key: cord-0794841-ldwt2glc
authors: Hejazi, Omar I.; Loke, Yue-Hin; Harahsheh, Ashraf S.
title: Short-term Cardiovascular Complications of Multi-system Inflammatory Syndrome in Children (MIS-C) in Adolescents and Children
date: 2021-10-22
journal: Curr Pediatr Rep
DOI: 10.1007/s40124-021-00258-5
sha: 267c0a851bfe97ff2c37f8758e2a0fe13ab2ec6a
doc_id: 794841
cord_uid: ldwt2glc

PURPOSE OF REVIEW: We provide the readers with a review of cardiac complications in children with multi-system inflammatory syndrome in children (MIS-C) and its short-term outcomes. RECENT FINDINGS: Recent reports described the acute cardiac manifestations of MIS-C in children and provided a glimpse of the short-term outcomes. SUMMARY: Children with MIS-C have been reported to acutely have variable degrees of cardiac findings including abnormal cardiac enzymes, abnormal electrocardiographs, decreased systolic function, coronary artery abnormalities from coronary dilation to giant aneurysms, mitral valve regurgitation, tricuspid valve regurgitation, aortic valve insufficiency, pericardial effusion, diastolic dysfunction, abnormal cardiac strain, and abnormal cardiac MRI. The majority of these abnormalities resolved during short-term follow-up. Further studies are needed to assess if transient or persistent cardiac complications are associated with long-term adverse cardiac events in children with MIS-C. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40124-021-00258-5.

On 4/26/2020, a new illness emerged in children exposed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. This illness, categorized by severe inflammatory response, received multiple nomenclature including the multi-system inflammatory syndrome in children (MIS-C) [2•, 3•] . As we passed the first anniversary, we provide the readers with a review of cardiac complications in children with MIS-C and its short-term outcomes.

Early in the 2019 coronavirus disease (COVID-19) pandemic, previously healthy children were thought to have been spared from severe disease [4] . However, we quickly learned how unpredictable this illness can be as MIS-C emerged with reports of mortalities in the pediatric population [5-7, 8•, 9, 10] . Following early experience, centers and societies developed diagnostic and treatment algorithms to properly treat children with MIS-C [11••, 12••] . It is now considered prudent for providers to identify cases of MIS-C early in their illness and provide timely immune modulation therapy. Children with MIS-C have been reported to have variable degrees of cardiac findings including abnormalities of cardiac enzymes, electrocardiogram (EKG), echocardiogram, and cardiac Magnetic Resonance Imaging (MRI) (Fig. 1, Tables 1-2 ).

Cardiac enzymes including B-type natriuretic peptide (BNP) (pg/mL), N-terminal BNP (NT-pro BNP) (pg/mL), and troponins were noted to be elevated in some patients with MIS-C. In patients who developed shock, the median (interquartile (IQR)) troponin (ng/L) was 45 ) and the median NT-pro BNP was 788 (174-10,548) [8•] . Other reports have also described similar elevation in cardiac enzymes [13••, 14-26] . Cardiac enzyme elevation has also been reported in other cardiac diseases. Troponin (ng/L) was noted to be elevated in children with acute myocarditis 80 (10-4930) [27] . NT-pro BNP (pg/mL) was shown to be elevated in children with cardiac disease (median: 548, range: 5-35,000) and helped differentiate them from other etiologies [28] . In some articles discussing MIS-C, the elevated cardiac enzymes were further stratified by clinical presentation. For example, the NT-pro BNP (ng/mL) and troponin were 2,148 ± 259 and 0.4 ± 0.5 in Kawasaki disease (KD), 7443 ± 15,975 and 1.0 ± 2.0 in incomplete KD, and 17,678 ± 39,609 and 1.0 ± 1.7 in shock presentations, respectively [29] . Matsubara 

MIS-C causes a variety of EKG changes. Conduction abnormalities including atrioventricular (AV) blocks, bradycardia, and tachyarrhythmias including ventricular arrhythmia, ST-segment or T-wave changes, and long QTc are all possible findings in MIS-C [8•, 16, 18, 20, 26, 29, 31] ( Table 2) . Further studies are needed to assess correlation of ECG changes with clinical outcomes or other cardiac findings.

Multiple echocardiographic findings have been reported in children with MIS-C including decreased systolic function, coronary artery abnormalities, valve regurgitation, and pericardial effusion.

