key: cord-0880725-akjcxqs1
authors: Das, Bibhuti B.; Kohli, Utkarsh; Ramachandran, Preeti; Nguyen, Hoang H.; Greil, Gerald; Hussain, Tarique; Tandon, Animesh; Kane, Colin; Avula, Sarvani; Duru, Chioma; Hede, Sannya; Sharma, Kavita; Chowdhury, Devyani; Patel, Sunil; Mercer, Christopher; Chaudhuri, Nita Ray; Patel, Bhavi; Khan, Danyal; Ang, Jocelyn Y.; Asmar, Basim; Sanchez, Joselito; Bobosky, Karyssa Ann; Cochran, Clinton D.; Gebara, Bassam M.; Gonzalez Rangel, Ismael E.; Krasan, Graham; Siddiqui, Owais; Waqas, Muhammad; El-Wiher, Nidal; Freij, Bishara J.
title: Myopericarditis following mRNA COVID-19 Vaccination in Adolescents 12 through 18 Years of Age
date: 2021-07-30
journal: J Pediatr
DOI: 10.1016/j.jpeds.2021.07.044
sha: 77e270fe547d49c3e980c64f4b659a96b42399ff
doc_id: 880725
cord_uid: akjcxqs1

OBJECTIVES: To characterize the clinical course and outcomes of children who developed probable myopericarditis after vaccination with the Pfizer- BioNTech (BNT162b2) COVID-19 mRNA vaccine. STUDY DESIGN: A cross-sectional study of 32 children, aged 12 through 18 years, diagnosed with probable myopericarditis following COVID-19 mRNA vaccination as per the CDC criteria for myopericarditis at 9 US centers between May 10, 2021 and June 20, 2021. We retrospectively collected the following data: demographics, SARS-CoV-2 virus detection or serologic testing, clinical manifestations, laboratory test results, imaging study results, treatment and time to resolutions of symptoms. RESULTS: Most (90%) cases followed the second dose of vaccine, and chest pain (100%) was the most common presenting symptom. Patients came to medical attention a median of 2 days (range: <1-20 days) after receipt of Pfizer mRNA COVID-19 vaccination. All adolescents had an elevated plasma troponin concentration. Echocardiographic abnormalities were infrequent, and 84% showed normal cardiac function at presentation. However, cardiac magnetic resonance imaging (CMR), obtained in 16 patients (50%), revealed that 15 (94%) had late gadolinium enhancement consistent with myopericarditis. Most were treated with ibuprofen or an equivalent NSAID for symptomatic relief, one patient was treated primarily with a corticosteroid orally and three patients were given a corticosteroid orally after initial administration of ibuprofen or NSAID; two patients also received intravenous immune globulin. Symptom resolution was observed within 7 days in all patients. CONCLUSIONS: Our data suggest that symptoms due to myopericarditis following mRNA COVID-19 vaccination tend to be mild and transient. Approximately one half of patients underwent CMR, which revealed evidence of myocardial inflammation despite a lack of echocardiographic abnormalities.

To characterize the clinical course and outcomes of children who developed probable myopericarditis after vaccination with the Pfizer-BioNTech (BNT162b2) COVID-19 mRNA vaccine.

Study design: A cross-sectional study of 32 children, aged 12 through 18 years, diagnosed with probable myopericarditis following COVID-19 mRNA vaccination as per the CDC criteria for myopericarditis at 9 US centers between May 10, 2021 and June 20, 2021. We retrospectively collected the following data: demographics, SARS-CoV-2 virus detection or serologic testing, clinical manifestations, laboratory test results, imaging study results, treatment and time to resolutions of symptoms.

Results: Most (90%) cases followed the second dose of vaccine, and chest pain (100%) was the most common presenting symptom. Patients came to medical attention a median of 2 days (range: <1-20 days) after receipt of Pfizer mRNA COVID-19 vaccination. All adolescents had an elevated plasma troponin concentration. Echocardiographic abnormalities were infrequent, and 84% showed normal cardiac function at presentation. However, cardiac magnetic resonance imaging (CMR), obtained in 16 patients (50%), revealed that 15 (94%) had late gadolinium enhancement consistent with myopericarditis. Most were treated with ibuprofen or an equivalent NSAID for symptomatic relief, one patient was treated primarily with a corticosteroid orally and three patients were given a corticosteroid orally after initial administration of ibuprofen or NSAID; two patients also received intravenous immune globulin. Symptom resolution was observed within 7 days in all patients.

