.
Abstract
Importance
Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening complication of COVID-19 infection. Data on midterm outcomes are limited.
Objective
To characterize the frequency and time course of cardiac dysfunction (left ventricular ejection fraction [LVEF] <55%), coronary artery aneurysms (z score ≥2.5), and noncardiac involvement through 6 months after MIS-C.
Design, Setting, and Participants
This cohort study enrolled participants between March 2020 and January 2022 with a follow-up period of 2 years. Participants were recruited from 32 North American pediatric hospitals, and all participants met the 2020 Centers for Disease Control and Prevention case definition of MIS-C.
Exposure
MIS-C after COVID-19 infection.
Main Outcomes and Measures
Outcomes included echocardiography core laboratory (ECL) assessments of LVEF and maximum coronary artery z scores (zMax); data collection on cardiac and noncardiac sequelae during hospitalization and at 2 weeks, 6 weeks, and 6 months after discharge; and age-appropriate Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health Instruments at follow-up. Descriptive statistics, linear regression models, and Kaplan-Meier analysis were used.
Results
Of 1204 participants (median [IQR] age, 9.1 [5.6-12.7] years; 724 male [60.1%]), 325 self-identified with non-Hispanic Black race (27.0%) and 324 with Hispanic ethnicity (26.9%). A total of 548 of 1195 participants (45.9%) required vasoactive support, 17 of 1195 (1.4%) required extracorporeal membrane oxygenation, and 3 (0.3%) died during hospitalization. Of participants with echocardiograms reviewed by the ECL (n = 349 due to budget constraints), 131 of 322 (42.3%) had LVEF less than 55% during hospitalization; of those with follow-up, all but 1 normalized by 6 months. Black race (vs other/unknown race), higher C-reactive protein level, and abnormal troponin level were associated with lowest LVEF (estimate [SE], −3.09 [0.98]; R2 = 0.14; P =.002). Fifteen participants had coronary artery z scores of 2.5 or greater at any time point; 1 participant had a large/giant aneurysm. Of the 13 participants with z scores of 2.5 or greater during hospitalization, 12 (92.3%) had normalized by 6 months. Return to greater than 90% of pre–MIS-C health status (energy, sleep, appetite, cognition, and mood) was reported by 711 of 824 participants (86.3%) at 2 weeks, increasing to 548 of 576 (95.1%) at 6 months. Fatigue was the most common symptom reported at 2 weeks (141 of 889 [15.9%]), falling to 3.4% (22 of 638) by 6 months. PROMIS Global Health parent/guardian proxy median T scores for fatigue, global health, and pain interference improved significantly from 2 weeks to 6 months (fatigue, 56.1 vs 48.9; global health, 48.8 vs 51.3; pain interference, 53.0 vs 43.3; P < .001) and by the 6-week visit were at least equivalent to prepandemic population norms.
Conclusions and Relevance
Results of this cohort study suggest that although children and young adults with MIS-C can have severe disease during the acute phase, most recovered quickly and had a reassuring midterm prognosis.
Introduction
Multisystem inflammatory syndrome in children (MIS-C) remains one of the most serious complications of COVID-19 infection in children. Multicenter publications have largely focused on the acute course and short-term outcomes after MIS-C,1,2,3,4 with a few single and multicenter studies suggesting that organ system dysfunction and laboratory abnormalities typically resolve.5,6,7,8 However, reports of persistent or new cardiovascular, neurologic, and neurobehavioral findings have raised concerns of longer-term sequelae in a subset of patients with MIS-C.5,6,9,10 To date, few large, multicenter cohorts of patients with MIS-C have been followed up prospectively to assess the impact of MIS-C on longer-term health.
In this analysis, we characterize cardiovascular and noncardiovascular outcomes through 6 months after MIS-C. Our study population was enrolled in the Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC) study, which aimed to characterize the frequency and time course of left ventricular (LV) dysfunction, coronary artery aneurysms (z score ≥2.5), noncardiac organ dysfunction, and major medical events.11
Methods
Study Design and Population
The design of the MUSIC study has been described previously.11 In brief, the MUSIC study included patients with MIS-C who were hospitalized from March 2020 to January 2022 across 32 North American centers, met the Centers for Disease Control and Prevention 2020 case definition of MIS-C2 according to local research teams, and were enrolled within 1 year of diagnosis. Participants self-identified with the following races and ethnicities: American Indian or Alaska Native, Asian, Black, Hawaiian Native or Other Pacific Islander, Hispanic or Latino, multiracial, White, other, or unknown. Race and ethnicity data were collected as prior studies have demonstrated a higher incidence of, and worse outcomes after, MIS-C in those of Black race and/or Hispanic ethnicity.12,13,14 Written informed consent and assent were obtained as appropriate. Those who were lost to follow-up or died could be enrolled under a waiver of consent. The study was conducted through the Pediatric Heart Network funded by the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), and approved by the single institutional review board (IRB), Cincinnati Children’s Hospital Medical Center, with reliance agreements from participating sites, or the site’s IRB or research ethics board. This ambidirectional cohort study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.