Decreased systolic function was defined as left ventricular ejection fraction (LVEF) below 55% [32] . Decreased LVEF was reported in 13-100% of published cohorts [13••, 14-16, 19, 21, 22, 25, 29, 30•, 33••] (Table 2 ). In some MIS-C patients, LV systolic dysfunction was reported in those who developed shock [8•] . LV systolic dysfunction was not only reported on admission but also occurred later during admission emphasizing the importance of frequent echocardiogram assessment in this population [26] . In a study that recruited MIS-C children with decreased LV function, 25 (71%) had mild to moderate systolic dysfunction (an EF between 30 and 50%) and 10 (29%) patients had severe systolic dysfunction (EF below 30%) [31] . Clark et al. further categorized the degree of systolic function impairment with 11 (32%) patients with mild systolic dysfunction (EF 41-50%), and six (17%) patients with moderate to severe systolic dysfunction (an EF < 40%) [20] . One patient was reported by Kappanayil et al. to have a severely reduced EF of 10% [24] . What is lacking in these studies is the timing of echocardiogram to immune therapy and declaration of simultaneous inotropic or respiratory support at the time of obtaining the echocardiogram. As EF is known to be preload dependent, one wonders if frequency of systolic dysfunction 

Coronary artery abnormality (CAA) was defined as a dilation if the Z score was 2 to < 2.5, small aneurysm 2.5 to < 5, moderate aneurysm 5 to < 10, and giant aneurysm referred to a Z score ≥ 10 or an actual measurement of ≥ 8 mm and has been described in children with MIS-C raising initial interest among the KD expert community [ 

Variable degrees of atrioventricular valve regurgitation and aortic valve insufficiency (AI) have been described in children with MIS-C. When excluding studies that included less than 50 patients, the reported incidence of valvular regurgitation or insufficiency is 24 [14] . It is yet to be determined if valve regurgitation in children with MIS-C relates to inflammation of the valve itself (valvulitis) or secondary to ventricular dilation. In one report, the authors concluded that the MR seen in 2 (50%) patients was related to LV dilation [26] .

Pericardial effusion occurred in 9-28% after excluding studies that included less than 50 patients ( 

In light of these clinical cardiac complications from MIS-C, multiple centers are proactively utilizing CMR to follow up these patients in prospective observational studies [44] [45] [46] . Such efforts are critical, as CMR findings from published case series are generally limited by inconsistent timing of CMR in relation to onset of disease (in some centers, CMR was performed during acute phase, whereas others waited at least 6 weeks to 3 months). In general, CMR findings include pericardial effusion, abnormal T2 myocardial values/ hyperintense myocardium on T2-weighted imaging (representing myocardial edema), early gadolinium enhancement (representing capillary leak/hyperemia), and late gadolinium enhancement (representing myocardial necrosis/fibrosis) [47] . [14] . This is of importance as late gadolinium enhancement was found to correlate with worse composite outcome of all-cause mortality, cardiac mortality, and/ or major adverse cardiovascular events in adults with acute myocarditis [48] . Although pediatric data is very limited, late gadolinium enhancement correlated with increased risk of worse outcomes [49, 50] . There is also ongoing assessment of native T1/T2 changes by parametric mapping which are now encouraged in CMR evaluation of nonischemic myocardial inflammation [47, 51] .

Abnormal myocardial strain and abnormal diastolic function have been described in children with MIS-C. Myocardial strain takes into account the heterogenous motion of the myocardial wall, providing an angle-independent quantification of deformation in radial, circumferential, and longitudinal directions. In general, the more negative a strain value, the better it corresponds to myocardial function. However, interpreting the significance of myocardial strain across MIS-C studies is challenged by interobserver variability that is vendor dependent (machine used for acquisition, and software used for strain analysis) [52] . Reference ranges have been developed for left ventricular strain values based on age and vendor [53] , and Valverde et al. used this to identify that 5/44 (11.4%) had reduced LVGLS [14] .

Other studies have opted to compare MIS-C patients against other historical cohorts such as healthy controls or KD patients. For example, Matsubara et al. reported that the median LVGLS in MISC was worse at − 16.2 (IQR − 19.5 to − 13.6), compared to healthy controls at − 22.5 (IQR − 23.7 to − 21.1, p < 0.001) and classic KD at − 20.1 (− 21.8 to − 18.1). Other systolic strain parameters such as global circumferential strain (GCS), LAS, and RVFWLS also demonstrated similar patterns. Interestingly, diastolic parameters such as circumferential/longitudinal strain rate in early diastole and peak pulsed wave tissue Doppler diastolic velocities in lateral mitral annulus were different and persisted despite subsequent improvement in systolic function [30•, 54, 55] .

Despite reported that patients with worse LVGLS had higher serum biomarkers and disease severity, i.e., more likely to present in shock, require intensive care unit (ICU) stay/inotropic support and mechanical life support, and longer hospital length of stay [55, 56 ••] . Early strain quantification may identify a sub-group to intensify monitoring and therapy to help prevent clinical deterioration.

