Longitudinal Echocardiographic Assessment of Coronary Arteries and Left Ventricular Function Following Multisystem Inflammatory Syndrome in Children (MIS-C)

Abstract

Myocardial dysfunction and coronary artery dilation have been reported in the acute setting of SARS-CoV-2 related multisystem inflammatory syndrome in children (MIS-C). Through a longitudinal echocardiographic single-center study of 15 children, we report the short-term outcomes of cardiac dysfunction and coronary artery dilation in MIS-C. COVID-19, a disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has accounted for over 460,000 deaths globally as of June 2020. [1] Children of all ages have been affected, although the clinical manifestations are less severe than adults. In early May, reports emerged from Europe and North America describing a hyperinflammatory condition in children related to SARS-CoV-2 and presenting with some features similar to Kawasaki disease and toxic shock syndrome [2,3]. On May 14, 2020, the Centers for Disease Control and Prevention (CDC) recognized this clinical complex as multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 and released a case definition based on clinical and laboratory criteria. [4] MIS-C patients come to medical attention with fever, elevated inflammatory markers, multisystem organ involvement (renal, gastrointestinal, neurologic, dermatologic, cardiac), with evidence of a current or recent SARS-CoV-2 infection or recent close contact with a known or suspected case of COVID-19. In a report describing the experience of MIS-C in New York, 80% of diagnosed children were admitted to the intensive care unit. Of the hospitalized children, 52% had myocardial dysfunction and 9% had coronary artery aneurysms. [5] Management for MIS-C has involved intravenous immunoglobulins, vasoactive agents, anticoagulants and immune-modulating drugs with varied response [6]. To date, reports are limited to description of cardiac findings during hospitalization, however there is paucity of data on the longitudinal follow-up and sequelae in this population. We sought to describe the echocardiographic manifestations of MIS-C including evolution of abnormalities of coronary artery dilation and ventricular systolic function over short-term follow-up after discharge from the hospital. Methods: A single-center retrospective review was conducted on all pediatric patients (<21 years of age) admitted with MIS-C to Mount Sinai Kravis Children’s Hospital between April 24 (first admission) and May 16, 2020 who had at least one echocardiogram performed during hospitalization. The determination of diagnosis of MIS-C was based on CDC criteria [4]. Only patients with confirmed SARS-CoV-2 infection by reverse transcriptase polymerase chain reaction (RT-PCR) and/or serology during hospitalization were included. All of the patients in our cohort were described previously in three recent multicenter publications [7],[8],[5] that focused on acute presentation and inpatient outcomes. Additionally, 4 patients from this cohort were described in a recent case series [9]. Clinical data including hospital course and laboratory results were collected. Serial echocardiograms performed from admission to most recent outpatient follow-up visit (until June 18, 2020) were reviewed. The timing of follow-up echocardiograms was based on the findings of initial echocardiogram and ongoing clinical status. Absolute dimensions (mm) and z-scores of proximal coronary arteries including the left main coronary artery (LMCA), left anterior descending coronary artery (LAD), left circumflex (LCx) coronary artery and right coronary artery (RCA) were recorded. Coronary aneurysms were defined using z-scores as per AHA Kawasaki guidelines (Small aneurysm ≥2.5 to <5, medium aneurysm ≥5 to <10 and large aneurysm ≥10 or absolute dimension ≥8 mm). [10] Boston Children’s Hospital Z-score system was utilized for all the echocardiographic measures.[11] Ventricular function, effusion, valvar function and coronary dimensions were tracked serially from date of admission to most recent outpatient follow-up visit. Results: Fifteen pediatric patients [mean age 11.5 (3-20) years, 60% male] met criteria for MIS-C in the study timeframe. Six patients (40%) had a positive nasopharyngeal SARS-CoV-2 PCR test (SARS-CoV-2 test, cobas® 6800 system, Roche Diagnostics) and all had a positive COVID-19 antibody test (Mt. Sinai Laboratory COVID-19 ELISA antibody test, FDA approved under emergency use authorization) [12] - The average length of stay in the hospital was 7.6 (±2.3) days. There was one death in a patient who required extracorporeal membrane oxygenation support. The average follow-up period of the cohort from admission was 28.1 (range 5-50) days. Detailed clinical information is depicted in the Table (available at www.jpeds.com). Table 1 Descriptive Clinical Data of the Study Population Clinical Variable, units (statistics) Patients with coronary artery involvement (n=4) Patients without coronary artery involvement (n=8) All patients (n=15) Age, years (mean ± SD) 10.25 ± 3.59 11.63 ± 3.81 11.53 ± 4.49 Sex, % (n) 75% (3) 50% 60% (9) BMI, kg/m2 (mean ± SD) 26.85 ± 8.35 20.45 ± 4.23 22.27 ± 6.62 BSA, m2 (mean ± SD) 1.24 ±0.37 1.42 ± 0.39 1.38 ± 0.43 Duration of symptoms at admission, days, % (n) 4.25 ±2.06 5 ±1 4.53 ± 1.41 Pressors administered % (n) 75% (3) 25% (2) 53.3% (8) Peak D-dimer, μg/ml (mean ± SD) 4.37 ±2.09 4.67 ±3.25 5.47 ± 4.82 Peak Troponin, ng/ml (mean ± SD) 0.98 ±1.63 5.84 ±10.23 3.73 ± 8.15 Peak Pro-BNP, pg/ml (mean ± SD) 839.59 ±634.55 1308.30 ±1226.23 