Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Variants on Short-and Mid-term Cardiac Outcomes in Multisystem Inflammatory Syndrome in Children

Multisystem inflammatory syndrome in children (MIS-C) is a hyper-inflammatory condition temporally associated with SARS-CoV-2 infection, with clinical overlap with Kawasaki disease (KD) and toxic shock syndrome. Given KD’s known acute and long-term cardiac complications, there is concern for cardiac outcomes in MIS-C. Infection rates and MIS-C frequency have varied with circulating SARS-CoV-2 variants. The study’s objective was to describe acute cardiac involvement and short- and mid-term cardiac outcomes in children with MIS-C across three SARS-CoV-2 variant waves (Wuhan, Alpha, Delta) during the first two years of the pandemic.

Design and setting: Single-center prospective follow-up of children with MIS-C hospitalized at Children’s of Alabama/University of Alabama at Birmingham, monitored in a multidisciplinary clinic. IRB-approved. Case definition: MIS-C per CDC criteria. Follow-up: Clinic visits at 4–6 weeks (short-term) and 6 months (mid-term) after diagnosis with serial laboratory tests, electrocardiography (ECG), and echocardiography (ECHO). Data collected: Demographics, clinical and laboratory results, and cardiac assessments (ECG and ECHO). Biomarker thresholds: Troponin I >0.04 ng/mL and B-type natriuretic peptide (BNP) >100 pg/mL considered elevated. ECG classified as normal or abnormal. ECHO parameters: (1) qualitative left ventricular (LV) systolic function (normal vs decreased); (2) quantitative LV ejection fraction (EF): normal (>54%), mild decrease (45%–54%), moderate (35%–44%), severe (<35%); (3) pericardial effusion (present/absent); (4) coronary artery (CA) aneurysm defined as z score ≥2.5. Variant-wave grouping: Group 1 (Wuhan): April–October 2020; Group 2 (Alpha/B.1.1.7): November 2020–July 2021; Group 3 (Delta/B.1.617.2): August–December 2021. Assignment based on CDC timelines when a variant accounted for >50% of US infections, offset >4 weeks to reflect MIS-C latency; no viral sequencing performed. Statistical analysis: Continuous variables compared by Kruskal–Wallis; categorical by χ2 or Fisher exact test. P<.05 significant. GraphPad Prism 8 used.

Cohort: 131 MIS-C patients (Group 1 n=32; Group 2 n=61; Group 3 n=38). Follow-up achieved in 103/131 (78.6%) at median 6 weeks (95% CI, 5–6) and 47/131 (35.9%) at 7 months (95% CI, 6–7). Demographics: Median age 10 years (range 0.75–17); 66.4% male; 49.6% Black. Acute illness: 36.6% (48/131) required vasopressors (median 24 hours). No deaths. Laboratory at diagnosis: Troponin I elevated in 52.7% (68/129); BNP elevated in 82.4% (108/131). At short- and mid-term follow-up, BNP and troponin were within normal ranges across all groups. ECG: Abnormal in 25% (28/112) during hospitalization with no significant differences among groups (P=.14); most common abnormality nonspecific ST–T changes (26/112; 23.2%). Short-term follow-up ECG normal in 98% (92/93), and mid-term 100% (41/41). Echocardiography at diagnosis: Abnormal in 41.2% (54/131). LV systolic dysfunction in 25.2% (33/131): mild 21, moderate 9, severe 3; no significant intergroup differences (Group 1 25%, Group 2 22.9%, Group 3 28.9%; P=.79). Pericardial effusion in 22.1% (29/131). CA aneurysms (z≥2.5) in 2.3%–2.35% (3/131). All children assessed at short- and mid-term had normal ECHO findings; the three with CA aneurysms normalized by ~6 weeks. Hospital length of stay: Median 4 days overall (IQR 3–6); shorter during Delta wave (Group 3 median 3.5 days) compared with Group 1 (5 days; P=.0004) and Group 2 (5 days; P=.0035). No significant differences between variant groups in biomarkers or LV function.

This prospective cohort demonstrates overall favorable cardiac outcomes in children with MIS-C, with normalization of cardiac biomarkers, ECG, and ECHO abnormalities by 5–6 weeks and sustained normal findings at ~7 months among those followed. Cardiac involvement at presentation (elevated troponin/BNP, LV dysfunction, pericardial effusion) was common but transient. There were no significant differences in the frequency or severity of cardiac involvement across variant waves (Wuhan, Alpha, Delta), suggesting that variant predominance did not materially alter MIS-C-related cardiac outcomes in this cohort. Hospital stays were shorter during the Delta period. The low rate of CA aneurysms (2.3%) and their rapid resolution may reflect the study’s focus on aneurysms (z≥2.5) rather than dilatation, aligning assessment with clinically meaningful outcomes. Transient ECG abnormalities, mainly nonspecific ST–T changes, resolved on follow-up and their clinical significance is uncertain. Findings are consistent with other smaller studies and suggest good short- to mid-term cardiac prognosis in MIS-C.

In a single-center prospective cohort of 131 children with MIS-C spanning Wuhan, Alpha, and Delta variant waves, cardiac outcomes were favorable, with normalization of biomarkers, ECG, and ECHO by short-term follow-up and no inter-variant differences in cardiac involvement severity or frequency. Hospitalization duration was shorter during the Delta wave. Overall, MIS-C in this cohort was associated with good short- to mid-term cardiac prognosis.

Major limitation was incomplete mid-term follow-up: 64% lacked mid-term data; 21.4% had no post-discharge follow-up; among those with short-term follow-up, many with normal ECHO (56/103; 54%) did not return mid-term. Lack of a control group and absence of cardiac MRI limit comparisons and detailed tissue characterization; MRI was considered cost-prohibitive and likely of low yield given ECHO normalization. Variant assignment was based on CDC temporal predominance rather than sequencing, introducing potential misclassification.