Risk of myocarditis and pericarditis after a COVID-19 mRNA vaccine booster and after COVID-19 in those with and without prior SARS-CoV-2 infection: A self-controlled case series analysis in England.

BACKGROUND: An increased risk of myocarditis or pericarditis after priming with mRNA Coronavirus Disease 2019 (COVID-19) vaccines has been shown but information on the risk post-booster is limited. With the now high prevalence of prior Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we assessed the effect of prior infection on the vaccine risk and the risk from COVID-19 reinfection. METHODS AND FINDINGS: We conducted a self-controlled case series analysis of hospital admissions for myocarditis or pericarditis in England between 22 February 2021 and 6 February 2022 in the 50 million individuals eligible to receive the adenovirus-vectored vaccine (ChAdOx1-S) for priming or an mRNA vaccine (BNT162b2 or mRNA-1273) for priming or boosting. Myocarditis and pericarditis admissions were extracted from the Secondary Uses Service (SUS) database in England and vaccination histories from the National Immunisation Management System (NIMS); prior infections were obtained from the UK Health Security Agency's Second-Generation Surveillance Systems. The relative incidence (RI) of admission within 0 to 6 and 7 to 14 days of vaccination compared with periods outside these risk windows stratified by age, dose, and prior SARS-CoV-2 infection for individuals aged 12 to 101 years was estimated. The RI within 27 days of an infection was assessed in the same model. There were 2,284 admissions for myocarditis and 1,651 for pericarditis in the study period. Elevated RIs were only observed in 16- to 39-year-olds 0 to 6 days postvaccination, mainly in males for myocarditis. Both mRNA vaccines showed elevated RIs after first, second, and third doses with the highest RIs after a second dose 5.34 (95% confidence interval (CI) [3.81, 7.48]; p < 0.001) for BNT162b2 and 56.48 (95% CI [33.95, 93.97]; p < 0.001) for mRNA-1273 compared with 4.38 (95% CI [2.59, 7.38]; p < 0.001) and 7.88 (95% CI [4.02, 15.44]; p < 0.001), respectively, after a third dose. For ChAdOx1-S, an elevated RI was only observed after a first dose, RI 5.23 (95% CI [2.48, 11.01]; p < 0.001). An elevated risk of admission for pericarditis was only observed 0 to 6 days after a second dose of mRNA-1273 vaccine in 16 to 39 year olds, RI 4.84 (95% CI [1.62, 14.01]; p = 0.004). RIs were lower in those with a prior SARS-CoV-2 infection than in those without, 2.47 (95% CI [1.32,4.63]; p = 0.005) versus 4.45 (95% [3.12, 6.34]; p = 0.001) after a second BNT162b2 dose, and 19.07 (95% CI [8.62, 42.19]; p < 0.001) versus 37.2 (95% CI [22.18, 62.38]; p < 0.001) for mRNA-1273 (myocarditis and pericarditis outcomes combined). RIs 1 to 27 days postinfection were elevated in all ages and were marginally lower for breakthrough infections, 2.33 (95% CI [1.96, 2.76]; p < 0.001) compared with 3.32 (95% CI [2.54, 4.33]; p < 0.001) in vaccine-naïve individuals respectively. CONCLUSIONS: We observed an increased risk of myocarditis within the first week after priming and booster doses of mRNA vaccines, predominantly in males under 40 years with the highest risks after a second dose. The risk difference between the second and the third doses was particularly marked for the mRNA-1273 vaccine that contains half the amount of mRNA when used for boosting than priming. The lower risk in those with prior SARS-CoV-2 infection, and lack of an enhanced effect post-booster, does not suggest a spike-directed immune mechanism. Research to understand the mechanism of vaccine-associated myocarditis and to document the risk with bivalent mRNA vaccines is warranted.

COVID-19 vaccination-related myocarditis: a Korean nationwide study.

AIMS: A comprehensive nationwide study on the incidence and outcomes of COVID-19 vaccination-related myocarditis (VRM) is in need. METHODS AND RESULTS: Among 44 276 704 individuals with at least 1 dose of COVID-19 vaccination, the incidence and clinical courses of VRM cases confirmed by the Expert Adjudication Committee of the Korea Disease Control and Prevention Agency were analyzed. COVID-19 VRM was confirmed in 480 cases (1.08 cases per 100 000 persons). Vaccination-related myocarditis incidence was significantly higher in men than in women (1.35 vs. 0.82 per 100 000 persons, P < 0.001) and in mRNA vaccines than in other vaccines (1.46 vs. 0.14 per 100 000 persons, P < 0.001). Vaccination-related myocarditis incidence was highest in males between the ages of 12 and 17 years (5.29 cases per 100 000 persons) and lowest in females over 70 years (0.16 cases per 100 000 persons). Severe VRM was identified in 95 cases (19.8% of total VRM, 0.22 per 100 000 vaccinated persons), 85 intensive care unit admission (17.7%), 36 fulminant myocarditis (7.5%), 21 extracorporeal membrane oxygenation therapy (4.4%), 21 deaths (4.4%), and 1 heart transplantation (0.2%). Eight out of 21 deaths were sudden cardiac death (SCD) attributable to VRM proved by an autopsy, and all cases of SCD attributable to VRM were aged under 45 years and received mRNA vaccines. CONCLUSION: Although COVID-19 VRM was rare and showed relatively favorable clinical courses, severe VRM was found in 19.8% of all VRM cases. Moreover, SCD should be closely monitored as a potentially fatal complication of COVID-19 vaccination.

