key: cord-0877340-fq8zlil9
authors: Matsubara, Daisuke; Kauffman, Hunter L.; Wang, Yan; Calderon-Anyosa, Renzo; Nadaraj, Sumekala; Elias, Matthew D.; White, Travus J.; Torowicz, Deborah L.; Yubbu, Putri; Giglia, Therese M.; Hogarty, Alexa N.; Rossano, Joseph W.; Quartermain, Michael D.; Banerjee, Anirban
title: Echocardiographic Findings in Pediatric Multisystem Inflammatory Syndrome Associated with COVID-19 in the United States
date: 2020-09-02
journal: J Am Coll Cardiol
DOI: 10.1016/j.jacc.2020.08.056
sha: 3efd45a232ddf9a87b9f2e295449cc50e174668d
doc_id: 877340
cord_uid: fq8zlil9

Background Centers from Europe and United States have reported an exceedingly high number of children with a severe inflammatory syndrome in the setting of COVID-19, which has been termed multisystem inflammatory syndrome in children (MIS-C). Objectives This study aimed to analyze echocardiographic manifestations in MIS-C. Methods We retrospectively reviewed 28 MIS-C, 20 healthy controls and 20 classic Kawasaki disease (KD) patients. We reviewed echocardiographic parameters in acute phase of MIS-C and KD groups, and during subacute period in MIS-C group (interval: 5.2 ± 3 days). Results Only 1 case in MIS-C (4%) manifested coronary artery dilatation (z score=3.15) in acute phase, showing resolution during early follow up. Left ventricular (LV) systolic and diastolic function measured by deformation parameters, were worse in MIS-C compared to KD. Moreover, MIS-C patients with myocardial injury (+) were more affected than myocardial injury (-) MIS-C with respect to all functional parameters. The strongest parameters to predict myocardial injury in MIS-C were global longitudinal strain (GLS), global circumferential strain (GCS), peak left atrial strain (LAS) and peak longitudinal strain of right ventricular free wall (RVFWLS) (Odds ratio: 1.45 (1.08-1.95), 1.39 (1.04-1.88), 0.84 (0.73-0.96), 1.59 (1.09-2.34) respectively). The preserved LVEF group in MIS-C showed diastolic dysfunction. During subacute period, LVEF returned to normal (median: from 54% to 64%, p<0.001) but diastolic dysfunction persisted. Conclusions Unlike classic KD, coronary arteries may be spared in early MIS-C, however, myocardial injury is common. Even preserved EF patients showed subtle changes in myocardial deformation, suggesting subclinical myocardial injury. During an abbreviated follow-up, there was good recovery of systolic function but persistence of diastolic dysfunction and no coronary aneurysms. Condensed abstract Multisystem inflammatory syndrome in children (MIS-C) is an illness that resembles Kawasaki Disease (KD) or toxic shock, reported in children with a recent history of COVID-19 infection. This study analyzed echocardiographic manifestations of this illness. In our cohort of 28 MIS-C patients, left ventricular systolic and diastolic function were worse than in classic KD. These functional parameters correlated with biomarkers of myocardial injury. However, coronary arteries were typically spared. The strongest predictors of myocardial injury were global longitudinal strain, right ventricular strain, and left atrial strain. During subacute period, there was good recovery of systolic function, but diastolic dysfunction persisted.

The novel coronavirus disease of 2019 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has infected individuals of all ages in nearly every country on Earth. In Europe, Italy was the first country to be affected significantly by the outbreak of COVID-19, which began there in February, 2020 More recently, several centers in the United States and Europe have reported similar KDlike illness or symptoms of toxic shock syndrome, in children who have tested positive for COVID-19 (2, 3) . These patients may develop a cytokine storm possibly due to activation of macrophages, similar to the secondary hemophagocytic lymphohistiocytosis syndrome triggered by some other viral infections (4) . The condition has been termed "Multi-system Inflammatory Syndrome in Children (MIS-C)" or "Paediatric multisystem inflammatory syndrome (PMIS)" and is characterized by a hyperinflammatory syndrome with multi-organ dysfunction (3, 5, 6) .

