SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19.

SARS-CoV-2 infection for most children results in mild or minimal symptoms, though in rare cases severe disease can develop, including a multisystem inflammatory syndrome (MIS-C) with myocarditis. Here, we present longitudinal profiling of immune responses during acute disease and following recovery in children who developed MIS-C, relative to children who experienced more typical symptoms of COVID-19. T cells in acute MIS-C exhibited transient signatures of activation, inflammation, and tissue residency which correlated with cardiac disease severity, while T cells in acute COVID-19 upregulated markers of follicular helper T cells for promoting antibody production. The resultant memory immune response in recovery showed increased frequencies of virus-specific memory T cells with pro-inflammatory functions in children with prior MIS-C compared to COVID-19 while both cohorts generated comparable antibody responses. Together our results reveal distinct effector and memory T cell responses in pediatric SARS-CoV-2 infection delineated by clinical syndrome, and a potential role for tissue-derived T cells in the immune pathology of systemic disease.

Ventricular function and tissue characterization by cardiac magnetic resonance imaging following hospitalization for multisystem inflammatory syndrome in children: a prospective study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe life-threatening manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that often presents with acute cardiac dysfunction and cardiogenic shock. While recovery from acute illness is excellent, the long-term myocardial impact is unknown. OBJECTIVE: To compare cardiac MRI findings in children 6-9 months after their hospitalization with MIS-C against MRI findings in healthy controls to assess for residual myocardial disease. MATERIALS AND METHODS: We prospectively performed cardiac MRI on 13 children 6-9 months following their hospitalization with MIS-C: eight of these children had a history of left ventricle ejection fraction (LVEF) < 50%, persistent symptoms, or electrocardiogram (ECG) abnormalities and underwent clinical MRI; five of these children without cardiac abnormalities during their hospitalization underwent research MRIs. We compared their native T1 and T2 mapping values with those of 20 normal controls. RESULTS: Cardiac MRI was performed at 13.6 years of age (interquartile range [IQR] 11.9-16.4 years) and 8.2 months (IQR 6.8-9.6 months) following hospitalization. Twelve children displayed normal ejection fraction: left ventricle (LV) 57.2%, IQR 56.1-58.4; right ventricle (RV) 53.1%, IQR 52.0-55.7. One had low-normal LVEF (52%). They had normal extracellular volume (ECV) and normal T2 and native T1 times compared to controls. There was no qualitative evidence of edema. One child had late gadolinium enhancement (LGE) with normal ejection fraction, no edema, and normal T1 and T2 times. When stratifying children who had MIS-C according to history of LVEF <55% on echocardiography, there was no difference in MRI values. CONCLUSION: Although many children with MIS-C present acutely with cardiac dysfunction, residual myocardial damage 6-9 months afterward appears minimal. Long-term implications warrant further study.

Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.

BACKGROUND: Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision to vaccinate youth. METHODS: We retrospectively collected data on patients <21 years old presenting before July 4, 2021, with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions. RESULTS: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1-20.3; interquartile range [IQR], 14.5-17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0-22; IQR, 1-3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0-10; IQR, 2-3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50-15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25-1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction <55% on echocardiogram. Of 97 patients who underwent cardiac MRI at a median 5 days (range, 0-88; IQR, 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25). CONCLUSIONS: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.

Longitudinal Outcomes for Multisystem Inflammatory Syndrome in Children.

BACKGROUND: In spring 2020, a novel hyperinflammatory process associated with severe acute respiratory syndrome coronavirus 2 multisystem inflammatory syndrome in children (MIS-C) was described. The long-term impact remains unknown. We report longitudinal outcomes from a New York interdisciplinary follow-up program. METHODS: All children <21 years of age, admitted to NewYork-Presbyterian with MIS-C in 2020, were included. Children were followed at 1 to 4 weeks, 1 to 4 months, and 4 to 9 months postdischarge. RESULTS: In total, 45 children were admitted with MIS-C. The median time to last follow-up was 5.8 months (interquartile range 1.3-6.7). Of those admitted, 76% required intensive care and 64% required vasopressors and/or inotropes. On admission, patients exhibited significant nonspecific inflammation, generalized lymphopenia, and thrombocytopenia. Soluble interleukin (IL) IL-2R, IL-6, IL-10, IL-17, IL-18, and C-X-C Motif Chemokine Ligand 9 were elevated. A total of 80% (n = 36) had at least mild and 44% (n = 20) had moderate-severe echocardiographic abnormalities including coronary abnormalities (9% had a z score of 2-2.5; 7% had a z score > 2.5). Whereas most inflammatory markers normalized by 1 to 4 weeks, 32% (n = 11 of 34) exhibited persistent lymphocytosis, with increased double-negative T cells in 96% of assessed patients (n = 23 of 24). By 1 to 4 weeks, only 18% (n = 7 of 39) had mild echocardiographic findings; all had normal coronaries. At 1 to 4 months, the proportion of double-negative T cells remained elevated in 92% (median 9%). At 4 to 9 months, only 1 child had persistent mild dysfunction. One had mild mitral and/or tricuspid regurgitation. CONCLUSIONS: Although the majority of children with MIS-C present critically ill, most inflammatory and cardiac manifestations in our cohort resolved rapidly.