Our data suggest that symptoms due to myopericarditis following mRNA COVID- 19 3 Since April 2021, an increase in myopericarditis has been reported temporally associated with COVID-19 vaccination, particularly among adolescents. The American Academy of Pediatrics (AAP) and the American Heart Association (AHA) have endorsed CDC recommendations and reiterated the potential benefits of COVID-19 vaccination, which outweigh the apparent small risk of myopericarditis in children 12 years of age and older. [4] [5] We summarize our findings in 32 adolescents 12 through 18 years of age with vaccine-associated myopericarditis from 9 centers across the US.

A multi-institutional group of pediatric cardiologists, pediatric intensivists, and pediatric infectious disease physicians from 9 centers across the United States pooled their data for this retrospective case series. Children were included in the study if they presented with probable myopericarditis after mRNA COVID-19 vaccination between May 10, 2021 and June 20, 2021 and were aged 12 through 18 years. Clinical and laboratory data were collected free of personal identifiers except for age, race, and sex-and submitted by collaborating authors via secure email.

We collected the data retrospectively according to the institutional review board policies of each of the participating institutions.

Patient data included age, sex, race and ethnicity, history or evidence of prior SARS-CoV-2 infection (ie, either rapid COVID-19 test or PCR for SARS-CoV-2), and symptoms at presentation (i.e., chest pain, fever, shortness of breath, fatigue, nausea, vomiting, abdominal pain, or any other unusual symptoms). The laboratory data included testing to detect other viral causes of myocarditis, serum concentrations of an inflammatory marker (C-reactive protein) and cardiac biomarker (troponin), electrocardiographic findings, echocardiographic findings, and cardiac magnetic resonance imaging (CMR) findings. Results of serologic testing for SARS-CoV-2 antibodies as performed at the discretion of, and using tests available to, the reporting sites were collected. Additional data included the duration of hospitalization and details of the therapy administered.

The Table summarizes the characteristics of 32 adolescents, 12 through 18 years of age, who had probable myopericarditis as per the CDC defined criteria for diagnosis of myocarditis and pericarditis. 6 Twenty-eight (87.5%) were males, and 29 (90 %) presented after the second dose of the mRNA COVID-19 vaccine. Three adolescents (~10%) (Patients 4, 8, and 27) had probable myopericarditis after the first dose. One of these patients (Patient 4) had evidence of probable myopericarditis 20 days after the first dose, with complete clinical resolution. He again presented with chest pain and was diagnosed with probable myopericarditis 1 day after the second dose of the vaccine.

The most common presenting symptom was chest pain. A few patients had additional symptoms, including fever, shortness of breath, fatigue, nausea, vomiting, and abdominal pain (Table) . After the second dose of vaccine, 72% and 86% of patients reported onset of symptoms Hospitalized patients had stays of 2-7 days (median 3 days). All recovered clinically and were discharged home in less than 7 days. Three patients (Patients 4, 10 and 32) did not require hospitalization and were followed as outpatients. Most patients were treated with ibuprofen or an equivalent NSAID and responded well; one was treated primarily with a corticosteroid orally, three with a corticosteroid after initial ibuprofen or NSAID administration due to rising troponin concentration; two (Patients 5 and 31) also received intravenous immune globulin in addition to other therapies, which was based on physician and family preference than specific clinical criteria.

All afflicted adolescents made a complete clinical recovery in 1 week and were doing well at the most recent follow up.

Our report represents a large series of adolescents with myopericarditis following mRNA COVID-19 vaccination. 6 vaccination after analyzing VAERS data; many more cases are under review currently. 9 The preliminary estimated risk of myocarditis following administration of the Pfizer-BioNTech COVID-19 mRNA vaccine is 1.2 and 10.4 per million after administration of the first and second dose, respectively among those 16 through 39 years of age. 10 In a report from the Israeli Ministry of Health, one in 3000 to one in 6000 men aged 16 through 24 years who received the mRNA COVID-19 vaccine developed myocarditis/pericarditis. 11 Ninety percent of affected individuals in Israel were young men. Although the background rate of myocarditis in this population is high, the rate following vaccination appeared to be 5-25 times higher than the background rate. 11 European Medicines Agency also has reported myocarditis/ pericarditis related to mRNA vaccination but concluded no indication of a causal relation with the vaccine. 12 The striking male preponderance in our cohort is consistent with reports in young adults and small series of adolescents. 6 vaccine and found that his antibody responses to 18 different SARS-CoV-2 antigens did not differ from (and were lower for some antigens) vaccinated controls who did not develop complications.