As we commemorated the 1-year anniversary of the first report of MIS-C, several publications have reported the short-term outcomes of cardiac complications in children with MIS-C. Although rare, mortality occurred in 1-2% of patients with MIS-C [13••, 57] . Of the 286 children with MIS-C, one patient died after developing ventricular arrhythmia and another patient developed dilated cardiomyopathy and was listed for heart transplantation [14] . In Bautista-Rodriguez et al.'s report, a patient died after suffering a massive myocardial infarction after developing giant coronary artery aneurysms in all three vessels, another patient died while on ECMO due to cerebral injury, and a third patient died after several cardiac arrests [29] .

ECG abnormalities normalized prior to discharge in 22-100% of patients at a median of 5 days in some patients [14, 20, 26] . LV dysfunction resolved in 58-100% of those with initial systolic dysfunction at a median time of only 2 days in some cohorts [14, 17, 18, 24, 31, 58] . Others also reported that all cardiac findings, including any ECG abnormalities (including 3rd degree AV block), reduced LVEF, MR, and CAAs resolved within 2 weeks [16, 18, 20] [57] .

In some cohorts, cardiac complications persisted at time of last follow-up [21, 33••] . One study found that, at the time of discharge, cardiac complications persisted in 3 (25%) patients [15] . One patient had persistent LAD prominence [17] . As mentioned earlier, GLS remained low and the RV dysfunction persisted despite normalization of LVEF [30• ]. Follow-up for patients in Ramcharan et al. revealed that atrioventricular valve regurgitation persisted in 7/13 (54%) patients. The patient with the lowest EF (28%) (severely reduced) improved to 53% (mildly reduced) at discharge. Mildly decreased systolic function persisted in 1/8 (12.5%) patients [26] . Some studies provided follow-up data on the patients with worst disease (i.e., admitted to ICU). Only two patients out of the 7 who were admitted to the ICU had persistent mild LV dysfunction [19] .

CAAs persisted in few patients with MIS-C. Although cardiac systolic dysfunction, MR, and AI resolved, mild CA enlargement and a small aneurysm in the right CA persisted in one patient [22] . In Gaitonde et al., 2 (16%) had persistent CA dilation at time of last follow-up [42] . Sanil et al. reported resolution of CAAs in 5/6 patients at the 3-and 10-week follow-up visits. The only patient with persistent CAA had CA Z score of 2.4 (dilation) [56 ••] . In a study that focused on follow-up of patients with MISC, after 6 months, one patient had a medium CA aneurysm (Z score 9.8) that was stable [58] . These reports highlight that although mortality did occur in children with MIS-C, it is very rare. More importantly, during the short-term follow-up, most of the cardiac findings resolved.

Supplemental tables 3 to 7 display the demographics, clinical presentations, laboratory evaluation therapies received, clinical course, and outcomes of children with MIS-C. To help ensure we did not double count in the tables, we excluded any US-based study that included patients prior to 1/11/2021 as they were included in Belay et al.'s manuscript [13••] (supplemental Fig. 2 ).

As our community expands its investigations of this relatively new illness, we ought to work collaboratively to answer: 

Cardiac complications in children with MIS-C are not uncommon and have been reported across the globe. Although mortality has occurred, it is very rare and the majority of children with MIS-C had resolution of their cardiac complications. Further studies are needed to assess if transient or persistent cardiac complications are associated with long-term adverse cardiac events.

The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s40124-021-00258-5.

The authors wish to thank Angela J. Doty, MD, and Lindsay Attaway for their editorial assistance.

Author Contribution Omar I. Hejazi contributed to literature review and drafting the manuscript. Yue-Hin Loke was involved in literature review and with revising the manuscript. Ashraf S. Harahsheh was involved in manuscript design, literature review, and manuscript revision. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding All authors have reported that they have no relationships relevant to the contents of this paper to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Dr. Harahsheh is supported by

have been highlighted as: • Of importance •• Of major importance 1. Paediatric multisystem inflammatory syndrome temporally associated with COVID-19

Accessed on 5/16/2020. The CDC case definition utilized in the United States

Multisystem inflammatory syndrome in children: is there a linkage to Kawasaki disease?

