Cardiovascular Follow-up of Patients Treated for MIS-C

CPET was performed using an upright cycle ergometer for patients with height ≥135 cm or treadmill for those 1.09), peak oxygen uptake and percent-predicted were also recorded. Peak oxygen uptake of <80% predicted was considered abnormal and reflective of reduced functional capacity. In patients who achieved a peak HR ≥180 beats per minute, the ECG tracing was assessed for ST-segment and T-wave changes and presence of ectopy with exercise. Studies were excluded for patients who neither achieved an adequate RER nor peak HR. Stress echocardiogram was performed for patients who performed CPET using the cycle ergometer. Ventricular function was assessed at rest, and augmentation of myocardial wall segments was assessed during exercise.

Forty-six patients (27 with myocardial injury, 19 without) underwent CPET and had sufficient peak HR for analysis and inclusion (Table 3). No patients had ST-segment or T-wave changes with exercise. Two patients, both in the myocardial injury group, had ectopy during CPET. One had premature ventricular complexes (PVCs) during mid and late exercise, and 1 had PVCs during early recovery. Thirty-seven patients had adequate RER to assess functional capacity. Of those with adequate RER, 11 of 15 (73%) without myocardial injury had reduced functional capacity versus 18 of 22 (82%) with myocardial injury, which was not a statistically significant difference.

Thirty-nine patients underwent stress echocardiography. Only 1 patient, who had myocardial injury, had mildly reduced LV function with exercise. There was not a statistically significant difference in occurrence of ectopy, reduced functional capacity, or abnormal stress echocardiogram between the 2 groups.

MIS-C is a new disease entity that emerged during the recent SARS-CoV-2 pandemic for which long-term outcomes remain unknown. Understanding the prevalence and persistence of residual cardiovascular pathology is essential in determining long-term prognosis and management. To our knowledge, this is the first study to examine CMR, ambulatory rhythm monitoring, and CPET in concert in MIS-C patients and the first study to compare midterm results of these modalities between patients with and without myocardial injury during acute illness. Our results show that both groups of patients have abnormal findings on follow-up testing, without a statistically significant difference in the prevalence of abnormal findings. This suggests that all patients treated for MIS-C, regardless of the severity of the initial illness, warrant cardiology follow-up.

Elevation of T1, T2, and ECV on CMR can occur in a variety of disease processes, including cardiomyopathy, myocardial ischemia/infarction, myocarditis, and systemic inflammatory processes.^23,24 These abnormalities can indicate intracellular and extracellular changes (ECV only reflects extracellular changes), including edema, hyperemia, and fibrosis.^23,–25 Patients with myocarditis have demonstrated rapid improvement in native T1, T2, and ECV, often within 8 weeks of diagnosis.^26,27 LGE is typically thought to represent myocardial scarring, and in myocardial infarction has been well-established to detect extent of disease and to indicate prognosis.^26,28,–30 However, the persistence and implication of LGE in myocarditis is less clear. Although some studies have demonstrated persistence of LGE in most patients, others have demonstrated resolution in one-third to half, making a correlation with true fibrosis less clear.^27,31 

In our study, the most common CMR abnormality was elevated ECV, followed by elevated native T1 and presence of LGE. It is unclear whether these findings are reflective of a transient inflammatory process or myocardial fibrosis. Additional CMR studies at later time points will be needed to assess whether the changes resolve. Compared with many other studies, we found an overall higher prevalence of abnormal CMR findings. It is possible that either differences in the virus or in the hosts in our population may have contributed to these findings. Throughout the pandemic, there have been regional and temporal variations in the circulating strains of SARS-CoV-2,³² as well as regional and temporal differences in the clinical presentation of MIS-C.^33,–36 It is possible that differences in the acute disease course may also manifest in differences in residual pathology. However, on the basis of our study design, we cannot confirm this hypothesis.

To date, few studies have assessed ambulatory rhythm monitoring in patients after treatment of MIS-C. Özgür et al described a series of 17 patients, only 1 of whom had an abnormal finding of 13% PVCs.³⁷ In a study of 20 patients by Gentili et al, there were no findings of ectopy exceeding 50 beats per 24 hours, complex arrhythmia, or elevated average HR. In contrast, in our study, 9% had documented arrhythmia and 14% had an intermediate result. Although there was a higher prevalence of abnormal and intermediate findings in patients with myocardial injury, this did not reach statistical significance. However, it is possible that our study was underpowered to detect a significant difference.

Most of the patients who underwent CPET had reduced functional capacity, a finding that has been documented in 2 other studies.^38,39 This is difficult to interpret in this study population because there are multiple potential confounders. Firstly, a significant proportion of the patients were overweight or obese when diagnosed with MIS-C. Many had a further increase in BMI between hospitalization and CPET, which could have been contributed to by being restricted from strenuous exercise. Because no patients had CPET before hospitalization, it is unclear whether some or all may have been deconditioned at baseline. However, these findings further highlight the importance of determining which patients truly need exercise restrictions to prevent new or worsening obesity and other health problems.

Abnormalities on different testing modalities did not frequently cooccur. Twenty-nine patients underwent all 3 tests, and 23 underwent 2 tests. Twelve of 52 (23%) patients had abnormalities on 2 modalities and only 1 of 29 (3%) had abnormalities on all 3. Eighty-five percent of those with >1 abnormality had evidence of myocardial injury during acute illness. Interestingly, none of the patients with nonsustained ventricular tachycardia on ambulatory rhythm monitoring had abnormal CMR findings.

Overall, our results demonstrate residual subclinical cardiovascular pathology in a large proportion of patients after treatment of MIS-C, with no difference in prevalence between patients who had myocardial injury during hospitalization and those who did not. Therefore, for patients who report cardiovascular symptoms after treatment of MIS-C, pediatricians should have a low threshold to refer for further cardiovascular evaluation and workup.

Furthermore, many of the patients in our study population were of racial and/or ethnic minority backgrounds, which put them at higher risk for both coronavirus disease 2019 (COVID-19) and MIS-C.^40,41 As previously noted, most of these patients were also overweight or obese, which has also been associated with increased risk for severe COVID-19 illness. Independent of COVID-19, obesity and social determinants of health are risk factors for the development of cardiovascular disease in adulthood.^42,43 Thus, in the setting of an additional cardiovascular insult from MIS-C, these patients may warrant longer-term cardiology follow-up during childhood and adolescence.

This was a retrospective study reflecting the experience of a single center. Because patients were referred for and underwent follow-up cardiac studies at different times, not all patients had data for all 3 modalities. This made understanding associations between abnormalities on different modalities more difficult. The risk of type II error should also be considered in comparisons between the groups with and without myocardial injury.

CHLA has treated a large cohort of patients with MIS-C to date, accounting for ∼2.3% of cases nationally. Additionally, our study population appears demographically relatively similar to those of several other published studies assessing follow-up of patients treated for MIS-C in terms of age, sex, prevalence of overweight/obesity, and representation within the study population of groups that have been disproportionately affected by COVID-19–related illnesses.^11,–15 This suggests reasonable generalizability of our results; however, it is possible that this may be limited by differences in susceptibility to disease or other, more difficult to measure population differences. We do not have any data to suggest that the findings of our study are generalizable to patients who had COVID-19 but not MIS-C, or to adults who were treated for multisystem inflammatory syndrome in adults.