MIS-C across three SARS-CoV-2 variants: Changes in COVID-19 testing and clinical characteristics in a cohort of U.S. children.

As new variants of SARS-Co-V 2 have emerged over time and Omicron sub-variants have become dominant, the severity of illness from COVID-19 has declined despite greater transmissibility. There are fewer data on how the history, diagnosis, and clinical characteristics of multisystem inflammatory syndrome in children (MIS-C) have changed with evolution in SARS-CoV-2 variants. We conducted a retrospective cohort study of patients hospitalized with MIS-C between April 2020 and July 2022 in a tertiary referral center. Patients were sorted into Alpha, Delta, and Omicron variant cohorts by date of admission and using national and regional data on variant prevalence. Among 108 patients with MIS-C, significantly more patients had a documented history of COVID-19 in the two months before MIS-C during Omicron (74%) than during Alpha (42%) (p = 0.03). Platelet count and absolute lymphocyte count were lowest during Omicron, without significant differences in other laboratory tests. However, markers of clinical severity, including percentage with ICU admission, length of ICU stay, use of inotropes, or left ventricular dysfunction, did not differ across variants. This study is limited by its small, single-center case series design and by classification of patients into era of variant by admission date rather than genomic testing of SARS- CoV-2 samples.     Conclusion: Antecedent COVID-19 was more often documented in the Omicron than Alpha or Delta eras, but clinical severity of MIS-C was similar across variant eras. What is Known: • There has been a decrease in incidence of MIS-C in children despite widespread infection with new variants of COVID-19. • Data has varied on if the severity of MIS-C has changed over time across different variant infections. What is New: • MIS-C patients were significantly more likely to report a known prior infection with SARS-CoV-2 during Omicron than during Alpha. • There was no difference in severity of MIS-C between the Alpha, Delta, and Omicron cohorts in our patient population.

COVID-19 Positive Versus Negative Complete Kawasaki Disease: A Study from the International Kawasaki Disease Registry.

To determine clinical differences for children with complete Kawasaki disease (KD) with and without evidence of preceding SARS-CoV-2 infection. From January 2020, contemporaneous patients with complete KD criteria were classified as either SARS-CoV-2 positive (KDCOVID+; confirmed household exposure, positive PCR and/or serology) or SARS-CoV-2 negative (KDCOVID-; negative testing and no exposure) and compared. Of 744 patients in the International Kawasaki Disease Registry, 52 were KDCOVID- and 61 were KDCOVID+. KDCOVID+ patients were older (median 5.5 vs. 3.7 years; p < 0.001), and all additionally met diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C). They were more likely to have abdominal pain (60% vs. 35%; p = 0.008) and headache (38% vs. 10%; p < 0.001) and had significantly higher CRP, troponin, and BUN/creatinine, and lower hemoglobin, platelets, and lymphocytes. KDCOVID+ patients were more likely to have shock (41% vs. 6%; p < 0.001), ICU admission (62% vs. 10%; p < 0.001), lower left ventricular ejection fraction (mean lowest LVEF 53% vs. 60%; p < 0.001), and to have received inotropic support (60% vs. 10%; p < 0.001). Both groups received IVIG (2 doses in 22% vs. 18%; p = 0.63), but KDCOVID+ were more likely to have received steroids (85% vs. 35%; p < 0.001) and anakinra (60% vs. 10%; p = 0.002). KDCOVID- patients were more likely to have medium/large coronary artery aneurysms (CAA, 12% vs. 0%; p = 0.01). KDCOVID+ patients differ from KDCOVID-, have more severe disease, and greater evidence of myocardial involvement and cardiovascular dysfunction rather than CAA. These patients may be a distinct KD phenotype in the presence of a prevalent specific trigger.

Tachyarrhythmias During Hospitalization for COVID-19 or Multisystem Inflammatory Syndrome in Children and Adolescents.

