Symptomatic Acute in 7 Adolescents After Pfizer-BioNTech COVID-19 Vaccination Mayme Marshall, MD,a Ian D. Ferguson, MD,b Paul Lewis MD, MPH,a Preeti Jaggi, MD,c Christina Gagliardo, MD,d,e James Stewart Collins, MD,f Robin Shaughnessy, MD,a Rachel Caron, BA,a Cristina Fuss, MD,g Kathleen Jo E. Corbin, MD, MHS,b Leonard Emuren, MBBS, PhD,b Erin Faherty, MD,b E. Kevin Hall, MD,b Cecilia Di Pentima, MD, MPH,d,e Matthew E. Oster, MD, MPH,c Elijah Paintsil, MD,b Saira Siddiqui, MD,d Donna M. Timchak, MD,d,h Judith A. Guzman-Cottrill, DOa

Trials of coronavirus disease 2019 (COVID-19) vaccination included limited abstract numbers of children, so they may not have detected rare but important aDepartment of Pediatrics, Oregon Health and Science adverse events in this population. We report 7 cases of acute myocarditis or University, Portland, Oregon; bDepartment of Pediatrics, in healthy male adolescents who presented with chest pain all Yale University, New Haven, Connecticut; cDepartment of Pediatrics, Emory University and Children’s Healthcare of within 4 days after the second dose of Pfizer-BioNTech COVID-19 vaccination. Atlanta, Atlanta, Georgia; dGoryeb Children’s Hospital, Five patients had fever around the time of presentation. Acute COVID-19 was Atlantic Health System, Morristown, New Jersey; eThomas Jefferson University, Philadelphia, Pennsylvania; fSpectrum ruled out in all 7 cases on the basis of negative severe acute respiratory Health, Grand Rapids, Michigan; gDepartment of Radiology, syndrome coronavirus 2 real-time reverse transcription polymerase chain Oregon Health and Science University, Portland, Oregon; and hIrving Medical Center, Columbia University, New York, reaction test results of specimens obtained by using nasopharyngeal swabs. New York None of the patients met criteria for multisystem inflammatory syndrome in Drs Marshall and Guzman-Cottrill drafted the initial children. Six of the 7 patients had negative severe acute respiratory syndrome manuscript, designed the data collection instruments, coronavirus 2 nucleocapsid antibody assay results, suggesting no previous collected data, participated in literature review, and reviewed and revised the manuscript; Drs Jaggi and infection. All patients had an elevated troponin. Cardiac MRI revealed late Lewis drafted case details for the initial manuscript, designed the data collection instruments, collected gadolinium enhancement characteristic of myocarditis. All 7 patients resolved data, and reviewed and revised the manuscript; Drs their symptoms rapidly. Three patients were treated with nonsteroidal Collins, Ferguson Gagliardo, and Shaughnessy drafted case details for the initial manuscript, collected data, antiinflammatory drugs only, and 4 received intravenous immunoglobulin and and reviewed and revised the manuscript; Drs Corbin, ’ Di Pentima, Emuren, Faherty, Fuss, Hall, Oster, Paintsil, corticosteroids. In this report, we provide a summary of each adolescent s Siddiqui, and Timchak reviewed clinical data and clinical course and evaluation. No causal relationship between vaccine critically reviewed and revised the manuscript for important intellectual subject matter content; Ms administration and myocarditis has been established. Continued monitoring Caron participated in drafting the initial manuscript, and reporting to the US Food and Drug Administration Vaccine Adverse Event the data collection, and the literature review; and all authors approved the final manuscript as submitted Reporting System is strongly recommended. and agree to be accountable for all aspects of the work. DOI: https://doi.org/10.1542/peds.2021-052478 Accepted for publication May 28, 2021 Address correspondence to Judith Guzman-Cottrill, DO, On December 11, 2020, the US Food years. This vaccine was Department of Pediatrics, Oregon Health and Science and Drug Administration issued an demonstrated to have a 94% to 95% University, 707 SW Gaines Rd, Mail Code CDRC-P, Portland, OR 97239. E-mail: [email protected] emergency use authorization (EUA) efficacy in preventing COVID-19 PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, for the Pfizer-BioNTech coronavirus infection in participants aged 16 to 1098-4275). disease 2019 (COVID-19) mRNA 55 years and 100% efficacy in the Copyright © 2021 by the American Academy of Pediatrics vaccine for prevention of COVID-19 group of those aged 12 to 15 FINANCIAL DISCLOSURE: The authors have indicated for individuals aged $16 years.1 On years.1,2 Systemic reactogenicity they have no financial relationships relevant to this article to disclose. May 10, 2021, the US Food and Drug occurred more commonly in younger Administration revised the EUA for patients and after the second dose of To cite: this vaccine to include children aged vaccine.1 Marshall M, Ferguson I D, Lewis P, et al. $12 years.1 The Pfizer vaccine Symptomatic Acute Myocarditis in 7 Adolescents After Pfizer-BioNTech COVID-19 Vaccination. remains the only vaccine with an Postimmunization myocarditis is a Pediatrics. 2021;148(3):e2021052478 EUA for children aged 12 to 17 known rare adverse event after other

