Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis.

BACKGROUND: Cases of adolescents and young adults developing myocarditis after vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-targeted mRNA vaccines have been reported globally, but the underlying immunoprofiles of these individuals have not been described in detail. METHODS: From January 2021 through February 2022, we prospectively collected blood from 16 patients who were hospitalized at Massachusetts General for Children or Boston Children's Hospital for myocarditis, presenting with chest pain with elevated cardiac troponin T after SARS-CoV-2 vaccination. We performed extensive antibody profiling, including tests for SARS-CoV-2-specific humoral responses and assessment for autoantibodies or antibodies against the human-relevant virome, SARS-CoV-2-specific T-cell analysis, and cytokine and SARS-CoV-2 antigen profiling. Results were compared with those from 45 healthy, asymptomatic, age-matched vaccinated control subjects. RESULTS: Extensive antibody profiling and T-cell responses in the individuals who developed postvaccine myocarditis were essentially indistinguishable from those of vaccinated control subjects, despite a modest increase in cytokine production. A notable finding was that markedly elevated levels of full-length spike protein (33.9±22.4 pg/mL), unbound by antibodies, were detected in the plasma of individuals with postvaccine myocarditis, whereas no free spike was detected in asymptomatic vaccinated control subjects (unpaired t test; P<0.0001). CONCLUSIONS: Immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals who developed myocarditis and individuals who did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post-mRNA vaccine myocarditis, advancing insight into its potential underlying cause.

Diagnostic Yield of Cardiac Biomarker Testing in Predicting Cardiac Disease and Multisystem Inflammatory Syndrome in Children in the Pandemic Era.

OBJECTIVES: This study aimed to assess whether elevations in cardiac biomarkers are associated with pediatric cardiac diagnoses in the era of COVID-19 and multisystem inflammatory syndrome in children (MIS-C). STUDY DESIGN: This single-center retrospective study analyzed children with a troponin drawn in the emergency department or inpatient unit between April 21 and December 31, 2020. The primary outcome was the presence of a cardiac diagnosis or MIS-C. Relationships among demographics, complaint, cardiac diagnostics, and cardiac biomarkers were analyzed. RESULTS: Four hundred eighty-six patients (mean ± SD; age 13.1 ± 7.8 years; 46.7% women) met inclusion criteria, for whom a cardiac diagnosis (excluding MIS-C) was made in 27 (5.6%) patients, with MIS-C diagnosed in 14 (2.9%) patients. The sensitivity and specificity of an elevated initial high-sensitivity troponin T (hsTropT) value (>14 ng/L) in predicting the composite outcome of a cardiac diagnosis or MIS-C were 54% and 89%, respectively. Four percent of patients with negative initial troponin values were found to have a cardiac diagnosis or MIS-C. Multivariable regression analysis demonstrated that elevated hsTropT (>14 ng/L; odds ratio [OR] [95% confidence interval]: 4.9 [1.70-14.0]) and elevated N-terminal pro B-type natriuretic peptide values (>500 pg/mL; 6.4 [2.01-20.1]) were associated with increased odds of a cardiac diagnosis or MIS-C. CONCLUSIONS: Children with elevated cardiac biomarkers have increased odds of a cardiac diagnosis or MIS-C and warrant workup regardless of indication for testing. Although a negative hsTropT may reassure providers, further investigation is critical in developing algorithms to reliably exclude cardiac disease.

Operational Innovation in the Provision of Pediatric Extracorporeal Membrane Oxygenation for Multisystem Inflammatory Syndrome in Children.

Treatment of multisystem inflammatory syndrome in children (MIS-C) can require significant critical care resources. Our aim is to alert mixed pediatric and adult hospitals worldwide of the possibility that pediatric and adult patients may simultaneously require cannulation to extracorporeal membrane oxygenation (ECMO) for MIS-C and severe COVID-19. We conducted a retrospective review of operations required to treat cardiogenic shock in 3 pediatric patients with a diagnosis of MIS-C admitted to a single medium-sized pediatric referral center located within a large academic medical center over a 14-day period. At this time, a large number of adult patients required ECMO for severe COVID-19 at our institution. Of the 11 pediatric patients who presented with MIS-C during the first surge of 2020, 2 patients required cannulation to venoarterial extracorporeal membrane oxygenation (VA-ECMO), and a third patient developed a life-threatening arrhythmia requiring transfer to a neighboring institution for consideration of VA-ECMO when our institution's ECMO capacity had briefly been reached. Pediatric referral centers located within institutions providing ECMO to adult patients with severe COVID-19 may benefit from frequent and direct communication with their adult and regional colleagues to devise a collaborative plan for safe and timely provision of ECMO to patients with MIS-C as the ongoing pandemic continues to consume this limited, lifesaving resource.