The disease appears to be a delayed post-infectious response with a lag-time of 4-6 weeks following mostly asymptomatic exposure to the SARS-CoV-2 (7) . This diagnosis has received wide-spread coverage in the lay press and has been a cause for consternation for both physicians and parents alike, due to a paucity of published research about its cardiac manifestations.

Recent studies have described coronary artery anomalies and conventional echocardiographic parameters like EF and annular velocities in MIS-C patients. However, the J o u r n a l P r e -p r o o f detailed analysis of cardiac mechanics using deformation parameters are lacking. Deformation parameters are sensitive tools to detect subtle changes in myocardial function and have not been studied in this disease (8). Moreover, comparison of MIS-C with classic KD is sparse in published literature and needs to be studied in greater detail.

Our group set out to analyze primarily the cardiac manifestations of MIS-C, following a positive diagnosis of COVID-19. Our aim was to describe anatomic and functional echocardiographic manifestations of this disease in children. We hypothesize that MIS-C may be associated with reduced systolic and diastolic function similar to other forms of viral myocarditis and may produce dilatation of coronary arteries similar to KD.

This is a retrospective, single-center study performed at The Children's Hospital of Philadelphia, USA. We retrospectively reviewed data from patients who were admitted to our institution and its affiliate institutions with the diagnosis of MIS-C over a two-month period, from April 10 to June 7, 2020. The clinical diagnosis of MIS-C was made according to the health advisory put forth by the Centers for Disease Control and Prevention (CDC), USA and the World Health Organization (WHO) (3, 5) .

All patients were tested for the SARS-CoV-2 virus during the hospital course by nasopharyngeal swab polymerase chain reaction (PCR) and a chemiluminescent microparticle immunoassay for the qualitative detection of IgG antibodies to the nucleocapsid protein of the SARS-CoV-2. The patients were formally diagnosed with COVID-19 infection if any of these tests were positive. We excluded MIS-C patients with underlying cardiac diseases, with acute respiratory distress syndrome, those treated with extracorporeal membrane oxygenation therapy, J o u r n a l P r e -p r o o f as well as those who had undergone chemotherapy in the past. We classified MIS-C patients as "KD-like" or "Toxic shock-like" based on their symptoms. Shock like presentation was characterized by signs of cardiovascular collapse requiring volume resuscitation and vasopressors, and requiring intensive care. Moreover, we divided MIS-C patients into two groups: a clinically suspected myocardial injury (+) group versus myocardial injury (-) group.

Since none of the patients underwent endomyocardial biopsies or cardiac magnetic resonance imaging (CMRI), we defined myocardial injury based on two biomarkers, elevated Brain Natriuretic Peptide (BNP) (>500 pg/mL) and/or positive Troponin-I (> 0.3 ng/mL) (9, 10). We further divided MIS-C patients into two additional groups: preserved left ventricle (LV) ejection fraction (EF) group (LVEF≥ 55%) versus impaired LVEF (LVEF< 55%) group (11).

As a control group, we included 20 healthy controls among similar age groups with no structural and functional heart defects, who visited our hospital before the COVID-19 pandemic for evaluation of heart murmurs, chest pain or syncope. In addition, we included a second control group of 20 consecutive patients of classic KD from the pre-COVID-19 pandemic era (from January, 2019 to December, 2019). These classic KD patients had no previous episodes of KD and were studied within the first 7 days of their illness.

We reviewed echocardiographic images in the acute phase in our MIS-C and KD groups. In majority the initial echocardiographic examination was performed before the administration of intravenous immunoglobulin. Follow-up echocardiographic images in subacute period were also reviewed in the MIS-C group.

2D echocardiography was performed by experienced cardiac sonographers using 2 different ultrasound systems. In order to observe infection control protocols, for some of the J o u r n a l P r e -p r o o f MIS-C patients, Affiniti 70C ultrasound system (Philips Medical Systems, Andover, MA, USA) was used. For the rest of the COVID-19 patients, all the KD patients and all normal controls, the EPIC CVx ultrasound system (Philips Medical Systems, Andover, MA, USA) was used.