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 148, number 3, September 2021:e2021052478 CASE REPORT vaccinations, particularly after Vaccine Adverse Event Reporting of 12.3 mg/L (normal range: <1.0 smallpox vaccination.3 Recently, the System (VAERS). mg/dL). Cardiac MRI revealed late news media have highlighted reports gadolinium enhancement of myocarditis after COVID-19 mRNA PATIENT 1 characteristic for myocarditis (Fig 1). vaccination involving US military A previously well 16-year-old male 4,5 patients and patients from Israel. individual presented to an Echocardiogram was normal. The Israeli cohort identified a male emergency department (ED) with Troponin I peaked at 12.43 ng/mL predominance with an incidence of 1 fatigue, poor appetite, fever of in 20 000 (men aged 18 to 30 years).  (normal range for this hospital: 38.3 C, and pain in the chest and <0.80 ng/mL) (Table 1). A However, a conclusive causal link to both arms 2 days after his second nasopharyngeal swab for severe vaccination has not been confirmed at Pfizer-BioNTech COVID-19 vaccine acute respiratory syndrome this time. Additionally, 2 recently dose. He had no history of recent coronavirus 2 (SARS-CoV-2) published European case reports viral illness symptoms and no polymerase chain reaction (PCR) describe myocarditis after COVID-19 known COVID-19 exposures. was negative, as was the patient’s mRNA vaccination in a 56-year-old Evaluation included an serum SARS-CoV-2 nucleocapsid man with previous COVID-19 and a electrocardiogram (ECG) that antibody. All other viral diagnostic 39-year-old man with no history of revealed atrioventricular 6,7 studies were negative (Table 1). He COVID-19. In this report, we dissociation with junctional escape remained well appearing, summarize case histories of 7 healthy and ST elevation and an elevated hemodynamically stable, and in male adolescents aged 14 to 19 years troponin I (2.59 ng/mL, normal normal throughout the who developed acute myocarditis or range for this hospital: <0.03 ng/ 6-day hospitalization. He received myopericarditis within 4 days after mL). He was transferred to the 100 g (1.5 g/kg) of intravenous receiving the second dose of the PICU of a tertiary care children’s immunoglobulin (IVIg), then 10 mg/ Pfizer-BioNTech COVID-19 vaccine, hospital for suspected myocarditis. kg of methylprednisolone none of whom met criteria for Inflammatory markers were mildly intravenously on 3 consecutive days, multisystem inflammatory syndrome elevated, with D-dimer 1.52 ug/ followed by a planned 12-week oral in children (MIS-C). All 7 patients mL, erythrocyte sedimentation prednisone taper. He also received were vaccinated in April and May of rate (ESR) of 43 mm/hour, and three 15- to 30-mg doses of 2021 and have been reported to the maximum C-reactive protein (CRP) intravenous ketorolac for pain. By 3

FIGURE 1 Cardiac MRI of patient 1. Four chamber (A) and short axis (B) postcontrast images depicting apical and midchamber lateral wall subepicar- dial late gadolinium enhancement (arrows). Pattern and distribution are highly characteristic for myocarditis.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 MARSHALL et al EITISVlm 4,nme ,Spebr2021 September 3, number 148, Volume PEDIATRICS TABLE 1 Summary of Diagnostics and Therapeutics: 7 Cases of Symptomatic Myocarditis After Dose 2 of Pfizer-BioNTech COVID-19 Vaccine Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Laboratory findings on admission Troponin (normal Troponin High-sensitivity troponin Troponin Troponin Troponin Troponin Troponin I: 22.1 range), ng/mL I: 2.59 (<0.03) T: 232 (<14) I: 5.55 (<0.045) T:1.09 (<0.01) T: 3.2 (<0.01) T: 0.66 (<0.01) (<0.045) Brain natriuretic ——————107.9 peptide (normal < 100), pg/mL