Ventricular tachycardia after naloxone administration in an adolescent.

Naloxone is a medication with a largely benign safety profile that is frequently administered in the emergency department to patients presenting with altered mental status. Ventricular tachycardia has been reported after naloxone administration in adult patients with prior use of opiate or sympathomimetic medications. However, no such reports exist in the pediatric population or in patients who have no known history of opiate or sympathomimetic medication use. We describe a case of ventricular tachycardia after naloxone administration in a 17-year-old male with no known prior use of opiate or sympathomimetic agents who presented to the emergency department with altered mental status of unknown etiology. Emergency physicians may wish to prepare for prompt treatment of ventricular arrythmias when administering naloxone to pediatric patients presenting with altered mental status.

Distinguishing Features of Patients Evaluated for Multisystem Inflammatory Syndrome in Children.

OBJECTIVES: Given the significant overlap of multisystem inflammatory syndrome in children (MIS-C) with other common childhood illnesses presenting to the emergency department, extensive workup of this syndrome has become necessary. Nevertheless, little has been published on the factors differentiating MIS-C from other conditions in the acute care setting. We investigated differences in presentation and laboratory studies between suspected versus confirmed MIS-C patients. METHODS: This was a retrospective cohort study on patients 21 years or younger undergoing investigation for possible MIS-C at a single institution between April 21 and July 1, 2020. The primary outcome was diagnosis of MIS-C or an alternative final diagnosis. Clinical features and laboratory findings from initial presentation were collected and analyzed. RESULTS: A total of 106 patients (median, 4 years; 55.7% male) were included, of whom 17 (16%) of 106 met the criteria for MIS-C. Multisystem inflammatory syndrome in children patients were significantly more likely to report a coronavirus disease 2019 exposure (odds ratio (OR), 13.17 [3.87-44.9]), have gastrointestinal symptoms (OR, 3.81 [1.02-14.19]), and have a significantly higher odds of having abnormal laboratory values including high-sensitivity troponin T (OR, 13 [4.0-42.2]), N-terminal B-type natriuretic peptide (OR, 8.4 [2.3-30.1]), D-dimer (OR, 13 [1.6-103]), and ferritin (OR, 7.8 [2.2-27.2]). There were also differences between groups in inflammatory markers: C-reactive protein (median, 134.45 mg/L vs 12.6 mg/L; P < 0.05) and procalcitonin (1.71 ng/mL vs 0.14 ng/mL; P < 0.001). CONCLUSIONS: Higher elevations in key laboratory studies may help to distinguish between MIS-C patients and non-MIS-C patients presenting to the emergency department.

Kawasaki Disease Features and Myocarditis in a Patient with COVID-19.

A 10-year-old male with prolonged fever, rash, and conjunctivitis presented to the emergency department with concern for Kawasaki disease, found to have myocarditis and PCR positive for SARS-CoV-2.

Readmissions Following Congenital Heart Surgery in Infants and Children.

Thirty-day readmission after congenital heart surgery (CHS) is an important outcome given the vulnerability of pediatric patients. We hypothesized that readmissions after pediatric CHS are common and identifiable risk factors exist. We obtained State Inpatient Databases for Washington, New York, Florida, and California and selected CHS admissions age < 19 years. The main outcome was readmission defined as non-elective hospitalization < 31 days of discharge from index CHS admission. In multivariable analyses using generalized estimating equations, we examined associations of patient-level characteristics (age, sex, race, household income, insurance status, genetic syndromes, co-morbidities, RACHS-1 surgical risk category and complication) and admission characteristics [weekend admission, urgent/emergent admission, and high resource use (HRU)] with 30-day pediatric readmission after adjusting for case mix. Among 8585 index admissions we identified 967 readmissions (11.3%). Median length of stay for readmissions was 5 days, median total charge of $31,973, and mortality rate 1.8%. Among readmissions, 1.7% underwent another CHS of which 44% were HRU, complication rate 88% and mortality 6.25%. In multivariable analysis, age 1 month-1 year AOR 1.3 p = 0.01; Hispanic ethnicity AOR 1.2 p = 0.03; government-insurance AOR 1.3 p = 0.01; RACHS-1 3 complexity AOR 2.4 p < 0.001; RACHS-1 4 + complexity 2.0 p = 0.001; HRU AOR 1.4 p = 0.02; complications AOR 1.1 p = 0.04; and emergent index admission AOR 2.0 p < 0.001 were risk factors for readmission. Over 11% of pediatric CHS admissions result in an unplanned readmission. Hispanic ethnicity, government insurance, HRU admissions, higher case complexity, complications, and emergent index admission are risk factors for readmission.