Study time points included hospital admission (baseline) and discharge; 2 weeks, 6 weeks, and 6 months postdischarge; and annually until 2 years after MIS-C. Data collected included patient characteristics, body mass index (BMI) and z score,15 and weight categories (normal/underweight, BMI z score ≤1.0) vs overweight (BMI z score >1.0 and ≤2) vs obese (BMI z score >2); sociodemographic factors including Social Deprivation Index based on zip code,16 as zip code data were more complete and accurate than the collected census tract data; past medical history; presentation and hospital course, including myocardial involvement (defined as elevated troponin I level >0.04 ng/mL [to convert to grams per liter, multiply by 1] or troponin T level >0.014 ng/mL [to convert to micrograms per liter, multiply by 1] and/or decreased ventricular systolic function); satisfying American Heart Association (AHA) criteria for Kawasaki disease17; measures of general health after hospital discharge, including return to pre–MIS-C health status with respect to energy, appetite, sleep, mood, and cognition (parent/guardian proxy with ability to consider participant input), as well as the age-appropriate (pediatric and/or parent/guardian proxy or adult) Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health instrument.18 This analysis included data entered into REDCap software (Vanderbilt University) by November 1, 2022, with ongoing data collection.
Echocardiography Core Laboratory
Sites transferred deidentified echocardiograms obtained during study windows. Only a subset of echocardiograms were reviewed by the echocardiography core laboratory (ECL) because its funding was interrupted after the MUSIC study was incorporated into the NIH RECOVER (Researching COVID to Enhance Recovery) initiative; before this funding hiatus, the ECL prioritized review of echocardiograms of participants with serial studies. Echocardiograms at 6 months were not required per protocol in participants who had 2 consecutive normal echocardiograms. Standardized assessment of LV volumes in diastole and systole were made from parasternal and apical imaging, and LV ejection fraction (LVEF) was calculated using the 5/6 area-length method. Dimensions of the proximal left anterior descending artery (LAD) and right coronary artery (RCA) were measured from parasternal short-axis imaging; if only one was visualized adequately to measure, determination of zMax (ie, ECL assessments of LVEF and maximum coronary artery z scores) was based on available data. z Scores were calculated using the Boston equations.17,19 Coronary artery aneurysms were categorized as small (z score 2.5 to <5), medium (z score 5 to <10), or large/giant (z score ≥10).17
Outcomes of Interest
Primary outcomes were lowest LVEF and highest z score of the LAD or RCA (zMax) in the 6 months after MIS-C, based on ECL interpretation. Secondary cardiac outcomes included frequency of LVEF less than 55% and percentage with mild (45%-54%), moderate (35%-44%), and severe (<35%) LV dysfunction; frequency of proximal RCA or LAD z scores of 2.5 or greater; and time to LVEF normalization. Secondary noncardiac outcomes included frequency of intensive care unit (ICU) admissions and length of stay (ICU and/or hospital), mortality, symptoms and organ system abnormalities at follow-up, return to pre–MIS-C state of health, and scores on the PROMIS Global Health instrument (pain interference, global health, and fatigue for participants <18 years; mental and physical health for participants ≥18 years). PROMIS tool raw scores were converted to T scores, with mean (SD) of 50 (10) representing population norms.20
Statistical Analysis
Descriptive statistics included mean, SD, median, quartiles, and percentages. Wilcoxon rank sum and Fisher exact tests were used to compare participants who had echocardiograms reviewed by the ECL and those who did not. Wilcoxon signed rank tests were used to compare PROMIS T scores with the prepandemic norm of 50. Repeated measures analysis of variance was used to test for differences in LVEF, LAD z score, RCA z score, zMax, and PROMIS T scores over time, with post hoc Tukey tests to assess differences between time points.
Bivariable linear regression models were used to assess the association between covariates of interest, determined a priori (eTable 1 in Supplement 1) and lowest LVEF and highest zMax. Covariates significant at level 0.20 in bivariable modeling were candidates for multivariable modeling. Backward selection at level 0.05 was used in model building. Kaplan-Meier analysis was used to determine time to normalization of LVEF. The small number of those with zMax of 2.5 or greater precluded time to normalization analysis for the coronary arteries.
All analyses were conducted using SAS Enterprise Guide, version 7.15 (SAS Institute Inc), and statistical significance was tested at a 2-sided P value <.05.