Background Cardiac complications related to COVID-19 in children and adolescents include ventricular dysfunction, myocarditis, coronary artery aneurysm, and bradyarrhythmias, but tachyarrhythmias are less understood. The goal of this study was to evaluate the frequency, characteristics, and outcomes of children and adolescents experiencing tachyarrhythmias while hospitalized for acute severe COVID-19 or multisystem inflammatory syndrome in children. Methods and Results This study involved a case series of 63 patients with tachyarrhythmias reported in a public health surveillance registry of patients aged <21 years hospitalized from March 15, 2020, to December 31, 2021, at 63 US hospitals. Patients with tachyarrhythmias were compared with patients with severe COVID-19-related complications without tachyarrhythmias. Tachyarrhythmias were reported in 22 of 1257 patients (1.8%) with acute COVID-19 and 41 of 2343 (1.7%) patients with multisystem inflammatory syndrome in children. They included supraventricular tachycardia in 28 (44%), accelerated junctional rhythm in 9 (14%), and ventricular tachycardia in 38 (60%); >1 type was reported in 12 (19%). Registry patients with versus without tachyarrhythmia were older (median age, 15.4 [range, 10.4-17.4] versus 10.0 [range, 5.4-14.8] years) and had higher illness severity on hospital admission. Intervention for treatment of tachyarrhythmia was required in 37 (59%) patients and included antiarrhythmic medication (n=31, 49%), electrical cardioversion (n=11, 17%), cardiopulmonary resuscitation (n=8, 13%), and extracorporeal membrane oxygenation (n=9, 14%). Patients with tachyarrhythmias had longer hospital length of stay than those who did not, and 9 (14%) versus 77 (2%) died. Conclusions Tachyarrhythmias were a rare complication of acute severe COVID-19 and multisystem inflammatory syndrome in children and adolescents and were associated with worse clinical outcomes, highlighting the importance of close monitoring, aggressive treatment, and postdischarge care.

Follow-up cardiac magnetic resonance in children with vaccine-associated myocarditis.

Myocarditis is a rare complication of the COVID-19 mRNA vaccine. We previously reported a case series of 15 adolescents with vaccine-associated myocarditis, 87% of whom had abnormalities on initial cardiac magnetic resonance (CMR), including late gadolinium enhancement (LGE) in 80%. We performed follow-up CMRs to determine the trajectory of myocardial recovery and better understand the natural history of vaccine-associated myocarditis. Case series of patients age < 19 years admitted to Boston Children's Hospital with acute vaccine-associated myocarditis following the BNT162b2 vaccine who had abnormal CMR at the time of initial presentation, and underwent follow-up testing. CMR assessment included left ventricular (LV) ejection fraction, T2-weighted myocardial imaging, LV global native T1, LV global T2, extracellular volume (ECV), and late gadolinium enhancement (LGE). Ten patients (9 male, median age 15 years) with vaccine-associated myocarditis underwent follow-up CMR at a median of 92 days (range 76-119) after hospital discharge. LGE was persistent in 80% of patients, though improved from prior in all cases. Two patients (20%) had abnormal LV global T1 at presentation, which normalized on follow-up. ECV decreased between acute presentation and follow-up in 6/10 patients; it remained elevated at follow-up in 1 patient and borderline in 3 patients. CONCLUSION: CMR performed ~3 months after admission for COVID-19 vaccine-associated myocarditis showed improvement of LGE in all patients, but persistent in the majority. Follow-up CMR 6-12 months after acute episode should be considered to better understand the long-term cardiac risks. WHAT IS KNOWN: • Myocarditis is a rare side effect of COVID-19 mRNA vaccine. •Late gadolinium enhancement is present on most cardiac magnetic resonance at the time of acute presentation. WHAT IS NEW: •Late gadolinium enhancement improved on all repeat cardiac magnetic resonance at 3-month follow-up. •Most patients still had a small amount of late gadolinium enhancement, the clinical significance of which is yet to be determined.