Discriminating Multisystem Inflammatory Syndrome in Children Requiring Treatment from Common Febrile Conditions in Outpatient Settings.

OBJECTIVES: To examine whether patients with multisystem inflammatory syndrome in children (MIS-C) demonstrated well-defined clinical features distinct from other febrile outpatients, given the difficulties of seeing acute care visits during the severe acute respiratory syndrome coronavirus 2 pandemic and the risks associated with both over- and underdiagnosis of MIS-C. STUDY DESIGN: This case-controlled study compared patients diagnosed with and treated for MIS-C at a large urban children's hospital with patients evaluated for fever at outpatient acute care visits during the peak period of MIS-C. Symptomatology and available objective data were extracted. Comparisons were performed using t tests with corrections for multiple comparisons, and multivariable logistic regression to obtain ORs. RESULTS: We identified 44 patients with MIS-C between April 16 and June 10, 2020. During the same period, 181 pediatric patients were evaluated for febrile illnesses in participating outpatient clinics. Patients with MIS-C reported greater median maximum reported temperature height (40°C vs 38.9, P < .0001), and increased frequency of abdominal pain (OR 12.5, 95% CI [1.65-33.24]), neck pain (536.5, [2.23-129,029]), conjunctivitis (31.3, [4.6-212.8]), oral mucosal irritation (11.8, [1.4-99.4]), extremity swelling or rash (99.9, [5-1960]), and generalized rash (7.42, [1.6-33.2]). Patients with MIS-C demonstrated lower absolute lymphocyte (P < .0001) and platelet counts (P < .05) and greater C-reactive protein concentrations (P < .001). CONCLUSIONS: Patients treated for MIS-C due to concern for potential cardiac injury show combinations of features distinct from other febrile patients seen in outpatient clinics during the same period.

Impact of Coronavirus Disease 2019 (COVID-19) on Patients With Congenital Heart Disease Across the Lifespan: The Experience of an Academic Congenital Heart Disease Center in New York City.

Background We sought to assess the impact and predictors of coronavirus disease 2019 (COVID-19) infection and severity in a cohort of patients with congenital heart disease (CHD) at a large CHD center in New York City. Methods and Results We performed a retrospective review of all individuals with CHD followed at Columbia University Irving Medical Center who were diagnosed with COVID-19 between March 1, 2020 and July 1, 2020. The primary end point was moderate/severe response to COVID-19 infection defined as (1) death during COVID-19 infection; or (2) need for hospitalization and/or respiratory support secondary to COVID-19 infection. Among 53 COVID-19-positive patients with CHD, 10 (19%) were <18 years of age (median age 34 years of age). Thirty-one (58%) had complex congenital anatomy including 10 (19%) with a Fontan repair. Eight (15%) had a genetic syndrome, 6 (11%) had pulmonary hypertension, and 9 (17%) were obese. Among adults, 18 (41%) were physiologic class C or D. For the entire cohort, 9 (17%) had a moderate/severe infection, including 3 deaths (6%). After correcting for multiple comparisons, the presence of a genetic syndrome (odds ratio [OR], 35.82; P=0.0002), and in adults, physiological Stage C or D (OR, 19.38; P=0.002) were significantly associated with moderate/severe infection. Conclusions At our CHD center, the number of symptomatic patients with COVID-19 was relatively low. Patients with CHD with a genetic syndrome and adults at advanced physiological stage were at highest risk for moderate/severe infection.

Cardiac workup and monitoring in hospitalised children with COVID- 19.

Approximately, 1.7 million individuals in the United States have been infected with SARS-CoV-2, the virus responsible for the novel coronavirus disease-2019 (COVID-19). This has disproportionately impacted adults, but many children have been infected and hospitalised as well. To date, there is not much information published addressing the cardiac workup and monitoring of children with COVID-19. Here, we share the approach to the cardiac workup and monitoring utilised at a large congenital heart centre in New York City, the epicentre of the COVID-19 pandemic in the United States.