Downloaded from NT-proBNP (normal 428 — 376 — 978 149 — <125), pg/mL Peripheral white blood 6.97 8.69 11.8 12.6 16.3 5.0 8.11 cell count, thousands of cells per mm3 Absolute lymphocyte 1.69 1.39 2.13 2.3 4.1 1.4 1.05 www.aappublications.org/news count, thousands of cells per mm3 Absolute neutrophil 4.65 5.93 7.46 9.5 9.8 2.8 4.73 count, thousands of cells per mm3 Platelet count, 198 208 231 236 297 189 208 thousands of cells per mm3 Albumin (g/dL) 3.9 4.1 4.1 4.4 4.0 3.8 3.5 Aspartate transaminase, 54 29 41 82 150 59 87

byguest on September30, 2021 U/L Alanine transaminase, 30 14 33 20 46 22 38 U/L Ferritin, ug/L 70 — 90 103 347 65 84 CRP (normal <1.0), 0.99 6.7 2.5 12.7 18.1 1.5 7.7 mg/dL ESR, mm/h 18 13 6 40 38 3 10 Prothrombin time, ——14.0 — 12.1 11.4 14.8 seconds Partial thromboplastin 22.3 — 31.4 — 30.4 27.9 35.6 time, seconds International normalized 1.11 — 1.06 — 1.13 1.06 1.2 ratio INR Other pertinent laboratory findings Troponin I: 12.43 (<0.80) Troponin T: 1.09 (<0.01) Troponin T: 3.33 (<0.01) Troponin T: 0.82 (<0.01) 3 4 TABLE 1 Continued Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Highest troponin High-sensitivity troponin Troponin I: 12.20 Troponin I: 22.1 (normal range), T: 388 (<14) (<0.045) (<0.045) ng/mL Lowest troponin before Troponin I: 1.42(<0.80) — Troponin I: 5.79 (<0.045) Troponin T: 0.4 (<0.01) Troponin T: 0.96 (<0.01) Troponin T: 0.01 (<0.01) Troponin I: 8.02 discharge (normal (<0.045) range), ng/mL Highest BNP (normal ——————205(<100) range), pg/mL

Downloaded from Highest NT-proBNP 482 pg/mL (<125) — 376 pg/mL (<300) — 978 pg/mL (<125) 275 pg/mL (<125) — (normal range) Highest CRP (normal 1.23 6.7 2.53 12.7 18.1 1.8 12.7 <1.0), mg/dL COVID-19 PCR result Negative Negative Negative Negative Negative Negative Negative COVID-19 spike antibody ——Positive (Roche) Positive (Roche) Positive (Roche) Positive (Roche) —

www.aappublications.org/news (manufacturer) COVID-19 nucleocapsid Negative (Abbott) — Negative (Roche) Negative (Roche) Negative (Roche) Negative (Roche) Negative (Abbott) antibody result (manufacturer) Respiratory pathogen Negative (BioFire) Negative (BioFire) Negative (BioFire) Negative (BioFire) Negative (BioFire) Negative (BioFire) Negative (BioFire) panel PCR resulta (manufacturer) Adenovirus diagnostics Negative serum PCR — Negative serology Negative serum PCR Negative serum PCR — Negative serum PCR result Enterovirus diagnostics Negative serum PCR — Negative serology Negative serum PCR Negative serum PCR Negative serum PCR Negative serum PCR

byguest on September30, 2021 result Cytomegalovirus Negative serum PCR — Negative serology Negative serum PCR Negative serum PCR Negative serum PCR Negative serology diagnostics result Epstein-Barr virus ——Negative serology Negative serum PCR Negative serum PCR Negative IgM, positive IgG Negative serology diagnostics result antibody Other diagnostics ——Negative parvovirus, — Negative parvovirus and Negative Lyme serology, Negative parvovirus bartonella, and Lyme bartonella serology, negative mycoplasma IgM, positive parvovirus serology, negative urine negative HHV-6 serum serum PCR, negative IgG antibody, negative drug screen PCR parvovirus serum PCR mycoplasma PCR (throat swab) Diagnostic imaging findings Cardiac MRI LGE (subepicardial) LGE involving mid LV wall, LGE (subepicardial) Fibrosis, myocardial LGE (epicardial) involving LGE, diffuse myocardial LGE (subepicardial) involving lateral LV apex, myocardial edema of involving basal edema, hyperemia, mild anterior and lateral LV edema involving mid and myocardial edema of basal inferolateral LV anterolateral and basal mitral regurgitation (RF wall, no myocardial apical LV free wall, lateral LV wall, left wall to midventricular 18%) edema myocardial edema, axillary adenopathy inferolateral LV hyperemia segments, myocardial ASALe al et MARSHALL edema, elevated extracellular volume fraction (29.2%) weeks after presentation, troponin had returned to normal.