A Description of Data Handling Practices and Software Tools Developed by the Boston Children's Hospital Echo Core Laboratory

Ultrasound 'Echocardiogram (echo)' images generated by commercial scanners are non-invasive, economical, and have therefore become an important clinical and research tool for cardiovascular disease. The Boston Children's Hospital (BCH, USA) cardiology department has developed echo image handling processes and software tools to simplify and manage the flow of echo data from sites participating in multi-center research studies. With frequent needs to correlate echocardiographic findings with surgical outcomes and more recently, better understand the acute and long-term effects of the SARS-CoV-2 pandemic on the heart in a multiinstitutional collaborative [1], the need for a central corelab for image review and reporting has spurred the development of new software tools that seamlessly prepare, transmit and measure echocardiographic images and generate reports formatted to merge easily with clinical databases. In this paper we provide a descriptive guide to these software tools, and offer suggested approaches to data preparations that can simplify corelab processing.

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 3.

OBJECTIVE: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of SARS-CoV-2 infection. Recommendations are also provided for children with hyperinflammation during COVID-19, the acute, infectious phase of SARS-CoV-2 infection. METHODS: The Task Force is composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting. RESULTS: The guidance was approved in June 2020 and updated in November 2020 and October 2021, and consists of 41 final guidance statements accompanied by flow diagrams depicting the diagnostic pathway for MIS-C and recommendations for initial immunomodulatory treatment of MIS-C. CONCLUSION: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available.

The NHLBI Study on Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC): Design and Objectives.

BACKGROUND: The Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC) study aims to characterize the frequency and time course of acute and long-term cardiac and non-cardiac sequelae in multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C), which are currently poorly understood. METHODS: This multicenter observational cohort study will enroll at least 600 patients <21 years old who meet the Centers for Disease Control and Prevention case definition of MIS-C across multiple North American centers over 2 years. The study will collect detailed hospital and follow-up data for up to 5 years, and optional genetic testing. Cardiac imaging at specific time points includes standardized echocardiographic assessment (all participants) and cardiac magnetic resonance imaging (CMR) in those with left ventricular ejection fraction (LVEF) <45% during the acute illness. The primary outcomes are the worst LVEF and the highest coronary artery z-score of the left anterior descending or right coronary artery. Other outcomes include occurrence and course of non-cardiac organ dysfunction, inflammation, and major medical events. Independent adjudication of cases will classify participants as definite, possible, or not MIS-C. Analysis of the outcomes will include descriptive statistics and regression analysis with stratification by definite or possible MIS-C. The MUSIC study will provide phenotypic data to support basic and translational research studies. CONCLUSION: The MUSIC study, with the largest cohort of MIS-C patients and the longest follow-up period to date, will make an important contribution to our understanding of the acute cardiac and non-cardiac manifestations of MIS-C and the long-term effects of this public health emergency.

Coagulation profiles and viscoelastic testing in multisystem inflammatory syndrome in children.

OBJECTIVE: To characterize viscoelastic testing profiles of children with multisystem inflammatory syndrome in children (MIS-C). METHODS: This single-center retrospective review included 30 patients diagnosed with MIS-C from March 1 to September 1, 2020. Thromboelastography (TEG) with platelet mapping was performed in 19 (63%) patients and compared to age- and sex-matched controls prior to cardiac surgery. Relationships between TEG parameters and inflammatory markers were assessed using correlation. RESULTS: Patients with MIS-C had abnormal TEG results compared to controls, including decreased kinetic (K) time (1.1 vs. 1.7 minutes, p < .01), increased alpha angle (75.0° vs. 65.7°, p < .01), increased maximum amplitude (70.8 vs. 58.3 mm, p < .01), and decreased lysis in 30 minutes (Ly30) (1.1% vs. 3.7%, p = .03); consistent with increased clot formation rate and strength, and reduced fibrinolysis. TEG maximum amplitude was moderately correlated with erythrocyte sedimentation rate (ESR) (r = 0.60, p = .02), initial platelet count (r = 0.67, p < .01), and peak platelet count (r = 0.51, p = .03). TEG alpha angle was moderately correlated with peak platelet count (r = 0.54, p = .02). Seventeen (57%) patients received aspirin (ASA) and anticoagulation, five (17%) received only ASA, and three (10%) received only anticoagulation. No patients had a symptomatic thrombotic event. Six (20%) patients had a bleeding event, none of which was major. CONCLUSIONS: Patients with MIS-C had evidence of hypercoagulability on TEG. Increased ESR and platelets were associated with higher clot strength. Patients were prophylactically treated with ASA or anticoagulation with no symptomatic thrombosis or major bleeding. Further multicenter study is required to characterize the rate of thrombosis and optimal thromboprophylaxis algorithm in this patient population.

