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.

SARS-CoV-2 Infection and Associated Cardiovascular Manifestations and Complications in Children and Young Adults: A Scientific Statement From the American Heart Association.

Coronavirus disease 2019 (COVID-19) resulted in a global pandemic and has overwhelmed health care systems worldwide. In this scientific statement, we describe the epidemiology, pathophysiology, clinical presentations, treatment, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and multisystem inflammatory syndrome in children and young adults with a focus on cardiovascular manifestations and complications. We review current knowledge about the health consequences of this illness in children and young adults with congenital and acquired heart disease, the public health burden and health disparities of this infection in these populations, and vaccine-associated myocarditis.

Disproportionate Negative Career Impact of the COVID-19 Pandemic on Female Pediatric Cardiologists in the Northeast United States.

The COVID-19 pandemic has had a dramatic impact on practicing physicians, with effects in clinical practice, academic pursuits, research endeavors, and personal lives. Women in medicine have been uniquely impacted. We examined the impact of the pandemic on the careers of pediatric cardiologists in the Northeast with an anonymous online survey. Participants reported demographic data, information on work hours, administrative burden, career satisfaction, academic productivity, and burnout. We approached 490 cardiologists and received 127 completed surveys (response rate 26%; 49% female). Among all respondents, 72% reported increased burnout, 43% reported decreased career satisfaction, and 57% reported decreased academic productivity. In multivariable ordinal regression analysis, when compared to male physicians, females were 2.4 times more likely to report decreased overall career satisfaction (p = 0.027), 2.6 times more likely to report decreased academic productivity (p = 0.028), and 2.6 times more likely to report increased feelings of burnout "to a large degree" (p = 0.022). Among all respondents, decreased career satisfaction was independently associated with increased household responsibility (OR = 4.4, p = 0.001). Increased administrative burden was independently associated with decreased academic productivity (OR = 2.6, p = 0.038). Open-ended responses highlighted loss of community due to remote work and blurring of the boundaries between work and home. Conversely, respondents appreciated flexibility to work remotely. In conclusion, the majority of pediatric cardiologists in the Northeast experienced negative career impacts due to the COVID-19 pandemic. Important gender differences emerged, with female physicians disproportionately reporting increased burnout, decreased career satisfaction, and decreased academic productivity.

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.

Activity During the COVID-19 Pandemic in Children with Cardiac Rhythm Management Devices.

Decreased physical activity is associated with cardiovascular, metabolic and mental health disease. While decreases in physical activity during the COVID-19 pandemic have been described in the general population, there is a paucity of data regarding children with underlying cardiovascular disease. We hypothesized there would be a decrease in physical activity at the onset of the COVID-19 pandemic. Performed a single-center, retrospective cohort study of children aged < 19 years with cardiac rhythm management devices. Patients were included if they had device-measured physical activity data from > 80% of dates from February 3, 2020 through June 30, 2020. Patients with significant neurologic/neuromuscular disease were excluded. We identified 144 patients with a median age of 15.4 years. 47% were female. 34% had congenital heart disease, 20% had cardiomyopathy, 19% had an inherited arrhythmia syndrome and 5% had atrioventricular block without congenital heart disease. 47% of patients had an implantable loop recorder, 29% had a permanent pacemaker and 24% had an implantable cardioverter-defibrillator. We observed a significant decrease in device-measured physical activity from baseline (February 3-March 9), with up to a 21% decrease in physical activity during mid-March through early May. Activity levels returned to pre-pandemic levels in June. Physical activity sharply declined in children with cardiac rhythm management devices at the onset of the COVID-19 pandemic. These data highlight the importance of finding strategies to maintain physical activity during the current pandemic and future public health crises.

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.

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.

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.

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.

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.

Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children.

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.