Standard echocardiographic measurements were made in accordance with ASE guidelines including LVEF using Simpson's biplane method, the early and late mitral inflow peak velocities by spectral Doppler, tricuspid annular plane systolic excursion (TAPSE) by M-mode and the early diastolic septal and lateral mitral annular peak velocities and lateral tricuspid annular peak velocity by tissue Doppler. LVEF was confirmed by expert reviewers in all MIS-C patients.

In addition, we paid special attention to evaluate coronary artery abnormalities in both the KD and MIS-C groups in accordance with standard guidelines. Coronary artery z-scores were derived from previously described normative data (Boston z score system) and used to classify coronary artery abnormalities as follows; Normal= <2, Dilatation= > 2 to <2.5, Aneurysm= ≥2.5.

Based on the AHA statement paper of the Kawasaki disease committee, we defined ectasia as coronary dilatation without a segmental aneurysm (12). Before listing coronary arteries as dilated or aneurysmal, the measurements were rechecked by 2 investigators (AB, MQ) blinded to clinical data.

Myocardial deformation was assessed offline using two-dimensional speckle tracking vendor-independent software (2D CPA 1.3.0.91; TomTec Imaging Systems, Munich, Germany).

The endocardial border in LV was automatically traced after manually setting the timing of enddiastole and end-systole in a single-loop. The trace was adjusted manually if needed.

Peak longitudinal strain (LS) and systolic longitudinal strain rate (LSR) were calculated by the software from 4, 3, and 2-chamber images, and averaged for global LS (GLS) and global J o u r n a l P r e -p r o o f LSR (GLSR). Longitudinal early diastolic strain rate (EDSR L ), peak global left atrial strain (LAS), and peak longitudinal strain of the right ventricular free wall (RVFWLS) were measured from 4 chamber images. Peak circumferential strain (CS), systolic circumferential SR (CSR), circumferential early diastolic strain rate (EDSR C ) were measured from mid-cavity short-axis views. Segments with unreliable tracking on visual inspection were excluded from the analysis.

Continuous data were expressed as median and interquartile range (IQR). Differences between an acute and a follow-up study in the MIS-C group were assessed using Wilcoxon signed rank sum test while in independent 3 groups were assessed using Kruskal-Wallis test followed by Steel-Dwass's test for pairwise comparisons. For conventional diastolic parameters we did not perform statistical analysis between MIS-C and KD groups, due to a big difference in age between the two groups. To asses for predictors of myocardial injury in patients presenting with MIS-C, a logistic regression analysis was performed for each echocardiographic measurement of interest adjusted by age and sex. Correlation coefficients between 2 variables were calculated using Spearman's rank order correlation test. A p value < 0.05 was considered as statistical significance. Paired t-test was performed to analyze the follow-up data. Intra-and inter-observer variabilities for deformation parameters used in this study have shown high degree of reproducibility in our laboratory, based on several recent research projects and were not repeated for this study (13, 14, 15) . J o u r n a l P r e -p r o o f

A total of 28 MIS-C patients were included in this study. Table 1 shows demographic data for our 3 groups of patients, while Supplementary Table 1 Table 3 . During early follow-up (interval of 5.2 ± 3 days) we evaluated 20 out of 28 patients (71%) in MIS-C cohort, since some patients were followed by other institutions. Table 2 shows conventional echocardiographic parameters and Table 3 shows the results of coronary artery echocardiography. It is noteworthy, that among 28 MIS-C patients only 1 case Compared to the classic KD group, MIS-C patients had more mitral regurgitation (MR) (46% vs 15%, p=0.06), more pericardial effusion (32% vs 15%, p=0.46) and more pleural effusion (39% vs 0%, p=0.004). In addition, MIS-C patients with suspected myocardial injury (+) showed a greater frequency of these anomalies than the myocardial injury (-) cases. Table 4 shows the results of deformation parameters in 3 groups. Compared to the normal group, MIS-C patients showed both LV systolic and LV diastolic dysfunction. In addition, peak LA strain and peak RVFWS were also significantly lower in MIS-C patients. (table 7 ). In addition, the preserved LVEF group showed diastolic dysfunction in many echocardiographic parameters.