Association of Myocarditis With BNT162b2 Messenger RNA COVID-19 Vaccine in a Case Series of Children.

Importance: The BNT162b2 (Pfizer-BioNTech) messenger RNA COVID-19 vaccine was authorized on May 10, 2021, for emergency use in children aged 12 years and older. Initial reports showed that the vaccine was well tolerated without serious adverse events; however, cases of myocarditis have been reported since approval. Objective: To review results of comprehensive cardiac imaging in children with myocarditis after COVID-19 vaccine. Design, Setting, and Participants: This study was a case series of children younger than 19 years hospitalized with myocarditis within 30 days of BNT162b2 messenger RNA COVID-19 vaccine. The setting was a single-center pediatric referral facility, and admissions occurred between May 1 and July 15, 2021. Main Outcomes and Measures: All patients underwent cardiac evaluation including an electrocardiogram, echocardiogram, and cardiac magnetic resonance imaging. Results: Fifteen patients (14 male patients [93%]; median age, 15 years [range, 12-18 years]) were hospitalized for management of myocarditis after receiving the BNT162b2 (Pfizer) vaccine. Symptoms started 1 to 6 days after receipt of the vaccine and included chest pain in 15 patients (100%), fever in 10 patients (67%), myalgia in 8 patients (53%), and headache in 6 patients (40%). Troponin levels were elevated in all patients at admission (median, 0.25 ng/mL [range, 0.08-3.15 ng/mL]) and peaked 0.1 to 2.3 days after admission. By echocardiographic examination, decreased left ventricular (LV) ejection fraction (EF) was present in 3 patients (20%), and abnormal global longitudinal or circumferential strain was present in 5 patients (33%). No patient had a pericardial effusion. Cardiac magnetic resonance imaging findings were consistent with myocarditis in 13 patients (87%) including late gadolinium enhancement in 12 patients (80%), regional hyperintensity on T2-weighted imaging in 2 patients (13%), elevated extracellular volume fraction in 3 patients (20%), and elevated LV global native T1 in 2 patients (20%). No patient required intensive care unit admission, and median hospital length of stay was 2 days (range 1-5). At follow-up 1 to 13 days after hospital discharge, 11 patients (73%) had resolution of symptoms. One patient (7%) had persistent borderline low LV systolic function on echocardiogram (EF 54%). Troponin levels remained mildly elevated in 3 patients (20%). One patient (7%) had nonsustained ventricular tachycardia on ambulatory monitor. Conclusions and Relevance: In this small case series study, myocarditis was diagnosed in children after COVID-19 vaccination, most commonly in boys after the second dose. In this case series, in short-term follow-up, patients were mildly affected. The long-term risks associated with postvaccination myocarditis remain unknown. Larger studies with longer follow-up are needed to inform recommendations for COVID-19 vaccination in this population.

Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes.

BACKGROUND: The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. METHODS: We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. RESULTS: A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis. CONCLUSIONS: Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.).

Socioeconomic and Racial and/or Ethnic Disparities in Multisystem Inflammatory Syndrome.