Results
Patient Characteristics
We enrolled 1210 participants (1121 by consent, 89 by waiver of consent); 6 were found to be ineligible after enrollment and excluded from the analysis. Of the remaining 1204 participants (median [IQR] age, 9.1 [5.6-12.7] years; 476 female [39.5%]; 724 male [60.1%]; 4 unknown/refused [0.3%]). Participants self-identified with the following races and ethnicities: 1 American Indian or Alaska Native (0.1%), 40 Asian (3.3%), 325 Black (27.0%), 2 Hawaiian Native or Other Pacific Islander (0.2%), 324 Hispanic or Latino (26.9%), 32 multiracial (2.7%), 376 White (31.2%), 12 other (1.0%), and 92 unknown or refused (7.6%). Most had government insurance (536 [44.5%] US; 64 [5.3%] non-US) or private insurance (498 [41.4%]); 285 (25.9%) had overweight, and 220 (20.0%) had obesity (Table 1). Approximately one-third of participants (380 of 1171 [32.5%]) reported a preexisting condition other than obesity, most commonly asthma (105 of 1171 [9.0%]) (eTable 2 in Supplement 1).
Table 1. Baseline Characteristics (N = 1204).
| Characteristic | No. (%) or median (IQR) |
|---|---|
| Age, y (n = 1174) | 9.1 (5.6 to 12.7) |
| Age category, y | |
| <1 | 21 (1.7) |
| 1-4 | 228 (18.9) |
| 5-9 | 430 (35.7) |
| 10-14 | 354 (29.4) |
| 15-20 | 141 (11.7) |
| >20 | 0 |
| Sex (n = 1200) | |
| Female | 476 (39.5) |
| Male | 724 (60.1) |
| Unknown or refused | 4 (0.3) |
| Race and ethnicity | |
| American Indian or Alaska Native, non-Hispanic | 1 (0.1) |
| Asian, non-Hispanic | 40 (3.3) |
| Black, non-Hispanic | 325 (27.0) |
| Hawaiian Native or Other Pacific Islander, non-Hispanic | 2 (0.2) |
| Hispanic or Latino | 324 (26.9) |
| Multiracial, non-Hispanic | 32 (2.7) |
| White, non-Hispanic | 376 (31.2) |
| Other, non-Hispanic | 12 (1.0) |
| Unknown or refused | 92 (7.6) |
| Insurance | |
| Private | 498 (41.4) |
| Self-pay | 21 (1.7) |
| US government (eg, Medicaid) | 536 (44.5) |
| Other governmental insurance outside the US | 64 (5.3) |
| Dual coverage | 16 (1.3) |
| Unknown | 69 (5.7) |
| CDC BMI z score (n = 1098) | 0.85 (−0.09 to 1.78) |
| BMI z score category | |
| Overweight: 1 <BMI z score <2 | 285 (25.9) |
| Obesity: BMI z score ≥2 | 220 (20.0) |
Abbreviations: BMI, body mass index; CDC, Centers for Disease Control and Prevention.
Clinical Presentation and Hospital Course
Mean (SD) total fever days were 5.2 (2.2) days. Most participants (1031 of 1074 [96.0%]) had antibodies against the SARS-CoV-2 virus, and 363 of 1035 (35.1%) were polymerase chain reaction positive for the virus at admission or during hospitalization. Gastrointestinal symptoms were present in 1103 of 1176 participants (93.8%), including nausea or loss of appetite (887 of 1143 [77.6%]), abdominal pain (779 of 1147 [67.9%]), vomiting (781 of 1152 [67.8%]), or diarrhea (581 of 1151 [50.5%]). Criteria for complete or incomplete Kawasaki disease17 were met in 301 of 1112 participants (27.1%) (eTable 3 in Supplement 1).
Most participants (62.4%) were in the ICU, with median (IQR) length of stay (LOS) of 3 (2-5) days and hospital LOS of 5 (4-8) days. Oxygen or respiratory support was required in 463 of 1138 participants (40.7%), with 80 (7%) requiring mechanical ventilation. Most participants received intravenous immunoglobulin (1093 of 1155 [94.6%]) or corticosteroids (922 of 1177 [78.3%]), although other anti-inflammatories such as anakinra (240 of 1204 [19.9%]) and infliximab (134 [11.1%]) were also used (eTable 4 in Supplement 1). Nearly half (548 of 1195 [45.9%]) received vasoactive support, and 17 of 1195 participants (1.4%) were supported by extracorporeal membrane oxygenation (eTable 4 in Supplement 1). Three participants (0.3%) died during the hospitalization, and 1 underwent heart transplant (eTable 5 in Supplement 1).
Cardiac Involvement
Myocardial involvement occurred in 690 of 1140 participants (60.5%). Troponin level was elevated in 538 of 966 participants (55.7%) (eTable 4 in Supplement 1). Among 809 participants, the median (IQR) maximum troponin I level was 0.06 (0.02-0.23) ng/mL, and among 175 participants, troponin T level was 0.02 (0.01-0.07) ng/mL. Seven participants (0.6%) had ventricular tachycardia, and 22 (1.9%) had atrioventricular block (eTable 4 in Supplement 1); 4 had Mobitz type 2, 1 had high-grade atrioventricular block, and 2 had complete heart block (eTable 5 in Supplement 1).