During early follow-up studies (interval of 5.2 ± 3 days), most of the MIS-C patients returned to normal LVEF (median LVEF: from 54% to 64%, p<0.001) but retained a lower GLS (median: from -15.5% to -18.7%, p<0.001). (Published vendor-and age-specific normal range for GLS is -19.5% to -20.8%, from meta-analysis in children) (17) . In addition, diastolic dysfunction persisted (Table 8, (Table 9) , with LAS and RVFWS showing the highest correlation.

with recent COVID-19 infection have presented with a KD-like or toxic shock like illness, J o u r n a l P r e -p r o o f known as MIS-C. In this pilot study, we have described detailed echocardiographic findings of MIS-C (Central Illustration). Recent studies from continental Europe, England (19) and the USA (20) have described coronary artery anomalies and conventional echocardiographic parameters in MIS-C patients. However, the detailed analysis of cardiac mechanics using deformation parameters derived not only from the LV, but also from the LA and RV in MIS-C patients, is novel and has not been reported previously in children and sparsely in adults (single study on RV strain in adults) (21) . This study demonstrates that the coronary arteries may not be frequently affected in the acute phase and in the early follow-up period of MIS-C. The major finding during the acute phase of MIS-C is a myocarditis-like picture, that may remain subtle and sub-clinical, particularly in the preserved EF cohort. Even in the presence of normal EF, the latter group showed distinct dysfunction in systolic and diastolic deformation parameters. LA strain, which is an index of atrio-ventricular coupling and a marker of diastolic dysfunction, was markedly reduced. In addition, RVFWS was significantly decreased in MIS-C patients, and proved to be strongly associated with myocardial injury in MIS-C. During early follow-up, most of the MIS-C patients returned to normal systolic function, however, diastolic dysfunction persisted.

The coronary arteries were spared in most MIS-C patients in our cohort of U.S. patients.

However, due to the small size of our cohort, no definitive statement can be made. Most patients with MIS-C who had a Kawasaki like presentation were treated with IVIG in our institution. In this pilot study, due to the small sample size, we cannot comment whether the use of IVIG had any coronary-protective effect. Due to unfamiliarity with MIS-C, physicians in most countries have empirically used all medications like aspirin, IVIG and methylprednisolone, that are usually J o u r n a l P r e -p r o o f reserved for treatment of KD, as previously described in a smaller case series at our institution (22) . Both in the treated and untreated groups, the coronary artery involvement was quite infrequent. This is in line with the findings of the Italian study by Verdoni (1) and the French study by Belhadjer et al (23) . In both these European studies, there was mild dilatation of the coronary arteries in < 20% patients, but no discrete, segmental aneurysms were noted in either European study. In our cohort, only 1 patient (4%) had coronary ectasia (z score: +3.15) in the acute phase, which returned to normal during the early follow-up stage. In the brief follow-up period described in our study, no other progressive coronary lesions were noted. However, a longer follow-up period may be needed to fully understand the outcome of this novel illness. The

Italian study used the older Japanese Ministry of Health and Welfare criteria for coronary aneurysms (>4 mm in patients ≥5 years of age), whereas, the French study utilized coronary artery z-scores and found 17% patients with coronary dilatation (z-score > 2 but <2.5) and no coronary aneurysms. It is our opinion that established coronary z-scores should be utilized worldwide, for reporting coronary dimensions in children with MIS-C. This would lead to consistency in data analysis across centers world-wide. Some studies in MIS-C have used a zscore of >2 to define coronary artery "aneurysms", which may lead to an overestimate of true coronary aneurysms. Researchers should take into account the phenomenon of transient coronary dilatation in viral myocarditis in children (24) and in non-KD, febrile illnesses, where the z scores may exceed 2 but virtually never >2.5 (25) . Moreover, the term "prominent" coronary arteries should be avoided, lest readers consider it as a true coronary artery abnormality, thereby, leading to unnecessary consternation (Figure 1 ). It has been proposed that transient coronary dilations in the acute phase of KD could reflect a physiologic response to increased myocardial J o u r n a l P r e -p r o o f of elevated bio-markers and decreased GLS, LAS and EDSR. The combination of these strain features is strongly suggestive of underlying myocarditis. This is supported by a case series that showed CMRI findings in MIS-C (30) . In the acute phase of MIS-C, 3 cases with increased BNP and troponin-I levels, showed diffuse myocardial hyperemia and edema by CMRI, without evidence of fibrosis/myocardial necrosis by late gadolinium enhancement, suggesting presence of myocarditis, in this limited number of patients.