OBJECTIVES: To characterize the socioeconomic and racial and/or ethnic disparities impacting the diagnosis and outcomes of multisystem inflammatory syndrome in children (MIS-C). METHODS: This multicenter retrospective case-control study was conducted at 3 academic centers from January 1 to September 1, 2020. Children with MIS-C were compared with 5 control groups: children with coronavirus disease 2019, children evaluated for MIS-C who did not meet case patient criteria, children hospitalized with febrile illness, children with Kawasaki disease, and children in Massachusetts based on US census data. Neighborhood socioeconomic status (SES) and social vulnerability index (SVI) were measured via a census-based scoring system. Multivariable logistic regression was used to examine associations between SES, SVI, race and ethnicity, and MIS-C diagnosis and clinical severity as outcomes. RESULTS: Among 43 patients with MIS-C, 19 (44%) were Hispanic, 11 (26%) were Black, and 12 (28%) were white; 22 (51%) were in the lowest quartile SES, and 23 (53%) were in the highest quartile SVI. SES and SVI were similar between patients with MIS-C and coronavirus disease 2019. In multivariable analysis, lowest SES quartile (odds ratio 2.2 [95% confidence interval 1.1-4.4]), highest SVI quartile (odds ratio 2.8 [95% confidence interval 1.5-5.1]), and racial and/or ethnic minority background were associated with MIS-C diagnosis. Neither SES, SVI, race, nor ethnicity were associated with disease severity. CONCLUSIONS: Lower SES or higher SVI, Hispanic ethnicity, and Black race independently increased risk for MIS-C. Additional studies are required to target interventions to improve health equity for children.

Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19.

Importance: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. Objective: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). Setting, Design, and Participants: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. Exposure: SARS-CoV-2. Main Outcomes and Measures: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. Results: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×103 cells/µL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days. Conclusions and Relevance: This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.

Detailed Assessment of Left Ventricular Function in Multisystem Inflammatory Syndrome in Children, Using Strain Analysis.

BACKGROUND: Cardiac manifestations in multisystem inflammatory syndrome in children (MIS-C) occur in ∼80% of patients. Left ventricular (LV) systolic dysfunction is the most frequent cardiac finding. METHODS: In this single-centre, retrospective cohort study, we report on detailed assessment of LV function in MIS-C patients using strain and strain rate analysis. We compare those with normal peak systolic strain z-scores (both longitudinal and circumferential strain) to those with abnormal peak systolic strain z-scores (decreased circumferential and/or longitudinal strain). RESULTS: Among 25 patients, 14 (56%) were male, 20 (80%) were Black or Hispanic, 13 (52%) were overweight/obese, and the median age was 11.4 years (interquartile range: 7.5 to 16). Median ejection fraction (EF) was 55.2% (interquartile range: 48.3% to 58%), with the abnormal strain patients having a lower EF (P < 0.01). Demographics were similar between groups. The abnormal strain patients had more organ systems involved and were more likely to require inotropic support. In a comparison of MIS-C patients with normal EF (n = 15) to controls, MIS-C patients had lower peak systolic strain as well as lower early diastolic strain rates. In patients with initially depressed function, EF normalized in 8 of 10 (80%), but 4 of 11 (36%) patients had persistently abnormal systolic strain after discharge. CONCLUSIONS: LV systolic dysfunction is common in the acute phase of MIS-C, and detection may be improved with strain imaging. Longitudinal cardiac follow-up is imperative, as some patients may be at risk for persistent LV dysfunction.