1487.64 ± 1774.84 IVIG administered, % (n) 100% (4) 87.5% (7) 80% (12) Corticosteroids administered, % (n) 25% (1) 12.5% (1) 20% (3) Tocilizumab administered, % (n) 100% (4) 62.5% (5) 60% (9) Anakinra administered, % (n) 25% (1) 0% (0) 13.3% (2) Therapeutic anticoagulation % (n) 100 (4)% 100% (8) 100% (15) Remdesivir administered, % (n) 25% (1) 12.5% (1) 20% (3) Plasma therapy administered, % (n) 0% 0% (0) 6.7% (1) ASA during admission, % (n) 50% (2) 0% (0) 13.3% (2) Site of coronary artery involvement (individual patient) 1 Mid-LAD, LMCA, mid-RCA N/A N/A 2 LAD 3 LAD 4 LMCA SD= standard deviation; BMI = body mass index, BSA= body surface area; LMCA= left main coronary artery, LAD= left anterior descending artery, RCA= right coronary artery The average LV ejection fraction (EF) at first echocardiogram was 49.5% (range 29-58%). Eight patients (53%) presented with LV dysfunction (EF <55%) ranging from mild to severe (n=2 with EF 50-54%; n=4 with EF 40-49% and n=2 with EF <35%). 10/13 of children (excluding one lost to follow up and one deceased patient) had recovery of cardiac function within one month of the initial study. Three patients continue to have low-normal systolic function (EF=50-55%) and are in ongoing follow-up. (Figure 1 , A) Of the four patients (27%) who had RV dysfunction on initial echocardiogram, all but one (deceased) had complete recovery of RV function on follow-up imaging. Two patients had pericardial effusions (small) on initial echocardiograms that resolved. Approximately half (n=8, 53%) of the cohort had mitral regurgitation (mild), all but two resolved over the study period. All patients received therapeutic anticoagulation. Aspirin was started in patients with coronary artery dilation and/or after discontinuation of enoxaparin in patients without dilation. Figure 1 Longitudinal echocardiographic data plotted on a line chart demonstrating the trajectory of each individual patient’s findingsover the study period. Time is depicted on the x-axis and is divided into intervals based on days since admission as described in the figures. A: Left ventricular ejection fraction (LVEF) over time. B: Left main coronary artery (LMCA) dimensions over time. C: Left anterior descending (LAD) artery dimensions over time. D: Right coronary artery (RCA) dimensions over time. Coronary artery evaluation was performed in 12 patients (80%) and 10/12 had more than one echocardiogram performed in the study period. Three patients did not have coronary arteries assessing during echocardiography, 2/3 were due to hemodynamically instability, and one patient was the first admission with MIS-C, before the importance of coronary artery assessment was recognized. Of the patients with coronary artery evaluation, one-third (n=4) had coronary involvement (z score >2.5). LMCA aneurysms (1 small, one medium) were seen in two patients; one resolved and one remains persistent at follow-up. (Figure 1, B and Figure 2 , A). LAD aneurysms were seen in three patients (2 small, 1 medium aneurysm). Within 30 days, all patients with LAD involvement had normal z-scores (Figure 1, C). Only one patient had an aneurysm in the RCA (small) that has remained aneurysmal, albeit slightly smaller on recent echocardiogram (Figure 1, D and Figure 2, B). Figure 2A Parasternal short-axis view demonstrates an aneurysm (arrow) at the bifurcation of left main coronary artery (LMCA) into left anterior descending and circumflex coronaries. 2B: Parasternal short-axis image shows a fusiform aneurysm (arrow) of the right coronary artery. Ao: Aorta, PA: Pulmonary artery. Discussion: This longitudinal study provides information on short-term echocardiographic outcomes of 15 patients with MIS-C. Although LV dysfunction was common at initial evaluation (53%), significant improvement was seen within a 30-day follow-up period. However, some patients had residual low-normal function at 4-6 weeks follow-up. Our findings are congruent to two larger multicenter studies from New York that showed 53%-65% of patients had evidence of myocardial dysfunction during hospitalization. Follow-up outpatient data on systolic function was not reported. [5] [7] We found that coronary artery abnormalities can be evident in the first two weeks and tend to have a rapid resolution, with only one patient in this study demonstrating persistence of aneurysms. One-third (33%) of our patients (4/12) had coronary aneurysms. This is higher than a recent report by Capone et al, in which 5 of the 33 (15%) patients with MIS-C showed evidence of coronary aneurysms during in-patient evaluation. [13] It is our practice, as with patients with Kawasaki disease, that children with MIS-C have serial coronary evaluations at 1-2 weeks with a follow-up at 4-6 weeks at minimum. [10] The majority of our patients (80%) received intravenous immunoglobulin therapy, akin to the treatment for Kawasaki disease. None of our patients showed evidence of coronary thrombosis, although all patients received therapeutic anticoagulation based on their hyper-inflammatory state and elevated D-dimer levels. Given the small sample size, clinical distinctions between patients with and without coronary aneurysms was not within the scope of this study. This study provides short-term longitudinal cardiac information for a small number of patients with MIS-C that may aid in clinical management and counseling of families. Medium and long-term follow-up using echocardiography as well as advanced imaging modalities such as cardiac magnetic resonance and computed tomography will be important to provide comprehensive data.