The use of LA strain in assessment of diastolic dysfunction is novel in this study and it proved to be the strongest single index associated with myocardial injury. Peak LAS has not been previously studied in children with myocarditis and may serve as a good index of atrioventricular coupling and LV diastolic dysfunction. Studies in children with enlarged LA from multiple causes, have demonstrated decreased peak longitudinal strain (decreased reservoir function) and increased LA stiffness (15) . Studies in adults with HFpEF have shown that LA strain decreases with worsening diastolic dysfunction in a stepwise fashion and reflects increased LV filling pressures (31) . In these publications in adults, there has been a call for incorporating LA strain into the 2016 diastolic function guidelines published by the ASE. CMRI feature tracking analysis of myocarditis in adults confirmed by the Lake Louise Criteria, showed significantly lower peak LA strain in myocarditis patients compared to controls (32) , which is in concordance with our study.

In addition to LV, the RV deformation was decreased in MIS-C patients, a finding that has been reported in a single study on adult patients with COVID-19 from Wuhan, China but not in children. They showed that RVFWLS cut off value of -23% was a significant predictor of mortality in adults aged 61 ± 14 years during a median follow-up period of 51 days (21) . Our J o u r n a l P r e -p r o o f MIS-C patients all survived with good outcome, however, in our study RVFWLS was strongly associated with myocardial injury.

An adult study from the Wuhan cohort concluded that myocardial damage contributed to 40% of SARS-CoV-2 deaths (33) . The incidence of myocarditis in 112 COVID-19 patients from Wuhan, China diagnosed by elevated Troponin-I (> 0.12 ng/mL), abnormalities on standard echocardiograms, and/or electrocardiograms was 12.5% (34) . Despite using a higher Troponin-I value (> 0.3 ng/mL) to define myocardial injury in our study, the incidence of myocardial injury was much higher (60%) in our MIS-C cohort. This is consistent with a paper by DuFort et al.

showing an incidence of myocarditis of 53% in MIS-C patients (29) .

A recent report from New York City, the initial epicenter of COVID-19 in the US, studied the impact of elevated troponin levels in >2700 hospitalized adults with COVID-19 infection (35) . They showed that even a small increase in Troponin I level (0.03-0.09 ng/mL) in adults with COVID-19, was significantly associated with higher risk of mortality during hospitalization. In contrast, most of our MIS-C patients, even with high Troponin I levels, recovered their systolic function quickly. Therefore, we speculate that the elevation in cardiac troponins may have less dire implications in children so far, likely due to a more transient type of cardiac injury and less co-morbidities. Clearly further studies are needed before a definitive statement can be made. In the largest study in hospitalized children so far, the diagnosis of SARS-CoV-2 infection was confirmed in 95 children. Out of these 95 children fortunately only 2 died (2.1%). This is far less than the death rate in hospitalized adults with COVID-19 with troponin elevation (~18.5%) (35) . Nevertheless, close longitudinal follow-up of these patients is essential.

MIS-C is a relatively rare disease affecting only 0.6% in children infected by COVID-19 (29) . Although MIS-C shares similarities with KD, it is notably distinct in that the coronary arteries may be often spared and there is a higher frequency of LV dysfunction, myocarditis and shock. However, the similarity of this condition to KD has received wide-spread attention both in the medical and lay community. The acute echocardiographic findings, which appear to be usually reversible from our study based on a U.S. population, may help U.S. clinicians educate families regarding the acute-and short-term status of the heart in MIS-C.