uenza 1, parain- PATIENT 2 fl LFNC None leads Patient 7 (LVEF 47%) furosemide A 19-year-old previously well male individual presented to a general voltage of extremity

and LV systolic function ED with acute, persistent chest uenza B, parain fl pain 3 days after his second Pfizer- BioNTech COVID-19 vaccine dose. He felt unwell for 3 days after uenza A, in fl None None

Normal Mildly depressed RV vaccination, with myalgias, fatigue, Patient 6 weakness, and subjective low- IVIg, PO prednisone NSAID, famotidine, ST elevation (diffuse) ST elevation, low grade fevers. He had no recent or ow nasal cannula; LV, left ventricular; LVEF, left ventricular fl remote history of viral illness and no known COVID-19 exposures. ECG revealed diffuse ST elevation consistent with acute myocardial None None Normal Patient 5 injury or . Urgent NSAID, IVIg, IV

wave abnormality cardiac catheterization revealed prednisone, aspirin methylprednisolone, PO Myocoplasma pneumonia. normal coronary arteries and

and normal left ventricular function. Initial high-sensitivity troponin T (232 ng/L, normal range: <14 ng/ None None L) and CRP (6.7 mg/dL, normal Normal Patient 4 prednisone ST elevation Sinus , T- range: <1.0 mg/dL) were highly elevated. Cardiac MRI confirmed methylprednisolone, PO myocarditis on the basis of the finding of patchy, midwall late gadolinium enhancement along the basal inferolateral wall segment. A — , not done. None None strain

Patient 3 nasopharyngeal swab for SARS- CoV-2 was negative. He remained T-wave abnormality and basal posterior ST elevation (diffuse), hemodynamically stable and was discharged from the hospital 2 days later with the diagnosis of myopericarditis. He was treated None None with 1 30 mg dose of intravenous Normal Borderline basal lateral (diffuse) Patient 2 Bordetella parapertussis, Bordetella pertussis, Chlamydophila pneumonia, ketorolac, 0.6 mg colchicine daily, and 650 mg aspirin 3 times daily. ST segment elevation NSAID, colchicine, aspirin NSAID, famotidine NSAID, IVIg, IV One week later, he was seen in follow-up. He complained of mild fatigue but had no chest pain or

None shortness of breath, and his ECG Normal Patient 1 famotidine

NSAID, IVIg, IV revealed , with a heart PO prednisone, Atrioventricular dissociation with junctional escape methylprednisolone, rhythm, ST elevation rate of 105 beats per minute. ST uenza 4, respiratory syncytial virus, fl segment resolution was noted. As a result of his , a 48- hour Holter monitor was done,

uenza 3, parain which revealed an average heart fl rate of 83 beats per minute with a ammatory agents Continued fl 1% premature ventricular or inotropic support and other relevant medications Antiin Vasoactive medications Oxygen supplementation None ECG Echocardiogram contraction burden. No other BioFire Respiratory Panel includes PCR for adenovirus, coronavirus 229E, coronavirus HKU1, coronavirus NL63, coronavirus OC43, metapneumovirus (human), rhinovirus or enterovirus, in Therapeutics uenza 2, parain ejection fraction; PO, per os (oral); q12hr, every 12 hours; RF, regurgitant fraction; RV, right ventricular; TABLE 1 HHV-6, human herpesvirus-6; IgG, immunoglobulin G;a IgM, immunoglobulin M; INR, international normalized ratio; IV, intravenous; LGE, late gadolinium enhancement; LFNC, low fl were noted. An