CONTEXTE: Des manifestations cardiaques sont observées chez environ 80 % des patients atteints du syndrome inflammatoire multisystémique de l'enfant (SIM-E). La dysfonction systolique ventriculaire gauche est le problème cardiaque observé le plus fréquemment. MÉTHODOLOGIE: Dans cette étude de cohorte rétrospective et unicentrique, nous rapportons les résultats d'une évaluation détaillée de la fonction ventriculaire gauche chez des patients atteints du SIM-E sous l'angle de l'étude des contraintes et des taux de contrainte. Nous comparons les patients dont les écarts z des pics de contrainte systolique sont normaux (contraintes tant longitudinales que circonférentielles) et ceux dont les écarts z des pics de contrainte systolique sont anormaux (réduction de la contrainte circonférentielle ou longitudinale). RÉSULTATS: Sur 25 patients, 14 (56 %) étaient de sexe masculin, 20 (80 %) étaient noirs ou hispaniques, 13 (52 %) étaient en surpoids ou obèses, et l'âge médian était de 11,4 ans (intervalle interquartile : de 7,5 à 16). La fraction d'éjection (FE) médiane était de 55,2 % (intervalle interquartile : de 48,3 % à 58 %), et était moins élevée chez les patients présentant une contrainte anormale (p < 0,01). Les caractéristiques démographiques étaient comparables dans tous les groupes. Les patients chez lesquels la contrainte était anormale présentaient un plus grand nombre d'organes atteints et étaient plus susceptibles de nécessiter un soutien inotrope. Comparativement au groupe témoin, les patients SIM-E ayant une FE normale (n = 15) présentaient un pic de contrainte systolique moins élevé et des taux de contrainte diastolique précoce plus faibles. Chez les patients dont la fonction était déprimée à l'origine, la FE s'est normalisée chez huit patients sur 10 (80 %), mais quatre sur 11 (36 %) présentaient une contrainte systolique persistant après leur sortie de l'hôpital. CONCLUSIONS: La dysfonction systolique ventriculaire gauche est fréquente dans la phase aiguë du SIM-E, et son repérage pourrait être amélioré par l'imagerie permettant de visualiser les contraintes. Un suivi cardiaque longitudinal est impératif, car certains patients peuvent être à risque de souffrir d'une dysfonction ventriculaire gauche persistante.

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2.

OBJECTIVE: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recommendations are also provided for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection. METHODS: The Task Force was composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting. RESULTS: The first version of the guidance was approved in June 2020, and consisted of 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. The document was revised in November 2020, and a new flow diagram with recommendations for initial immunomodulatory treatment of MIS-C was added. CONCLUSION: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available.

Review of Cardiac Involvement in Multisystem Inflammatory Syndrome in Children.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with substantial cardiovascular implications. Although infection with SARS-CoV-2 is usually mild in children, some children later develop a severe inflammatory disease that can have manifestations similar to toxic shock syndrome or Kawasaki disease. This syndrome has been defined by the US Centers for Disease Control and Prevention as multisystem inflammatory syndrome in children. Although the prevalence is unknown, >600 cases have been reported in the literature. Multisystem inflammatory syndrome in children appears to be more common in Black and Hispanic children in the United States. Multisystem inflammatory syndrome in children typically occurs a few weeks after acute infection and the putative etiology is a dysregulated inflammatory response to SARS-CoV-2 infection. Persistent fever and gastrointestinal symptoms are the most common symptoms. Cardiac manifestations are common, including ventricular dysfunction, coronary artery dilation and aneurysms, arrhythmia, and conduction abnormalities. Severe cases can present as vasodilatory or cardiogenic shock requiring fluid resuscitation, inotropic support, and in the most severe cases, mechanical ventilation and extracorporeal membrane oxygenation. Empirical treatments have aimed at reversing the inflammatory response using immunomodulatory medications. Intravenous immunoglobulin, steroids, and other immunomodulatory agents have been used frequently. Most patients recover within days to a couple of weeks and mortality is rare, although the medium- and long-term sequelae, particularly cardiovascular complications, are not yet known. This review describes the published data on multisystem inflammatory syndrome in children, focusing on cardiac complications, and provides clinical considerations for cardiac evaluation and follow-up.

Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach.