Severe coronavirus disease-2019 in children and young adults in the Washington, DC, Metropolitan Region

Children's hospital ambulatory response to the 2019 novel coronavirus disease (COVID-19) pandemic

Missed or delayed diagnosis of Kawasaki disease during the 2019 novel coronavirus disease (COVID-19) pandemic

The "golden hours" algorithm for the management of the multisystem inflammatory syndrome in children (MIS-C)

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

SARS-CoV-2-associated multisystem inflammatory syndrome in children: clinical manifestations and the role of infliximab treatment

Multisystem inflammatory syndrome of children: sub-phenotypes, risk factors, biomarkers, cytokine profiles and viral sequencing

Management of multisystem inflammatory syndrome in children associated with COVID-19: a survey from the International Kawasaki Disease Registry

Trends in geographic and temporal distribution of US children with multisystem inflammatory syndrome during the COVID-19 pandemic

Acute cardiovascular manifestations in 286 children with multisystem inflammatory syndrome associated with COVID-19 infection in Europe

Shock and myocardial injury in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection: what we know. Case Series and Review of the Literature

Cardiac findings in pediatric patients with multisystem inflammatory syndrome in children associated with COVID-19

Myocarditis in multisystem inflammatory syndrome in children associated with coronavirus disease 2019

Kawasaki-like disease and acute myocarditis in the SARS-CoV-2 pandemic-reports of three adolescents

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort

Cardiac abnormalities seen in pediatric patients during the SARS-CoV2 pandemic: an international experience

Defining Kawasaki disease and pediatric inflammatory multisystem syndrometemporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey

Pediatric inflammatory multisystem syndrome with central nervous system involvement and hypocomplementemia following SARS-COV-2 infection

Multiorgan inflammatory syndrome associated with SARS-CoV-2 in a child

Multisystem inflammatory syndrome in a neonate, temporally associated with prenatal exposure to SARS-CoV-2: a case report

Paediatric multisystem inflammatory syndrome associated with COVID-19: filling the gap between myocarditis and Kawasaki?

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

Cardiac troponin T: a marker in the diagnosis of acute myocarditis in children

N-terminal pro-B-type natriuretic peptide levels in children: comparison in cardiac and non-cardiac diseases

Multisystem inflammatory syndrome in children: an international survey

Echocardiographic findings in pediatric multisystem inflammatory syndrome associated with COVID-19 in the United States

Acute heart failure in multisystem inflammatory syndrome in children in the context of global SARS-CoV-2 pandemic

Comparison of echocardiographic and cardiac magnetic resonance imaging measurements of functional single ventricular volumes, mass, and ejection fraction (from the Pediatric Heart Network Fontan Cross-Sectional Study)

Cardiac echocardiogram findings of severe acute respiratory syndrome coronavirus-2-associated multi-system inflammatory syndrome in children

Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council

Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association

Low-molecular-weight heparin vs warfarin for thromboprophylaxis in children with coronary artery aneurysms after Kawasaki disease: a pragmatic registry trial

Medium-term complications associated with coronary artery aneurysms after Kawasaki disease: a study from the international Kawasaki Disease Registry

Comparison between currently recommended long-term medical management of coronary artery aneurysms after Kawasaki disease and actual reported management in the last two decades

Development and utility of quality metrics for ambulatory pediatric cardiology in Kawasaki disease

Kawasaki disease shock syndrome versus classical Kawasaki disease, a meta-analysis and comparison with SARS-CoV-2 multisystem inflammatory syndrome

Multisystem inflammatory syndrome associated with SARS-CoV-2 infection in 45 children: a first report from Iran

COVID-19-related multisystem inflammatory syndrome in children affects left ventricular function and global strain compared with Kawasaki disease

Cardiac MRI in children with multisystem inflammatory syndrome associated with COVID-19

Long-term outcomes after the multisystem inflammatory syndrome in children

COVID-19: pediatric research immune network on SARS-CoV-2 and MIS-C (PRISM)

830852? term= DeBia si& draw= 2& rank=1

Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations

Prognostic impact of late gadolinium enhancement by cardiovascular magnetic resonance in myocarditis: a systematic review and metaanalysis

Cardiovascular magnetic resonance techniques and findings in children with myocarditis: a multicenter retrospective study

Analysis of clinical parameters and cardiac magnetic resonance imaging as predictors of outcome in pediatric myocarditis

Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: a consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imaging (EACVI)

Head-to-head comparison of global longitudinal strain measurements among nine different vendors: the EACVI/ ASE inter-vendor comparison study

Reference ranges of left ventricular strain measures by two-dimensional speckletracking echocardiography in children: a systematic review and meta-analysis

Multimodality cardiac evaluation in children and young adults with multisystem inflammation associated with COVID-19

Detailed assessment of left ventricular function in multisystem inflammatory syndrome in children using strain analysis

Echocardiographic indicators associated with adverse clinical course and cardiac sequelae in multisystem inflammatory syndrome in children with coronavirus disease 2021

Characteristics and outcomes of US children and adolescents with multisystem inf lammatory syndrome in children (MIS-C) compared with severe acute COVID-19

6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study