Deep hypothermia attenuates microglial proliferation independent of neuronal death after prolonged cardiac arrest in rats.

INTRODUCTION: Conventional resuscitation of exsanguination cardiac arrest (CA) victims is generally unsuccessful. Emergency preservation and resuscitation is a novel approach that uses an aortic flush to induce deep hypothermia during CA, followed by delayed resuscitation with cardiopulmonary bypass. Minocycline has been shown to be neuroprotective across a number of brain injury models via attenuating microglial activation. We hypothesized that deep hypothermia and minocycline would attenuate neuronal death and microglial activation and improve outcome after exsanguination CA in rats. METHODS: Using isoflurane anesthesia, rats were subjected to a lethal hemorrhagic shock. After 5 min of no flow, hypothermia was induced with an aortic flush. Three groups were studied: ice-cold (IC) flush, room-temperature (RT) flush, and RT flush followed by minocycline treatment (RT-M). After 20 min of CA, resuscitation was achieved via cardiopulmonary bypass. Survival, Overall Performance Category (1 = normal, 5 = death), Neurologic Deficit Score (0%-10% = normal, 100% = max deficit), neuronal death (Fluoro-Jade C), and microglial proliferation (Iba1 immunostaining) in hippocampus were assessed at 72 h. RESULTS: Rats in the IC group had lower tympanic temperature during CA versus other groups (IC, 20.9 degrees C +/- 1.3 degrees C; RT, 28.4 degrees C +/- 0.6 degrees C; RT-M, 28.3 degrees C +/- 0.7 degrees C; P < 0.001). Although survival was similar in all groups (RT, 6/9; IC, 6/7; RT-M, 6/11), neurological outcome was better in the IC group versus other groups (Overall Performance Category: IC, 1 +/- 1; RT, 3 +/- 1; RT-M, 2 +/- 1; P < 0.05; Neurologic Deficit Score: IC, 8% +/- 9%; RT, 55% +/- 19%; RT-M, 27% +/- 16%; P < 0.05). Histological damage assessed in survivors showed selective neuronal death in CA1 and dentate gyrus, similar in all groups (P = 0.15). In contrast, microglial proliferation was attenuated in the IC group versus all other groups (P < 0.01). CONCLUSIONS: Deeper levels of hypothermia induced by the IC versus RT flush resulted in better neurological outcome in survivors. Surprisingly, deep hypothermia attenuated microglial activation but not hippocampal neuronal death. Minocycline had modest benefit on neurologic outcome in survivors but did not attenuate microglial activation in brain. Our findings suggest a novel effect of deep hypothermia on microglial proliferation during exsanguination CA.

Blood-brain barrier integrity in a rat model of emergency preservation and resuscitation.

UNLABELLED: Emergency Preservation and Resuscitation (EPR) represents a novel approach to treat exsanguination cardiac arrest (CA) victims, using an aortic flush to induce hypothermia during circulatory arrest, followed by delayed resuscitation with cardiopulmonary bypass (CPB). The status of the blood-brain barrier (BBB) integrity after prolonged hypothermic CA is unclear. The objective of this study was to assess BBB permeability in two EPR models in rats, associated with poor outcome. Rats subjected to traumatic brain injury (TBI) and naïve rats served as positive and negative controls, respectively. HYPOTHESIS: The BBB will be disrupted after TBI, but intact after prolonged hypothermic CA. METHODS: Four groups were studied: (1) EPR-IC (ice cold)-75 min CA at 15 degrees C; (2) EPR-RT (room temperature)-20 min CA at 28 degrees C; (3) TBI; (4) sham. Rats in EPR groups were subjected to rapid hemorrhage, followed by CA. Rats in the TBI group had a controlled cortical impact to the left hemisphere. Naïves were subjected to the same anesthesia and surgery. 1h after insult, rats were injected with Evans Blue (EB), a marker of BBB permeability for albumin. Rats were sacrificed after 5h and EB absorbance was quantified in brain samples. RESULTS: TBI produced an approximately 10-fold increase in EB absorbance in the left (injured) hemisphere vs. left hemisphere for all other groups (p=0.001). In contrast, EB absorbance in either EPR group did not differ from sham. CONCLUSION: BBB integrity to albumin is not disrupted early after resuscitation from prolonged CA treated with EPR. Neuroprotective adjuncts to hypothermia in this setting should focus on agents that penetrate the BBB. These findings also have implications for deep hypothermic circulatory arrest.