Echocardiographic Findings During Hospitalization and Follow-Up Through 6 Months
The ECL reviewed 1 or more echocardiograms from 349 participants (28.9%). A significantly higher proportion of Hispanic participants (116 of 349 [33.3%] vs 208 of 855 [24.3%]) and lower proportion of White participants (72 of 349 [20.6%] vs 305 of 855 [35.7%]) had an echocardiogram reviewed by the ECL compared with those who did not (P < .001); the groups did not differ significantly by age, sex, or BMI. Mild mitral regurgitation was common in 69 of 349 participants (20.4%), although only 5 (1.5%) had moderate regurgitation; all had mild or less mitral regurgitation by 6 months (eTable 6 in Supplement 1).
LVEF
Of the 348 participants for whom LVEF could be measured, 142 of 349 (40.8%) had LVEF less than 55% at any time point; of these, 97 (68.3%) had mildly depressed LVEF, 35 (24.6%) had moderately depressed LVEF, and 10 (7.0%) had severely depressed LVEF. The median (IQR) LVEF was significantly higher at follow-up (LVEF 6 months postdischarge, 65.3% [61.3%-67.7%]) compared with hospitalization (LVEF during hospitalization, 56.3% [49.7%-63.3%]) (eTable 6 and eFigure panel A in Supplement 1). Of 131 of 322 participants (42.3%) with LVEF less than 55% during hospitalization in whom follow-up echocardiograms were reviewed by the ECL (n = 122), 93% had LVEF greater than or equal to 55% by 30 days (eFigure panel E in Supplement 1), and all but 1 echocardiogram (99%) normalized by 6 months (LVEF of 54.5% at admission, 55% at 2 weeks, and 52.7% at 6 months). Statistically significant associations with lowest LVEF included race (driven by lower LVEF in participants of Black race, estimate [SE], −2.08 [1.21] vs other/unknown race, estimate [SE], 1.61 [1.21]; P = .01), higher C-reactive protein (CRP) level (estimate [SE], −0.02 [0.005]; P < .001), and abnormal troponin level (n = 299; estimate [SE], −3.09 [0.98]; R2 = 0.14; P =.002) (eTable 7 in Supplement 1).
Coronary Artery Involvement
Of 344 participants in whom LAD and/or RCA images were adequate for measurement, 15 participants (4.4%) had an LAD (n = 13) and/or RCA z score of 2.5 or greater (n = 9) at any time point, and 13 participants had zMax in the small aneurysm category, 1 in the moderate aneurysm category, and 1 in the large/giant aneurysm category (eTable 6 in Supplement 1). Median z scores over time of the LAD, RCA, and zMax are shown in eFigure panels B through D in Supplement 1. The median (IQR) zMax was lower after discharge compared with during hospitalization (worst during hospitalization zMax, 0.38; 95% CI, −0.29 to 1.11 vs 2 weeks zMax, −0.06; 95% CI, −0.64 to 0.68; P <.001 vs 6 weeks zMax, −0.23; 95% CI, −0.86 to 0.43; P <.001 vs 6 months zMax, −0.22; 95% CI, −0.91 to 0.47; P =.01) (eFigure panel D in Supplement 1). Among 13 of 15 participants who had an LAD or RCA z score of 2.5 or greater during hospitalization (including hospital discharge echocardiograms), 12 (92.3%) had normalization by 6 months: 11 had z scores less than 2.5 by 2-week follow-up; 1 who had a moderate-sized coronary artery aneurysm had normalization by 6 months, and another had a persistently large/giant coronary artery aneurysm at the 6-week visit but had no echocardiogram reviewed by the ECL after that. Of the remaining 2 participants with zMax of 2.5 or greater, 1 had normal z scores during hospitalization but had a zMax of 2.85 at 2 weeks, and 1 did not have an echocardiogram reviewed by the ECL before the 2-week visit, when the zMax was 2.52. No covariates were associated with higher zMax (eTable 8 in Supplement 1).
Follow-Up Through 6 Months
Follow-up data were available from 1097 participants at 2 weeks, 1052 at 6 weeks, and 868 at 6 months.
Cardiovascular and Other Systems Review
Cardiovascular and noncardiovascular organ system symptoms and findings through 6 months are in Table 2 and eTable 9 in Supplement 1. The most common symptoms reported at 2 weeks were fatigue (141 of 889 [15.9%]) and low stamina/energy (82 of 889 [9.2%]), both of which decreased to 3.4% (22 of 638) and 3.3% (21 of 638), respectively, by 6 months. Palpitations were the most common cardiovascular symptom reported at 2 weeks (17 of 1097 [1.5%]), which decreased to 0.6% (5 of 868) at 6 months; however, chest pain was reported increasingly over time, with 1.3% (14 of 1097) reporting chest pain at rest at 2 weeks and 2.2% (19 of 868) at 6 months. Neurologic symptoms were reported by 5.6% of participants (49 of 882) at 2 weeks, 3.9% (31 of 805) at 6 weeks, and 4.1% (26 of 628) at 6 months, with the most frequently reported symptom being headaches that impacted school attendance or activities. Although gastrointestinal symptoms were common during the acute phase of MIS-C, only 5.3% of respondents (47 of 884) reported gastrointestinal symptoms at 2 weeks.
