This is a literature report for the following literature source (Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults). Background: Rare cases of myocarditis have been reported in adults following COVID-19 vaccination, with most cases occurring in males <30 years old. Since the authorization to administer the Pfizer-BioNTech COVID-19 vaccine in those as young as 12 years of age, suspected myocarditis temporally related to the vaccine has also been reported in adolescents. Myocarditis has been associated with other vaccines, such as smallpox and influenza, though data are limited regarding symptoms, clinical course, and short-term outcomes of suspected myocarditis following COVID-19 vaccination. On June 23, 2021, the Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices reported a likely link between mRNA COVID-19 vaccination and myocarditis, particularly in those </ 39 years old. The authors aim to describe a large case series of suspected myocarditis temporally related with the COVID-19 vaccine in adolescents and young adults <21 years old. METHODS: The data that support the findings of this study are available from the corresponding author on reasonable request. Patients, the authors collected data retrospectively for adolescents and young adults <21 years old who presented with symptoms, laboratory markers, and/or imaging findings concerning for myocarditis within 30 days of COVID-19 vaccination from 26 pediatric medical centers prior to July 4, 2021. The authors included patients with clinically suspected myocarditis who had elevated troponin levels and abnormal electrocardiograms (ECGs), cardiac function on non-invasive imaging, or findings consistent with myocarditis on cardiac magnetic resonance imaging (cMRI), including myocardial edema or late gadolinium enhancement. Cases of suspected vaccine associated myocarditis (VAM) were categorized as probable or confirmed using the CDC case definitions. The authors excluded patients in whom troponin levels were not measured or had normal levels, or who had a plausible alternative etiology for suspected myocarditis. Evaluations for alternative etiologies were at the discretion of sites, based on local assessments. If a patient presented with symptoms and findings suggestive of myocarditis after more than one vaccine dose, the more severe presentation was added to the aggregate data for analysis. Data obtained: The authors collected de-identified and targeted demographic, clinical, laboratory, imaging and ECG, and short-term outcomes data. Prior COVID-19 infection was defined as having a personal history of laboratory- confirmed SARS CoV-2 testing and/or having had symptoms and immediate household family member(s) who tested positive for SARS CoV-2 but the patient was not tested. Left ventricular systolic function was categorized as normal if graded as normal by local assessment, or if left ventricular ejection fraction (LVEF) was >/55%; mildly decreased systolic function was defined as LVEF <45-54%, moderately decreased if 35-44%; and severely decreased if <35%. The decision and the timing to obtain cMRIs were at the discretion of the local clinical teams, and cMRIs were performed using local protocols. Data on cMRIs were collected retrospectively from clinical reports. Statistical analyses: Descriptive statistics include percentages for discrete variables and median values with range or interquartile range for continuous variables. Fisher's exact or Wilcoxon-Rank-Sum tests were used to compare markers of illness severity in patients who did vs. did not undergo cMRI, and time to cMRI in those that were normal vs. abnormal. Markers of illness severity included need for intensive care unit (ICU) stay, left ventricular dysfunction on echocardiogram, and troponin I levels, which were performed more frequently than troponin T. All analyses were performed using Stata 11.2 (Result: As of July 4, 2021, 146 episodes of clinically suspected VAM occurred in 145 adolescents and young adults <21 years old at 26 centers, with 6 patients excluded due to lack of abnormal troponin. Thus, 140 episodes in 139 patients were analyzed. One patient presented with suspected myocarditis following both doses of the Pfizer-BioNTech vaccine, with a more severe course after the 2nd dose; data from his 2nd episode are included in the aggregate analysis, as detailed below. The majority of patients were White (N=92, 66.2%), non-Hispanic (N=96, 69.1%), and male (N=126, 90.6%) with a median age of 15.8 years (range 12.1-20.3, IQR 14.5-17.0). Based on symptoms, laboratory and imaging data, 49 (35.0%) episodes of suspected myocarditis met criteria for confirmed myocarditis based on CDC classification, and the remaining 91 (65.0%) would be classified as probable. No patients underwent endomyocardial biopsy. Of the 140 episodes of clinically suspected VAM, 124 (88.6%) were evaluated with SARS CoV-2 PCR testing at the time of presentation, all of which were negative. Two patients had positive PCR testing within 32 days of presentation of suspected myocarditis, and thus were not tested again. Fifteen (10.7%) patients had evidence of previous COVID-19 infection by history (N=5), positive nucleocapsid antibodies (N=5), or both (N=5). Prior COVID-19 infection occurred <1 month to up to 10 months before the suspected myocarditis episode in the 10 patients with a known history. The majority (N=94, 67.6%) had no history of prior infection and/or had negative nucleocapsid antibodies to COVID-19, though in 30 patients (21.6%) the history was unknown and no nucleocapsid antibody testing was performed. Of the 12 patients who presented with myocarditis after the 1st dose of vaccine, six had a history of prior COVID-19 infection or had the presence of nucleocapsid antibodies. Evaluation for alternative microbial etiologies for suspected myocarditis varied, with no plausible alternatives determined by centers. None had a prior history of multisystem inflammatory syndrome in children (MIS-C). Vaccination Data, Symptoms, and Clinical Course: The majority of patients with suspected myocarditis received mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech and 5 (3.6%) after the Moderna vaccines. One case (0.7%) occurred after the Johnson and Johnson vaccine. The brand of vaccine was unknown in 2 patients. Patients presented more frequently after the 2nd dose (N=128, 91.4%). Onset of symptoms occurred at a median of 2 days (range 0-22, IQR 1-3) following vaccine administration, with 5 patients presenting with symptoms 7-20 days, and only 1 presenting with symptoms >/21 days after vaccination. Chest pain was the most common symptom, occurring in 138 patients (99.3%). Fever and shortness of breath each occurred in 30.9% and 27.3% of patients, respectively. Although 26 patients (18.7%) were managed in ICUs, inotropic/vasoactive support was used in only 2 (1.4%): one patient was treated with epinephrine and norepinephrine, and the other patient was treated with milrinone. No patient required extracorporeal membrane oxygenation (ECMO). All patients survived. The median hospital length of stay was 2 days (range 0-10, IQR 2-3). Most patients (N=113, 81.3%) were treated with nonsteroidal anti-inflammatory drugs (NSAIDs); 76 (54.7%) were treated with NSAIDs alone. Intravenous immunoglobulin (IVIG) was administered to 30 (21.6%) patients, with glucocorticoids also given to 30 patients. Glucocorticoid regimens varied, ranging from IV glucocorticoids alone (N=6) at doses of 0.5-10 mg/kg/day for 1-3 days, to oral glucocorticoids alone (N=2) at 0.5-0.67 mg/kg/day for 5-10 days, or IV and oral glucocorticoids (N=22) with a taper over 2-73 days. Colchicine was used in 11 patients (7.9%). Twelve patients (8.6%) had complete clinical improvement without any anti-inflammatory therapies. Laboratory data: All patients had elevated troponin I (median 8.12 ng/mL, IQR 3.50-15.90 ng/mL; N=111) or T (median 0.61 ng/mL, IQR 0.25-1.3 ng/mL; N=28). Median C-reactive protein (CRP) levels were mildly elevated (3.3 mg/dL, IQR 1.1-6.2 mg/dL; N=116). The median brain natriuretic peptide (BNP) level was within the normal range (55.0 pg/mL, IQR 18.9-147.0 pg/mL; N=101) and median NT-proBNP was mildly elevated (159 pg/mL, IQR 91.5-810.3 pg/mL; N=8). ECGs and Arrhythmias: Electrocardiograms were obtained in 138 patients (99.3%), of which 97 (69.8%) were abnormal. The most common abnormal ECG finding was ST segment and/or T wave abnormalities/elevation (N=95, 97.9%), with low voltages also seen in some (N=5, 3.6%). Of the 5 patients with low voltages, 3 had normal voltages within 3.5 weeks; one did not follow-up with the contributing site, and thus no follow-up ECGs were available; one continued to have low voltages at 5.5 weeks. Occasional premature ventricular (N=3) or atrial (N=1) contractions, atrial tachycardia (N=1), first degree atrioventricular block (N=1), and complete heart block (N=1) were observed, though uncommon Non-sustained ventricular tachycardia (VT) occurred in seven patients (5.0%), either on ECG, telemetry, or on ambulatory monitoring. Six had normal LVEF on echocardiogram, and one had mildly decreased systolic function (LVEF=50%). Of the six patients with VT who underwent cMRI, all had late gadolinium enhancement and myocardial edema. Two patients were treated with NSAIDs alone, one with IVIG and NSAIDs, two with IVIG and glucocorticoids, one with glucocorticoids and NSAIDS, and one with IVIG, glucocorticoids, and NSAIDs; this last patient had a 15-beat run of non-sustained VT on a Holter monitor and was readmitted and treated with atenolol. One patient presented to an emergency department with chest pain and was diagnosed with complete heart block. He was admitted to the pediatric ICU for monitoring, and no pacing was needed. Ventricular systolic function was normal on echocardiogram, and cMRI revealed late gadolinium enhancement without evidence of myocardial edema. This patient was treated with IVIG and steroids and his rhythm recovered within 24 hours of admission. Cardiac imaging: Echocardiography was performed in all patients. The majority (N=113, 81.3%) had normal systolic function, while 22 (15.8%) had mild, 2 (1.4%) had moderate, and 2 (1.4%) had severe dysfunction (Table 4). Twenty-five patients with LVEF<55% had recovery of systolic function to normal, with one patient awaiting outpatient follow-up at the time of this submission. Only one patient had a pericardial effusion, which was small. One patient had coronary artery dilation, with further details as noted below. Initial cMRI was performed in 97 patients at a median of 5 days (range 1-88, IQR 3-17) after symptom onset, of whom 75 (77.3%) had abnormalities. Among patients with abnormal cMRIs, late gadolinium enhancement was noted in 74 (98.7%) and myocardial edema was present in 54 (72.0%). Among the 97 cMRIs performed, 76.3% and 55.7% had evidence of late gadolinium enhancement or myocardial edema, respectively, and 49 (50.5%) met Lake Louise criteria for myocarditis. Of those with abnormal cMRIs, 62 (82.7%) occurred in patients with normal left ventricular systolic function on echocardiogram. Patients with vs. without a cMRI did not differ significantly with respect to ICU admission (24.1% vs. 16.7%, p=0.26), having mild left ventricular systolic dysfunction (23.2% vs. 11.9%, p=0.17), or troponin I levels (9.18 vs. 5.03 ng/mL, p=0.08). Median days from symptom onset to cMRI were significantly shorter for patients with abnormal vs. normal cMRIs (4 vs. 24 days, p<0.01). However, six of the 15 cMRIs performed >30 days after symptom onset had findings at LGE (even at up to 88 days), while seven of the 22 normal cMRIs were obtained within 7 days of symptom onset. In conclusion, the authors' case series demonstrates that myocarditis temporally related to COVID-19 vaccination is characterized by a mild illness with rapid resolution of symptoms in most patients. However, longer-term outcome data are lacking. We emphasize the importance of reporting suspected myocarditis cases after COVID-19 vaccination to the Vaccine Adverse Events Reporting System or similar reporting systems for patients in other countries to better define the characteristics of this syndrome and its relationship to receipt of COVID-19 vaccines. Future studies that focus on determining risk factors and mechanisms of development of myocarditis are urgently needed, particularly as COVID- 19 vaccines become more widely available to younger children in the future. Electrocardiographic abnormalities and rhythm disturbances seen in suspected myocarditis temporally related to vaccination (a) Diffuse ST elevation on the electrocardiogram of a 15-year-old male presenting with chest pain and elevated troponin levels 2 days after his 2nd Pfizer vaccine dose.; Sender's Comments: The information provided is too limited to make a meaningful medical assessment of the case. However, based on the available information in the case provided, the causal association between the reported event Myocarditis and the suspect drug BNT162B2 cannot be excluded considering drug-event temporal relationship. The case will be reassessed once new information is available. The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to Regulatory Authorities, Ethics Committees and Investigators, as appropriate.