Multisystem inflammatory syndrome in children (MIS-C) is a serious condition temporally associated with SARS-CoV-2 infection, sharing clinical similarities with Kawasaki disease (KD) and toxic shock syndrome. The increasing number of children infected with SARS-CoV-2 and the subsequent diagnoses of MIS-C raise concerns about potential long-term cardiac complications due to the overlap with KD, which is known to cause various cardiac issues, including arrhythmias, myocardial inflammation, valvular lesions, and coronary artery abnormalities. Although the pathogenesis of MIS-C remains unclear, it's believed to involve a dysregulated immune response to SARS-CoV-2 leading to myocardial dysfunction and coronary artery involvement. The emergence of various SARS-CoV-2 variants has resulted in varying infection rates and MIS-C frequency, making it crucial to understand the impact of different variants on cardiac outcomes in MIS-C. This study aimed to describe acute cardiac involvement and short-and mid-term cardiac outcomes in children with MIS-C following three different waves of SARS-CoV-2 infection during the first two years of the pandemic, focusing on the Wuhan, Alpha, and Delta variants.

Existing literature highlights the significant overlap in clinical presentation and treatment strategies between MIS-C and Kawasaki disease (KD), fueling concern about long-term cardiac sequelae in MIS-C. Studies have documented various cardiac abnormalities in MIS-C patients, including elevated cardiac biomarkers (troponin I and BNP), electrocardiogram (ECG) abnormalities, and echocardiogram (ECHO) findings such as decreased left ventricular function and coronary artery aneurysms. However, the available data often comes from small cohorts, with limited information on long-term outcomes and the influence of different SARS-CoV-2 variants. This lack of comprehensive data necessitates further research to fully understand the long-term cardiac implications of MIS-C and its potential variations based on the circulating SARS-CoV-2 variant.

This prospective cohort study enrolled 131 children diagnosed with MIS-C at Children's of Alabama/University of Alabama at Birmingham (UAB) between April 2020 and December 2021, following IRB approval. Patients were categorized into three groups based on the timing of their hospitalization, corresponding to the predominance of different SARS-CoV-2 variants: Group 1 (April-October 2020, Wuhan variant), Group 2 (November 2020-July 2021, Alpha variant), and Group 3 (August-December 2021, Delta variant). Data collected included demographics, clinical characteristics, laboratory tests (troponin I, BNP, SARS-CoV-2 PCR and IgG), ECG, and ECHO findings at diagnosis, short-term (4-6 weeks), and mid-term (6 months) follow-ups. Elevated troponin I (>0.04 ng/mL) and BNP (>100 pg/mL) were considered abnormal. ECG was categorized as normal or abnormal. ECHO parameters included left ventricular systolic function (qualitative and quantitative), pericardial effusion, and coronary artery aneurysms (z-score ≥2.5). The Kruskal-Wallis test was used to compare continuous variables, while χ² or Fisher's exact test was used for categorical variables. Statistical significance was set at p < 0.05.

The study comprised 131 children (median age 10 years; 66.4% male; 49.6% Black). Group 1, 2, and 3 included 32, 61, and 38 children respectively. 103 (78.6%) children had short-term follow-up, and 47 (35.9%) had mid-term follow-up. At diagnosis, elevated troponin I levels were observed in 52.7% and elevated BNP levels in 82% of the children. 48 children (36.6%) required vasopressors. There were no deaths. At short-term and mid-term follow-up, troponin I and BNP levels normalized in all groups. ECG abnormalities were present in 25% of children at diagnosis, but most (98-100%) showed normal ECG at follow-up. ECHO abnormalities, including decreased left ventricular function, were seen in 41.2% of children at diagnosis, but normalized at follow-up. Coronary artery aneurysms (z-score ≥2.5) were observed in only three children (2.3%) at diagnosis, all of whom recovered fully by follow-up. Children in group 3 (Delta variant) had significantly shorter hospitalization durations (3.5 days) compared to groups 1 and 2 (5 days). No significant differences were observed in the frequency or severity of cardiac involvement between the three groups at any time point.

This study demonstrates favorable short-and mid-term cardiac outcomes in children with MIS-C, with most cardiac abnormalities resolving within 5-6 weeks. The lack of significant differences in cardiac involvement between the three groups suggests that the SARS-CoV-2 variant may not significantly influence the short-and mid-term cardiac outcomes in MIS-C, contrary to some previous suggestions. The high rate of recovery observed in this study contrasts with some previous reports that found persistent cardiac abnormalities, which might be attributed to differences in the definition of coronary artery abnormalities. This study focused specifically on aneurysms (z-score ≥2.5), excluding dilations which may have less correlation with adverse outcomes. The study's findings are consistent with other smaller studies comparing MIS-C to KD, suggesting no significant differences in outcomes across different institutions or regions. However, the lack of a control group and cardiac MRI data are important limitations that may warrant future investigation.

This single-center prospective cohort study demonstrates favorable short-and mid-term cardiac outcomes in children with MIS-C, irrespective of the infecting SARS-CoV-2 variant (Wuhan, Alpha, or Delta). Most cardiac abnormalities resolved quickly, suggesting a generally good prognosis. Future research should focus on addressing the limitations of this study, such as the lack of mid-term follow-up in a larger percentage of the cohort and the absence of a control group, while also exploring long-term cardiac outcomes and the impact of potential confounding factors.

The major limitation is the relatively low rate of mid-term follow-up (35.9%). The reasons for attrition may include improvement in cardiac findings and families' perception of their children's well-being. Other limitations include the lack of a control group, the absence of cardiac MRI data, and the potential misclassification of children into variant groups due to the use of CDC-reported variant prevalence timelines instead of direct viral sequencing. The absence of viral sequencing data for each patient is a major limitation impacting the strength of the conclusion regarding variant effects.