PEDIATRICS Volume 148, number 3,Downloaded September from 2021 www.aappublications.org/news by guest on September 30, 2021 5 echocardiogram was normal. The left ventricular basolateral and prompted the diagnosis of colchicine (0.6 mg) and aspirin (325 posterior regional strain. Cardiac myopericarditis. At 1-week follow- mg) daily were continued. MRI revealed delayed enhancement up, he remained asymptomatic at the left ventricular subepicardial with normal troponin, CRP, and PATIENT 3 basal anterolateral segment and ECG; the echocardiogram was A 17-year-old previously well male basal to midventricular unchanged. individual presented with chest inferolateral segments, consistent pain 2 days after his second Pfizer- with myocardial necrosis. There PATIENT 4 BioNTech COVID-19 vaccine. Chest was evidence of diffuse fibrosis on An 18-year-old previously well male pain was worse when lying flat and T1-weighted imaging and individual was admitted with a chief was associated with left arm pain myocardial edema on T2 mapping. complaint of chest pain 3 days after and paresthesias. He had no recent Results for SARS-CoV-2 spike he received the second Pfizer- or remote history of viral illness antibody were positive, and BioNTech COVID-19 vaccine. Soon and no known COVID-19 nucleocapsid antibody were after vaccination, he had developed exposures. ECG revealed abnormal negative. Workup for other malaise, arthralgia, myalgia, and T waves with diffuse ST elevation infections and a urine drug screen subjective fever. He had no recent or consistent with pericarditis (Fig 2). result were negative. Troponin remote history of viral illness and Notable laboratory studies peaked at 12.200 ng/mL. The no known COVID-19 exposures. Two included elevated troponin I (5.550 patient’s symptoms resolved with days before admission, he noted ng/mL, normal range: <0.045 ng/ ibuprofen 600 mg orally every 6 midsternal chest pain and presented mL), N-terminal pro-brain hours, and he was discharged at 48 to his primary care physician, who natriuretic peptide (NT-proBNP) hours. On the basis of the noted ST elevation on ECG, (376 pg/mL, normal range: <100 characteristics of his chest pain, prompting transfer to an ED, where pg/mL) and CRP (25.3 mg/L, ECG findings, and prompt response evaluation revealed elevated normal range: <1.0 mg/dL). to antiinflammatory medication, troponin T (1.09 ng/mL, normal Echocardiogram revealed normal pericardial involvement was range: <0.01 ng/mL), ST elevation function and coronaries, no suspected. The presence of on ECG, and normal effusion, trace mitral and aortic elevated cardiac markers and echocardiogram. Cardiac MRI valve insufficiency, and decreased inflammation on cardiac MRI revealed edema, hyperemia, and

FIGURE 2 Patient 3 ECG with diffuse ST elevations seen, characteristic of pericarditis. aVF, augmented Vector Foot; aVL, augmented Vector Left; aVR, augmented Vector Right.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 6 MARSHALL et al fibrosis, consistent with myocarditis. Results of a nasopharyngeal SARS- but normal function and structure Results for a nasopharyngeal SARS- CoV-2 PCR were negative; antibody on echocardiogram. Cardiac MRI CoV-2 PCR were negative, and testing revealed positive spike and revealed diffuse edema and antibody testing revealed positive negative nucleocapsid antibodies subepicardial late gadolinium spike and negative nucleocapsid for SARS-CoV-2. He received 70 g enhancement. Results of a antibodies for SARS-CoV-2. Troponin IVIg and was started on nasopharyngeal SARS-CoV-2 PCR testing reduced over the course of methylprednisolone 30 mg were negative, and antibody the 3-day hospitalization, and intravenously every 12 hours (2 testing revealed positive spike and telemetry remained normal. He was doses), then transitioned to negative nucleocapsid antibodies treated with 70 g IVIg and received prednisone 30 mg orally every 12 for SARS-CoV-2. He was treated 30 mg methylprednisolone hours with a gradual taper over 4 with 70 g IVIg and started on intravenously every 12 hours for 2 weeks. He also received ibuprofen prednisone 30 mg orally twice doses, followed by prednisone 30 600 mg orally every 6 hours for daily with a gradual taper over 4 mg orally twice daily with a gradual the first 3 days and then as weeks. He did not receive any taper over 4 weeks. He also received needed. He was discharged from nonsteroidal antiinflammatory ibuprofen 600 mg orally every 6 the hospital with a 30-day drugs (NSAIDs). hours as needed for pain and was prescription for aspirin 81 mg by discharged with a 30-day mouth once daily. Troponin level Troponin T climbed after admission prescription for aspirin 81 mg orally initially fell by 50% over the first and remained elevated throughout once daily. At his first outpatient 48 hours, but, on the third day of the hospitalization. Chest pain follow-up the next week, he felt admission, there was an acute rise resolved after administration of 6 well, troponin had normalized, and that sustained for 12 hours before mg of morphine in the initial ED both echocardiogram and ECG serial reduction. At discharge, evaluation. Telemetry was normal remained normal. troponin T remained elevated throughout hospitalization. He was (0.96 ng/mL, normal range: <0.01 discharged 3 days after admission. PATIENT 5 ng/mL). Telemetry during the 5- He had not yet returned for follow- up visit at the time of this A 17-year-old previously well male day hospitalization revealed submission. individual was admitted with a occasional monomorphic chief complaint of chest pain. His premature ventricular contractions PATIENT 7 symptoms began 3 days after his and sinus bradycardia during sleep second Pfizer-BioNTech COVID-19 but was otherwise normal. Serial A 14-year-old previously well male vaccine dose with sore throat, echocardiograms were normal. On individual presented to an urgent headache, dry cough, and body follow-up 4 days after discharge, care clinic with pleuritic chest pain aches. He had no recent or remote the echocardiogram was normal, and shortness of breath 2 days after history of viral illness and no but ECG revealed diffuse T-wave receiving his second Pfizer- known COVID-19 exposures. He abnormalities. BioNTech vaccine. A measured fever  then developed subjective fever Patient 6 of 38.3 C began the day of and was treated for suspected vaccination. He had no recent or streptococcal pharyngitis with A 16-year-old previously well male remote history of viral illness and amoxicillin; however, a throat individual was admitted with a no known COVID-19 exposures. ECG swab yielded a negative chief complaint of chest pain. His revealed ST segment elevation streptococcal antigen test result. initial symptoms began 3 days consistent with . The next day, he developed after the second Pfizer-BioNTech Additional evaluation included an midsternal chest pain that was COVID-19 vaccine with malaise and echocardiogram that revealed mildly worse when lying flat and radiated subjective fever. He had no recent depressed left and right ventricular to the left arm. Evaluation in the or remote history of viral illness systolic function and elevated ED revealed elevated troponin T and no known COVID-19 troponin I (22.1 ng/mL, normal (3.21 ng/mL, normal range: <0.01 exposures. The night before range: <0.045 ng/mL). His ng/mL), ST elevation on ECG, and admission, he developed acute maximum temperature was 38.6C normal function and structure on midsternal chest pain that lasted on the day of admission. Results of a echocardiogram. Initial cardiac for 18 hours. Evaluation in the nasopharyngeal SARS-CoV-2 PCR MRI revealed diffuse, nearly ED revealed an elevated troponin T and serum nucleocapsid antibody complete transmural left (0.66 ng/mL, normal range: <0.01 were both negative. On hospital day free wall gadolinium enhancement. ng/mL) and ST elevation on ECG 3, cardiac MRI revealed areas with