Table 2. Select Organ Systems Review at 2 Weeks, 6 Weeks, and 6 Months After Hospital Dischargea.
| Organ systems review | No./total No. (%) | ||
|---|---|---|---|
| 2 wk (n = 1097) | 6 wk (n = 1052) | 6 mo (n = 868) | |
| Constitutional | 185/889 (20.8) | 78/812 (9.6) | 41/638 (6.4) |
| Fatigue | 141/889 (15.9) | 52/812 (6.4) | 22/638 (3.4) |
| Low stamina/energy | 82/889 (9.2) | 35/812 (4.3) | 21/638 (3.3) |
| Night sweats | 10/889 (1.1) | 2/812 (0.2) | 3/638 (0.5) |
| Unexplained fevers for at least 3 d | 4/889 (0.4) | 5/812 (0.6) | 4/638 (0.6) |
| Poor growth | 1/889 (0.1) | 0/812 (0) | 0/638 (0) |
| Cardiovascular | 102/1097 (9.3) | 69/1052 (6.6) | 66/868 (7.6) |
| Arrhythmia | 23/1097 (2.1) | 14/1052 (1.3) | 12/868 (1.4) |
| Chest pain (rest) | 14/1097 (1.3) | 19/1052 (1.8) | 19/868 (2.2) |
| Chest pain (exertion) | 10/1097 (0.9) | 10/1052 (1.0) | 11/868 (1.3) |
| Palpitations | 17/1097 (1.5) | 5/1052 (0.5) | 5/868 (0.6) |
| Tachycardia (nonphysiologic) | 7/1097 (0.6) | 2/1052 (0.2) | 3/868 (0.3) |
| Syncope (vasovagal) | 2/1097 (0.2) | 1/1052 (0.1) | 0/868 (0) |
| Immunologic/infectious | 5/883 (0.6) | 6/804 (0.7) | 5/628 (0.8) |
| Rheumatologic | 33/884 (3.7) | 19/803 (2.4) | 10/628 (1.6) |
| Joint pain and/or swelling | 12/884 (1.4) | 5/803 (0.6) | 3/628 (0.5) |
| Kidney | 7/884 (0.8) | 7/804 (0.9) | 6/628 (1.0) |
| Neurologic | 49/882 (5.6) | 31/805 (3.9) | 26/628 (4.1) |
| Headaches frequent or severe enough to impact school attendance or activities | 8/882 (0.9) | 5/805 (0.6) | 9/628 (1.4) |
| Decreased sense of taste | 1/882 (0.1) | 0/805 (0) | 0/628 (0) |
| Difficulty concentrating | 0/882 (0) | 0/805 (0) | 1/628 (0.2) |
| Mental slowness or COVID fog | 0/882 (0) | 0/805 (0) | 3/628 (0.5) |
| Pulmonary/respiratory | 15/884 (1.7) | 9/803 (1.1) | 14/628 (2.2) |
| Hematologic | 25/884 (2.8) | 13/805 (1.6) | 4/628 (0.6) |
| Gastrointestinal | 47/884 (5.3) | 29/804 (3.6) | 24/628 (3.8) |
| Persistent abdominal pain | 12/884 (1.4) | 7/804 (0.9) | 7/628 (1.1) |
| Dermatologic | 52/883 (5.9) | 26/803 (3.2) | 23/629 (3.7) |
| Genitourinary/reproductive | 4/884 (0.5) | 0/803 (0) | 3/628 (0.5) |
A complete list is available in eTable 9 in Supplement 1.
Return to Pre–MIS-C State of Health
Data from questionnaires on return to pre–MIS-C state of health through 6 months are summarized in Table 3 and eTable 10 in Supplement 1. The percentage of participants who reported being greater than 90% back to baseline in all 5 domains increased from 2 weeks (711 of 824 [86.3%]) to 6 months (548 of 576 [95.1%]). The greatest improvement was in energy level, with 637 of 819 (77.8%) reported as being greater than 90% back to baseline energy level at 2 weeks, rising to 542 of 574 (94.4%) at 6 months.