Other hypothesized mechanisms include induction of anti-idiotype cross-reactive antibody-mediated cytokine expression in the myocardium, leading to aberrant apoptosis, resulting in inflammation of the myocardium and pericardium. 16 Induction of a nonspecific innate inflammatory response by the mRNA vaccine or a molecular mimicry mechanism between viral spike protein and an unknown cardiac protein also has been postulated. 17 The mRNA in the vaccine is a potent immunogen and produces bystander or adjuvant effects by cytokine activation of pre-existing autoreactive immune cells. 18 The complication of mRNA vaccine-related myopericarditis has predominantly been reported in males. Whether hormonal or other differences play a role in expression of this disease has not been evaluated systematically.

The definitive diagnosis of myocarditis is established by histologic criteria, including acute myocyte injury with inflammatory cell infiltration, especially lymphocytes. 19 In most patients, myocarditis is transient and self-limited; therefore, endomyocardial biopsy is not justified. Elevated serum troponin concentration may indicate acute cardiac injury but is neither sensitive nor specific for the diagnosis of myocarditis. Because of variable clinical manifestations of myocarditis, it is helpful to follow the CDC definition of acute myocarditis and acute pericarditis. As demonstrated by our data, cardiac magnetic resonance (CMR) imaging with tissue characterization using T1 and T2 mapping is a useful noninvasive modality for diagnosing mRNA COVID-19 vaccine-associated myocarditis/pericarditis, especially in patients with normal echocardiographic findings. 20 Treatment considerations for non-vaccine-associated myocarditis include anti-inflammatory medications and guideline-directed medical therapy if left ventricular function is diminished. 21 There are no systematic data on specific treatment of COVID-19 vaccine-associated myocarditis. As shown in our study, ibuprofen or equivalent nonsteroidal anti-inflammatory drugs (NSAIDs) seem to provide a beneficial response and could be prudent initial management. The role of corticosteroids and IVIG remains unclear, but these agents could reduce the immune response triggered by the vaccine and have a role in NSAID-unresponsive patients.

There are several limitations to our study. We do not have the data on the total number of children vaccinated during the study period; therefore, the incidence of COVID-19 mRNA vaccine-associated myocarditis/pericarditis cannot be determined. Moreover, although the patients who were symptomatic and sought medical care were evaluated and diagnosed, several COVID-19 vaccine-associated myocarditis episodes could be subclinical or have trivial symptoms that did not lead to seeking medical care. Reported cases could underestimate the true incidence of mRNA COVID-19 vaccine-associated myocarditis/pericarditis. As the Pfizer-BioNTech (BNT162b2) vaccine is the only mRNA vaccine currently approved in individuals at 12 through 15 years of age, we have presumed that all patients received this vaccine (without verifying vaccination cards). Not all laboratory tests, including testing for other causes of viral myocarditis, serologic testing for COVID-19, and CMR, were available for each patient due to variability in practice among individual physicians and centers. The typical occurrence of non-COVID vaccine-associated myocarditis in children and adolescents is approximately 10-20/100,000 annually. 22 After the initiation of COVID-19 vaccination and relaxation of restrictions, there has been an increase in overall mobility after a prolonged period of lock-down. Therefore, there might have been an increase in non-mRNA COVID-19 vaccine-associated myocarditis of undetermined viral cause, which could have been misdiagnosed as COVID-19 vaccine-associated myocarditis.

The long-term impact of myopericardial inflammation following COVID-19 mRNA vaccine, especially in those with extensive myocardial involvement on CMR, remains unknown and needs to be systematically evaluated. Further studies are required to elucidate the pathophysiology that underlies this complication to seek mitigation strategies and to delineate optimal therapy. J o u r n a l P r e -p r o o f 

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Transient cardiac injury in adolescents receiving the BNT162b2 mRNA COVID-19 vaccine

CDC confirms 226 cases of myocarditis after COVID-19 vaccination in people 30 and under

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