PEDIATRICS Volume 148, number 3,Downloaded September from 2021 www.aappublications.org/news by guest on September 30, 2021 7 high T2 values indicating edema, T1 myocardial necrosis on cardiac MRI condition, underlying cause, and early postcontrast heterogeneity (patient 3). physician preference. Consistent indicating hyperemia, and late with a known male preponderance gadolinium enhancement indicating All patients in this series had of myocarditis and pericarditis, all 7 myocardial fibrosis, all primarily in myocarditis or myopericarditis, of our patients were male 10 the subepicardial mid- and apical- which is the term for diagnosis of individuals. left ventricle free wall. He was both myocardial and pericardial treated with NSAIDs (ketorolac at inflammation. These terms are often The Pfizer-BioNTech clinical trials 30 mg once, followed by naproxen used interchangeably, which can revealed an increased systemic at 250 mg every 12 hours) and make surveillance of these diseases reactogenicity and immunogenicity in younger study participants after furosemide. Echocardiogram was challenging. Myocarditis and mRNA vaccine.1 For example, 41.5% improved 1 day after admission. He pericarditis are rare diseases. The of adolescents developed chills after was discharged on hospital day 4 true baseline incidence of dose 2, compared with 35.1% of on the basis of improvement of myocarditis is unknown and varies subjects aged 18 to 55 years.1 In symptoms and ejection fraction; the by season, geography, and age: it terms of immunogenicity, an troponin had declined to 8.02 ng/ has been reported to occur in 1.95 analysis of SARS-CoV-2 50% mL. His final diagnosis was in 100 000 person-years in children < neutralizing titers 1 month after myopericarditis. On follow-up 13 aged 15 years in Finland and in 2.16 cases per 100 000 US military dose 2 revealed higher geometric days later, he appeared well but mean titer (GMT) in children aged reported chest pain with exertion service members in a 30-day 10 12 to 15 years (GMT 5 1239.5), despite instructions to avoid period. It is more common in male individuals, and, among children, compared with subjects aged 16 to strenuous exercise. An ECG 25 years (GMT 5 705.1).1 Adverse revealed nonspecific T-wave reveals a bimodal incidence pattern, < events often occurred more changes, and echocardiogram was with peaks at 2 years of age and in adolescence.11 An evaluation for frequently after dose 2 and within normal. potential viral causes is 2 days after vaccination and included injection site pain, fatigue, recommended, although a cause is DISCUSSION myalgia, chills, arthralgia, fever, usually not found.12 There have injection site swelling or redness, We report 7 cases of clinical been previous reports of nausea, malaise, and myocarditis or myopericarditis that myocarditis after smallpox lymphadenopathy.1 It is possible developed in male individuals aged vaccination.10 In patients with that myocarditis or myopericarditis 14 to 19 years within 4 days of myocarditis, restriction from may be an additional rare adverse receiving the second dose of the competitive sports is recommended event related to systemic Pfizer-BioNTech COVID-19 vaccine for at least 3 months until cleared reactogenicity, but, currently, no with no evidence of acute SARS-CoV- by a cardiologist to avoid sudden causal association has been 2 infection that did not fulfill criteria cardiac events while the heart established between this vaccine for MIS-C. Extensive diagnostic muscle recovers.13 Less is known and myopericarditis. evaluation for other myocarditis about the true incidence of etiologies was negative (Table 1), pericarditis. Pericarditis can occur in In our case series, 6 patients including respiratory pathogens the setting of a variety of infectious received NSAID treatment. Four 14 from nasopharyngeal swabs, serum and noninfectious illnesses. In a patients received IVIg and oral PCR tests, and infectious serologies. study of patients aged $16 years in prednisone; 1 of these 4 patients Additionally, all cardiac MRIs were Finland, the incidence rate of also initially received high-dose diagnostic for myocarditis on the hospitalizations for acute methylprednisolone (Table 1). The basis of the modified Lake Louise pericarditis was 3.32 in 100 000 recognition of a possible temporal criteria rather than MIS-C person-years, with male individuals relationship of COVID-19 vaccine characteristics described by at higher risk than female and myocarditis is critical because 8 Blondiaux et al (diffuse myocardial individuals,15 and, in 2007, the the correct diagnosis may spare edema without evidence of late incidence of acute pericarditis in 1 healthy adolescents and young gadolinium enhancement).9 There study was 27.7 cases per 100 000 adults presenting with chest pain was some suggestion of abnormal population per year.16 Treatment of and ECG ST elevation from left ventricular myocardial myocarditis and pericarditis may undergoing unnecessary invasive echocardiographic strain vary considerably depending on the medical procedures, such as cardiac corresponding to regions of patient characteristics, clinical catheterization. It is unclear if