Table 3. Return to Pre–Multisystem Inflammatory Syndrome in Children (MIS-C) Baseline Health Status at 2 Weeks, 6 Weeks, and 6 Months After Hospital Discharge, by Domain.
| Domain | Back to baseline, No./total No. (%) | |||||
|---|---|---|---|---|---|---|
| 2 wk | 6 wk | 6 mo | ||||
| >90% | 100% | >90% | 100% | >90% | 100% | |
| Energy | 637/819 (77.8) | 592/819 (72.3) | 679/751 (90.4) | 649/751 (86.4) | 542/574 (94.4) | 524/574 (91.3) |
| Appetite | 777/816 (95.2) | 763/816 (93.5) | 736/752 (97.8) | 729/752 (96.9) | 567/572 (99.1) | 560/572 (97.9) |
| Sleep | 739/800 (92.4) | 726/800 (90.8) | 719/744 (96.6) | 713/744 (95.8) | 553/569 (97.2) | 547/569 (96.1) |
| Cognition | 787/804 (97.8) | 777/804 (96.6) | 732/745 (98.2) | 725/745 (97.3) | 559/569 (98.2) | 552/569 (97.0) |
| Mood | 754/805 (93.7) | 741/805 (92.0) | 720/744 (96.8) | 711/744 (95.6) | 548/570 (96.1) | 539/570 (94.6) |
| All domains | 711/824 (86.3) | 555/824 (67.4) | 702/754 (93.1) | 619/754 (82.1) | 548/576 (95.1) | 502/576 (87.2) |
PROMIS Global Health 7 + 2
PROMIS Global Health scores (parent/guardian proxy and participant) for fatigue, global health, and pain interference through 6 months are summarized in the Figure and Table 4.18 Both parent/guardian proxy– and participant-reported median T scores of fatigue and pain interference were significantly improved at 6 weeks and 6 months compared with at 2 weeks (median parent/guardian proxy–reported fatigue T score at 2 weeks, 56.1; 95% CI, 48.9-56.1 vs 6 weeks, 48.9; 95% CI, 40.1-56.1; P <.001 vs 6 months, 48.9; 95% CI, 40.1-56.1; P <.001; pain interference T score at 2 weeks, 53.0; 95% CI, 43.3-58.5 vs 6 weeks, 43.3; 95% CI, 43.3-53.0; P <.001 vs 6 months, 43.3; 95% CI, 43.3-53.0; P <.001; median participant-reported fatigue T score at 2 weeks, 52.9; 95% CI, 46.4-59.1 vs 6 weeks, 46.4; 95% CI, 40.0-52.9; P =.002 vs 6 months, 46.4; 95% CI, 40.0-52.9; P <.001; pain interference T score at 2 weeks, 42.6; 95% CI, 42.6-54.7 vs 6 weeks, 42.6; 95% CI, 42.6-50.3; P =.04 vs 6 months, 42.6; 95% CI, 42.6-50.3; P =.04) (Figure). Parent/guardian proxy–reported global health also improved at 6 weeks and 6 months compared with 2 weeks, although participant-reported global health scores were not statistically different over time (Figure). Compared with prepandemic population norms (Table 4),18 parent/guardian proxy–reported median T scores for fatigue and pain interference were significantly higher (ie, worse) at 2 weeks, although were statistically similar or lower (ie, better) at 6 weeks and 6 months, whereas global health at 6 months was statistically better. Although participant-reported median T scores for fatigue were statistically similar at 2 weeks compared with prepandemic population norms (prepandemic population norm T score 50), they were statistically better at 6 weeks (vs 46.4; 95% CI, 40.0-52.2; P <.001) and 6 months (vs 46.4; 95% CI, 40.0-52.2; P <.001), and pain interference was statistically lower, ie, better (vs 2 weeks, 42.6; 95% CI, 42.6-54.7; P <.001 vs 6 weeks, 42.6; 95% CI, 42.6-50.3; P <.001 vs 6 months, 42.6; 95% CI, 42.6-50.3; P <.001) at all time points.
Figure. Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health 7 + 2 T scores.
Box and whisker plots of PROMIS Global Health 7 + 2 T scores for fatigue, global health, and pain interference at 2 weeks, 6 weeks, and 6 months after hospital discharge. A, Parent/guardian proxy responses. B, Participant (aged 7-17 years) responses. A higher PROMIS T score represents more of the concept being measured. The circles, plus signs, and x marks in both panels represent the means of the data.
Table 4. Median Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health 7 + 2 T Scores by Parent/Guardian Proxy and Participant Responses at 2 Weeks, 6 Weeks, and 6 Months After Hospital Discharge, With Comparison With Pre–COVID-19 Normative Data for Each Domaina,b.