The small sample size of MIS-C patients is an important limitation of this study. MIS-C is a novel disease and is not well studied. With this in mind, our study has enrolled perhaps the maximal achievable number of patients for a single, tertiary care center collected within a short time frame of 2 months, which is comparable even with multicenter U.S. and European studies (20, 23) . The short time frame was chosen as it is important to provide detailed cardiac findings about this virtually unknown disease, to front-line physicians. During data collection, echocardiography was performed under strict infection-control regulations, where sonographers were required to observe the appropriate protocol for contact minimization and the use of personal protective equipment. Therefore, under such circumstances, the quality of echocardiography may have been affected. In addition, the novel status of this condition and the need to report findings from acute stages, do not allow for prolonged longitudinal follow-up, similar to that performed in KD. Because of this urgency to disseminate our data, we were unable to perform the 2-6 week follow-up, that is typically performed in KD. A longer follow-up should be the focus of future studies. In this study our primary focus was to describe J o u r n a l P r e -p r o o f echocardiographic findings in MIS-C patients. We have, therefore, not delved into issues related to critical care, e.g. ventilator settings, coagulation status, renal dysfunction, brain related issues etc. Recently published U.S. and European studies have addressed these aspects (20, 23) . Classic KD (n=20)

GLS (%) Table 6 . Logistic regression analysis for predictors of myocardial injury in patients presenting with MIS-C.

Myo. injury (-) (n=11)

Myo. injury (+) (n=17) OR (95% CI) 

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study

Hyperinflammatory shock in children during COVID-19 pandemic

CDC Health Alert Network. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19). Available at

COVID-19: consider cytokine storm syndromes and immunosuppression

Multisystem inflammatory syndrome in children and adolescents with COVID-19

Guidance -Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS)

SARS-CoV-2-related Paediatric Inflammatory Multisystem Syndrome, an Epidemiological Study

Decreased Right Ventricular Longitudinal Strain in Children With Hypoplastic Left Heart Syndrome During Staged Repair and Follow-Up: Does It Have Implications in Clinically Stable Patients?

Left Atrial Mechanics in Children: Insights From New Applications of Strain Imaging

Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism

Rheumatology International Trials Organisation Collaborative Initiative

Reference Ranges of Left Ventricular Strain Measures by Two-Dimensional Speckle-Tracking Echocardiography in Children: A Systematic Review and Meta-Analysis

Normal Ranges of Right Ventricular Systolic and Diastolic Strain Measures in Children: A Systematic Review and Meta-Analysis

Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2

Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With SARS-CoV-2 Infection: A Multi-institutional Study From New York City

Prognostic Value of Right Ventricular Longitudinal Strain in Patients with COVID-19

Multisystem Inflammatory Syndrome in Children During the COVID-19 Pandemic: A Case Series

Acute Heart Failure in Multisystem Inflammatory Syndrome in Children (MIS-C) in the Context of Global SARS-CoV-2 Pandemic. Circulation

Coronary Artery Dilatation in Viral Myocarditis Mimics Coronary Artery Findings in Kawasaki Disease

Coronary Artery Dilation in Acute Kawasaki Disease and Acute Illnesses Associated With Fever

Paediatric Inflammatory Multisystem Syndrome: Temporally Associated With SARS-CoV-2 (PIMS-TS): Cardiac Features, Management and Short-Term Outcomes at a UK Tertiary Paediatric Hospital

Examining the Utility of Coronary Artery Lack of Tapering and Perivascular Brightness in Incomplete Kawasaki Disease

Describing Kawasaki shock syndrome: results from a retrospective study and literature review

Multisystem Inflammatory Syndrome in Children in New York State

Cardiac MRI of Children With Multisystem Inflammatory Syndrome (MIS-C) Associated With COVID-19: Case Series

LA Strain for Categorization of LV Diastolic Dysfunction

Left and Right Atrial Feature Tracking in Acute Myocarditis: A Feasibility Study

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Suspected Myocardial Injury in Patients With COVID-19: Evidence From Front-Line Clinical Observation in Wuhan, China

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection

We wish to express our deepest appreciation to the brave sonographers of our institution, who have acquired the images used for this study, during this ominous pandemic.