Downloaded from www.aappublications.org/news by guest on September 30, 2021 8 MARSHALL et al TABLE 2 Demographic and Clinical Characteristics of 7 Cases of Symptomatic Myocarditis After Dose 2 of Pfizer-BioNTech COVID-19 Vaccine Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Age, y 16 19 17 18 17 16 14 Sex Male Male Male Male Male Male Male Race or White White White White Hispanic White White ethnicity Wt, kg 68 68 71 69 64 71 92 BMI 24 19 21 21 19 22 28 Exposure to None None None None None None None COVID-19 in 14 d before illness onset Time between 2322432 vaccine dose 2 and symptom onset, d Total hospital 6224534 LOS, d ICU LOS, d 4 None None 4 5 2 2 Symptoms on presentation Chest pain Present Present Present Present Present Present Present Other pain Bilateral arm Myalgias Bilateral arm — Bilateral arm —— pain pain, numbness, pain, abdominal paresthesia pain Fever 38.3C by history Subjective, chills — Subjective Subjective — 38.3C by history Fatigue Present Present — Present ——— Other Nausea, Weakness — Nausea Nausea, SOB SOB vomiting, vomiting, anorexia, anorexia, SOB, headache palpitations LOS, length of stay; SOB, shortness of breath; —, not present. treatment with IVIg and/or and health care providers to stable during hospitalization. corticosteroids, in the absence of consider myocarditis in the However, no patient had evidence MIS-C criteria, is warranted with all evaluation of adolescents and of a preceding or concurrent cases of myocarditis that develop young adults who develop chest symptomatic viral illness to temporally after COVID-19 pain after COVID-19 vaccination. All implicate as an etiology of vaccination. Notably, 3 patients cases of myocarditis in patients myocarditis, and the lack of recovered with NSAID therapy with recent COVID-19 vaccination eosinophilia dissuades a alone. should be reported promptly to hypersensitivity reaction. The VAERS. pathophysiology of myocarditis in Myocarditis and myopericarditis thesepatientsisindeterminate, after COVID-19 vaccination appear Our case series has inherent and we do not know if it is the rare. As of May 23, 2021, the limitations. We compiled cases same or different from classic Centers for Disease Control and through personal communications myopericarditis or myopericarditis Prevention reports that 1 560 652 among colleagues rather than after other vaccines, associated people aged <18 years have using a systematic surveillance with acute COVID-19, or with MIS- completed a 2-dose series of system to identify cases. It was not C.10,18–20 Given the nature of a case COVID-19 vaccine.17 Of these, possible to exclude all alternative series, we cannot determine the 652 758 adolescents received their etiologies including idiopathic and incidence rate of myocarditis and second dose >14 days ago.17 other infectious etiologies, and myopericarditis after COVID-19 Currently, the Pfizer-BioNTech there was not a systematic mRNA vaccination. Finally, a COVID-19 vaccine is the only diagnostic evaluation for other negative nucleocapsid antibody test COVID-19 vaccine authorized for viral etiologies. Cardiac biopsy was result does not conclusively rule children aged <18 years in the not performed on any patients out the possibility of natural United States. We urge physicians because they were all clinically infection.