| Parent/guardian proxy | 2 wk | 6 wk | 6 mo | ||||||
|---|---|---|---|---|---|---|---|---|---|
| No. | Median (IQR) | P value | No. | Median (IQR) | P value | No. | Median (IQR) | P value | |
| Fatigue | 150 | 56.1 (48.9-56.1) | <.001 | 230 | 48.9 (40.1-56.1) | <.001 | 301 | 48.9 (40.1-56.1) | <.001 |
| Global health | 150 | 48.8 (41.5-54.9) | .07 | 231 | 50.1 (44.9-59.0) | .06 | 301 | 51.3 (45.6-61.2) | <.001 |
| Pain interference | 149 | 53.0 (43.3-58.5) | <.001 | 228 | 43.3 (43.3-53.0) | .08 | 300 | 43.3 (43.3-53.0) | .006 |
| Participant (7-17 y) | |||||||||
| Fatigue | 170 | 52.9 (46.4-59.1) | .55 | 235 | 46.4 (40.0-52.9) | <.001 | 294 | 46.4 (40.0-52.9) | <.001 |
| Global health | 170 | 49.2 (43.9-55.3) | .50 | 235 | 50.1 (43.4-55.5) | .47 | 294 | 50.0 (43.3-55.7) | .61 |
| Pain interference | 170 | 42.6 (42.6-54.7) | <.001 | 235 | 42.6 (42.6-50.3) | <.001 | 292 | 42.6 (42.6-50.3) | <.001 |
| Participant (≥18 y) | |||||||||
| Global mental health | 13 | 53.3 (48.0-56.7) | .40 | 16 | 54.1 (52.2-63.6) | .3 | 15 | 55.6 (45.5-61.8) | .006 |
| Global physical health | 13 | 51.6 (44.3-54.4) | .72 | 16 | 55.4 (49.7-59.8) | .14 | 15 | 54.4 (48.0-62.2) | .002 |
With conversion of PROMIS raw scores to T scores, a mean of 50 and SD of ±10 represent population norms.18 Higher PROMIS T score represents more of the concept being measured.
Wilcoxon signed rank tests were used to compare median PROMIS T scores with the prepandemic norm of 50.
Discussion
In this multicenter cohort study of 1204 North American children and adolescents with MIS-C, most patients were critically ill during the acute phase, but 6-month cardiovascular and overall health outcomes were excellent. In standardized, centralized assessment of echocardiograms, LVEF in those with decreased systolic function during hospitalization had normalized by 6 months in 99%. Most coronary artery aneurysms were small and remodeled to normal lumen diameter; a large/giant coronary artery aneurysm was seen in only 1 patient. Although Black race (vs other/unknown race), higher CRP level, and elevated troponin level were independently associated with lowest LVEF in this study, the low R2 suggests that these factors account for a small part of the variance. Persistent symptoms at 6 months were rare. Taken together, midterm general health outcomes were excellent; by 6 months after discharge, more than 95% of participant/parent/guardian proxies reported return to greater than 90% of baseline status in all domains (energy, sleep, appetite, cognition, and mood), and PROMIS tool responses were at least similar to, if not statistically better than, prepandemic populations.
Although our findings are consistent with the literature on cardiovascular recovery after MIS-C,7,8,21,22,23,24,25,26 fewer studies have described longer-term noncardiovascular outcomes. In a multicenter cohort of 241 patients with MIS-C 2 to 4 months after hospitalization, having a preexisting respiratory condition was associated with persistent symptoms, whereas obesity and greater number of involved organ systems were associated with persistent activity impairment.10 In population-based studies from the Netherlands (N = 69 hospitalized patients in the ICU) and Sweden (N = 113), exercise intolerance was reported in 43%27 at 3 to 6 months and fatigue in 22% at approximately 2 months,28 respectively. Moreover, Penner et al5 found that 45% (N = 40) of patients had 6-minute walk-tests results that were less than the third percentile for sex and age at 6 months after MIS-C. In our cohort, fatigue was the most reported symptom after hospital discharge (approximately 16% at 2 weeks) but improved (3.4%) at 6 months. Moreover, both parent/guardian proxy and participant PROMIS fatigue scores at 6 weeks and 6 months were statistically better than population norms, which may reflect greater appreciation of resolving fatigue after hospitalization.
Neurological and behavioral sequelae of COVID-19–related illnesses, including MIS-C, have been of particular concern. One study5 reported 39% of patients with MIS-C had minor neurologic abnormalities on examination at 6 months, and a multicenter study29 of 64 patients with MIS-C and 44 sibling/community control patients found that patients with MIS-C were 4.7 times more likely to have abnormal neurologic examinations 6 to 12 months after hospital discharge. At 3 to 6 months after MIS-C, up to 22% of patients reported emotional/psychosocial difficulties,5,6,27,29 with 1 study6 reporting 20% of patients with sleep symptoms. Patients with MIS-C have scored worse on components of behavior and executive function at 3- to 6-month follow-up compared with general population norms27 and compared with sibling/community control patients at 6 to 12 months.29 In contrast only 2.1%, 2.4%, and 1.8% of our cohort reported being less than 90% back to baseline with regards to sleep, mood, and cognition, respectively, at 6 months. Reports of anxiety, depression, mood changes, or other behavioral disorders were rare (<1%) in the first 6 months. Better long-term outcomes in our cohort may be due to methodologic differences for assessment of symptoms. Questionnaires and surveys in our study could be completed remotely and thus carried less potential for selection bias toward inclusion of those with ongoing or new concerns. However, subtle neurobehavioral sequelae are better detected with standardized testing and comparison with contemporaneous controls than by survey.