Initial reports on COVID-19 described children as largely spared from severe manifestations, with only 2-6% of children requiring intensive care treatment. However, since mid-April 2020, clusters of pediatric cases of severe systemic hyperinflammation and shock epidemiologically linked with COVID-19 have been reported. This condition was named as SARS-Cov-2-associated multisystem inflammatory syndrome in children and showed similarities to Kawasaki disease. Here, we present a narrative review of cases reported in literature and we discuss the clinical acute and follow-up management of these patients. Patients with SARS-Cov-2-associated multisystem inflammatory syndrome frequently presented with persistent fever, gastrointestinal symptoms, polymorphic rash, conjunctivitis, and mucosal changes. Elevated inflammatory markers and evidence of cytokine storm were frequently observed. A subset of these patients also presented with hypotension and shock (20-100%) from either acute myocardial dysfunction or systemic hyperinflammation/vasodilation. Coronary artery dilation or aneurysms have been described in 6-24%, and arrhythmias in 7-60%. Cardiac support, immunomodulation, and anticoagulation are the key aspects for the management of the acute phase. Long-term structured follow-up of these patients is required due to the unclear prognosis and risk of progression of cardiac manifestations.Conclusion: Multisystem inflammatory syndrome is a novel syndrome related to SARS-CoV-2 infection. Evidence is still scarce but rapidly emerging in the literature. Cardiac manifestations are frequent, including myocardial and coronary involvement, and need to be carefully identified and monitored over time. What is Known: • Multisystem inflammatory syndrome in children (MIS-C) has been described associated with SARS-CoV-2. What is New: • Patients with MIS-C often present with fever, gastrointestinal symptoms, and shock. • Cardiac involvement is found in a high proportion of these patients, including ventricular dysfunction, coronary artery dilation or aneurysm, and arrhythmias. • Management is based on expert consensus and includes cardiac support, immunomodulatory agents, and anticoagulation. • Long-term follow-up is required due to the unclear prognosis and risk of progression of cardiac manifestation.

Atrioventricular Block in Children With Multisystem Inflammatory Syndrome.

BACKGROUND: Children are at risk for multisystem inflammatory syndrome in children (MIS-C) after infection with severe acute respiratory syndrome coronavirus 2. Cardiovascular complications, including ventricular dysfunction and coronary dilation, are frequent, but there are limited data on arrhythmic complications. METHODS: Retrospective cohort study of children and young adults aged ≤21 years admitted with MIS-C. Demographic characteristics, electrocardiogram (ECG) and echocardiogram findings, and hospital course were described. RESULTS: Among 25 patients admitted with MIS-C (60% male; median age 9.7 [interquartile range 2.7-15.0] years), ECG anomalies were found in 14 (56%). First-degree atrioventricular block (AVB) was seen in 5 (20%) patients a median of 6 (interquartile range 5-8) days after onset of fever and progressed to second- or third-degree AVB in 4 patients. No patient required intervention for AVB. All patients with AVB were admitted to the ICU (before onset of AVB) and had ventricular dysfunction on echocardiograms. All patients with second- or third-degree AVB had elevated brain natriuretic peptide levels, whereas the patient with first-degree AVB had a normal brain natriuretic peptide level. No patient with AVB had an elevated troponin level. QTc prolongation was seen in 7 patients (28%), and nonspecific ST segment changes were seen in 14 patients (56%). Ectopic atrial tachycardia was observed in 1 patient, and none developed ventricular arrhythmias. CONCLUSIONS: Children with MIS-C are at risk for atrioventricular conduction disease, especially those who require ICU admission and have ventricular dysfunction. ECGs should be monitored for evidence of PR prolongation. Continuous telemetry may be required in patients with evidence of first-degree AVB because of risk of progression to high-grade AVB.

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 1.

OBJECTIVE: To provide guidance on the management of multisystem inflammatory syndrome in children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and to provide recommendations for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection. METHODS: A multidisciplinary task force was convened by the American College of Rheumatology (ACR) to provide guidance on the management of MIS-C associated with SARS-CoV-2 and hyperinflammation in COVID-19. The task force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved 2 rounds of anonymous voting and 2 webinars. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate), and consensus was rated as low, moderate, or high based on dispersion of the votes along the numeric scale. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, as prespecified prior to voting. RESULTS: The ACR task force approved a total of 128 guidance statements addressing the management of MIS-C and hyperinflammation in pediatric COVID-19. These statements were refined into 40 final clinical guidance statements, accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. CONCLUSION: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. The guidance provided in this "living document" reflects currently available evidence, coupled with expert opinion, and will be revised as further evidence becomes available.