PEDIATRICS Volume 148, number 3,Downloaded September from 2021 www.aappublications.org/news by guest on September 30, 2021 9 In this report, we summarize a disease (via SARS-CoV-2 ABBREVIATIONS series of US cases of myocarditis nucleocapsid and spike protein and myopericarditis after the antibodies) is recommended for COVID-19: coronavirus disease Pfizer-BioNTech COVID-19 mRNA all cases of myocarditis that occur 2019 vaccine in adolescent male after COVID-19 mRNA vaccination, CRP: C-reactive protein individuals. All cases in this report as well as a comprehensive ECG: electrocardiogram ED: emergency department occurred after the second vaccine workup to exclude other EUA: emergency use dose. Fortunately, none of our infectious and noninfectious authorization patients was critically ill and each causes. The benefits of vaccination GMT: geometric mean titer was discharged from the hospital. significantly exceed possible risks. IVIg: intravenous At present, there is no definite Individuals and physicians are immunoglobulin causal relationship between these encouraged to follow the guidance MIS-C: multisystem inflammatory cases and vaccine administration. of the Centers for Disease Control syndrome in children and Prevention Advisory As of May 12, 2021, children in NSAID: nonsteroidal Committee on Immunization the United States aged $12 years antiinflammatory drug Practices.21 All cases of are now eligible to receive the NT-proBNP: N-terminal pro-brain myocarditis with or without Pfizer-BioNTech vaccine. Primary natriuretic peptide pericarditis occurring after care and ED physicians and health PCR: polymerase chain reaction COVID-19 vaccination should be care providers should consider SARS-CoV-2: severe acute promptly reported to VAERS. myocarditis an etiology of chest respiratory syndrome pain in patients with recent ACKNOWLEDGMENTS COVID-19 mRNA vaccination. coronavirus 2 Elevated serum troponin, an We thank our patients and their VAERS: Vaccine Adverse Event abnormal ECG, and an abnormal families, who consented to sharing Reporting System cardiac MRI were seen in all cases the details of their medical illnesses (Table 2). An evaluation for acute in this case report. We thank COVID-19 infection (via PCR of Katherine M. Mullin, MD who assis- respiratory tract sample) and past ted with case finding.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2021-052644.

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PEDIATRICS Volume 148, number 3,Downloaded September from 2021 www.aappublications.org/news by guest on September 30, 2021 11 Symptomatic Acute Myocarditis in 7 Adolescents After Pfizer-BioNTech COVID-19 Vaccination Mayme Marshall, Ian D. Ferguson, Paul Lewis, Preeti Jaggi, Christina Gagliardo, James Stewart Collins, Robin Shaughnessy, Rachel Caron, Cristina Fuss, Kathleen Jo E. Corbin, Leonard Emuren, Erin Faherty, E. Kevin Hall, Cecilia Di Pentima, Matthew E. Oster, Elijah Paintsil, Saira Siddiqui, Donna M. Timchak and Judith A. Guzman-Cottrill Pediatrics originally published online June 4, 2021; originally published online June 4, 2021;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2021/08/12/peds.2 021-052478 References This article cites 15 articles, 6 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2021/08/12/peds.2 021-052478#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Vaccine/Immunization http://www.aappublications.org/cgi/collection/vaccine:immunization _sub Cardiology http://www.aappublications.org/cgi/collection/cardiology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 30, 2021 Symptomatic Acute Myocarditis in 7 Adolescents After Pfizer-BioNTech COVID-19 Vaccination Mayme Marshall, Ian D. Ferguson, Paul Lewis, Preeti Jaggi, Christina Gagliardo, James Stewart Collins, Robin Shaughnessy, Rachel Caron, Cristina Fuss, Kathleen Jo E. Corbin, Leonard Emuren, Erin Faherty, E. Kevin Hall, Cecilia Di Pentima, Matthew E. Oster, Elijah Paintsil, Saira Siddiqui, Donna M. Timchak and Judith A. Guzman-Cottrill Pediatrics originally published online June 4, 2021; originally published online June 4, 2021;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2021/08/12/peds.2021-052478

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