Consistent with prior reports on coronary artery outcomes in MIS-C, we found lower frequency and severity of coronary artery aneurysms, with rarity of large/giant aneurysms, compared with findings seen in Kawasaki disease.30 The MUSIC cohort included a high percentage of individuals with overweight (26% vs 16.1%) and obesity (20% vs 19.3%) compared with 2017 to 2018 National Health and Nutrition Examination Surveys data of youth aged 2 to 19 years,31 and in 1 study,32 only approximately 19% of patients with Kawasaki disease had overweight/obesity. Having overweight/obesity may lead to underestimation of the frequency and severity of coronary artery involvement as determined by z scores, which are adjusted for body surface area. This hypothesis is supported by median z scores that fell below the population mean with later follow-up. However, differing pathobiology between these 2 hyperinflammatory conditions likely plays a key role in their coronary artery outcomes,33,34,35 and we cannot definitively distinguish if the participant in our cohort who had a large/giant aneurysm had Kawasaki disease or MIS-C.
Limitations
Our study had some limitations. Due to budget constraints, plans for central adjudication were abandoned, and only 28.9% of participants had echocardiograms reviewed by the ECL, thereby limiting the sample size for echocardiographic outcomes and potentially creating selection bias. Patients were treated at large North American centers and most received intravenous immunoglobulin and steroid treatment; outcomes thus may not be generalizable to patients with MIS-C at smaller centers or worldwide. We did not include a control group. Time to recovery analysis for the coronary arteries could not be performed due to the small number participants with z scores of 2.5 or greater. We did not test for strains of SARS-CoV-2 virus, and our results may not be applicable to strains circulating after January 2022.
Conclusions
In a large, multicenter cohort of children and adolescents with MIS-C, results suggest that cardiovascular and noncardiovascular morbidities were rare by 6 months after hospital discharge, despite severe illness in many patients during the acute phase. The longer-term health implications of MIS-C are unknown, and continued surveillance of MUSIC study participants is ongoing to characterize their health status up to 2 years after illness onset.
eFigure. Left Ventricular Ejection Fraction (LVEF) and Coronary Artery z Scores Over Time
eTable 1. Covariates Used in Bivariable Modeling for Worst LVEF and/or Left Anterior Descending or Right Coronary Artery zMax
eTable 2. Past Medical History
eTable 3. Symptoms at Presentation
eTable 4. Complete List of Data Collected From the Hospital Course
eTable 5. Expanded Details of Those Who Died or Had Heart Transplant, Ventricular Tachycardia, or High-Grade or Complete Heart Block During the Hospitalization for MIS-C
eTable 6. Echocardiography Core Laboratory Assessments of LVEF, Coronary Arteries, and Valvar Insufficiency Through 6 Months After MIS-C
eTable 7. Potential Associations with Lowest LVEF, Bivariable Modeling, and Multivariable Modeling
eTable 8. Potential Associations with Left Anterior Descending or Right Coronary Artery zMax, Bivariable Modeling, and Multivariable Modeling
eTable 9. Complete List of Organ Systems Review at 2 Weeks, 6 Weeks, and 6 Months After Hospital Discharge
eTable 10. Return to Pre-MIS-C Baseline Health Status at 2 Weeks, 6 Weeks, and 6 Months After Hospital Discharge, by Domain
Nonauthor Collaborators. MUSIC Study Investigators.
Data Sharing Statement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure. Left Ventricular Ejection Fraction (LVEF) and Coronary Artery z Scores Over Time
eTable 1. Covariates Used in Bivariable Modeling for Worst LVEF and/or Left Anterior Descending or Right Coronary Artery zMax
eTable 2. Past Medical History
eTable 3. Symptoms at Presentation
eTable 4. Complete List of Data Collected From the Hospital Course
eTable 5. Expanded Details of Those Who Died or Had Heart Transplant, Ventricular Tachycardia, or High-Grade or Complete Heart Block During the Hospitalization for MIS-C
eTable 6. Echocardiography Core Laboratory Assessments of LVEF, Coronary Arteries, and Valvar Insufficiency Through 6 Months After MIS-C
eTable 7. Potential Associations with Lowest LVEF, Bivariable Modeling, and Multivariable Modeling
eTable 8. Potential Associations with Left Anterior Descending or Right Coronary Artery zMax, Bivariable Modeling, and Multivariable Modeling
eTable 9. Complete List of Organ Systems Review at 2 Weeks, 6 Weeks, and 6 Months After Hospital Discharge
eTable 10. Return to Pre-MIS-C Baseline Health Status at 2 Weeks, 6 Weeks, and 6 Months After Hospital Discharge, by Domain
Nonauthor Collaborators. MUSIC Study Investigators.
Data Sharing Statement.