Incidence of myopericarditis after mRNA COVID-19 vaccination: A meta-analysis with focus on adolescents aged 12-17 years.

BACKGROUND: The incidence of myopericarditis after mRNA COVID-19 vaccination among adolescents aged 12-17 years remains unknown. Therefore, we conducted a study to pool the incidence of myopericarditis following COVID-19 vaccination in this age group. METHODS: We did a meta-analysis by searching 4 electronic databases until February 6, 2023. The following main keywords were used: "COVID-19", "vaccines", "myocarditis", "pericarditis", and "myopericarditis". Observational studies reporting on adolescents aged 12-17 years who had myopericarditis in temporal relation to receiving mRNA COVID-19 vaccines were included. The pooled incidence of myopericarditis and 95 % confidence interval (CI) were calculated using a single-group meta-analysis. RESULTS: Fifteen studies were included. The pooled incidences of myopericarditis after mRNA COVID-19 vaccination among adolescents aged 12-17 years were 43.5 (95 % CI, 30.8-61.6) cases per million vaccine doses for both BNT162b2 and mRNA-1273 (39 628 242 doses; 14 studies), and 41.8 (29.4-59.4) cases for BNT162b2 alone (38 756 553 doses; 13 studies). Myopericarditis was more common among males (66.0 [40.5-107.7] cases) than females (10.1 [6.0-17.0] cases) and among those receiving the second dose (60.4 [37.6-96.9] cases) than those receiving the first dose (16.6 [8.7-31.9] cases). The incidences of myopericarditis did not differ significantly when grouped by age, type of myopericarditis, country, and World Health Organization region. None of the incidences of myopericarditis pooled in the current study were higher than those after smallpox vaccinations and non-COVID-19 vaccinations, and all of them were significantly lower than those in adolescents aged 12-17 years after COVID-19 infection. CONCLUSIONS: The incidences of myopericarditis after mRNA COVID-19 vaccination among adolescents aged 12-17 years were very rare; they were not higher than other important reference incidences. These findings provide an important context for health policy makers and parents with vaccination hesitancy to weight the risks and benefits of mRNA COVID-19 vaccination among adolescents aged 12-17 years.

COVID-19 myocarditis and long-term heart failure sequelae.

PURPOSE OF REVIEW: The clinical syndrome of coronavirus disease 2019 (COVID-19) has become a global pandemic leading to significant morbidity and mortality. Cardiac dysfunction is commonly seen in these patients, often presenting as clinical heart failure. Accordingly, we aim to provide a comprehensive review on COVID-19 myocarditis and its long-term heart failure sequelae. RECENT FINDINGS: Several suspected cases of COVID-19 myocarditis have been reported. It is often not clear if the acute myocardial dysfunction is caused by myocarditis or secondary to generalized inflammatory state of cytokine release or microvascular thrombotic angiopathy. Ischemia may also need to be ruled out. Regardless, myocardial dysfunction in these patients is associated with poor overall prognosis. Laboratory testing, echocardiography, cardiac magnetic resonance imaging, and even endomyocardial biopsy may be needed for timely diagnosis. Several treatment strategies have been described, including both supportive and targeted therapies. SUMMARY: COVID-19 can cause a spectrum of ventricular dysfunction ranging from mild disease to fulminant myocarditis with hemodynamic instability. Future research is needed to understand the true prevalence of COVID-19 myocarditis, as well as to better define various diagnostic protocols and treatment strategies.

COVID-19, Myocarditis and Pericarditis.

Viral infections are a leading cause of myocarditis and pericarditis worldwide, conditions that frequently coexist. Myocarditis and pericarditis were some of the early comorbidities associated with SARS-CoV-2 infection and COVID-19. Many epidemiologic studies have been conducted since that time concluding that SARS-CoV-2 increased the incidence of myocarditis/pericarditis at least 15× over pre-COVID levels although the condition remains rare. The incidence of myocarditis pre-COVID was reported at 1 to 10 cases/100 000 individuals and with COVID ranging from 150 to 4000 cases/100 000 individuals. Before COVID-19, some vaccines were reported to cause myocarditis and pericarditis in rare cases, but the use of novel mRNA platforms led to a higher number of reported cases than with previous platforms providing new insight into potential pathogenic mechanisms. The incidence of COVID-19 vaccine-associated myocarditis/pericarditis covers a large range depending on the vaccine platform, age, and sex examined. Importantly, the findings highlight that myocarditis occurs predominantly in male patients aged 12 to 40 years regardless of whether the cause was due to a virus-like SARS-CoV-2 or associated with a vaccine-a demographic that has been reported before COVID-19. This review discusses findings from COVID-19 and COVID-19 vaccine-associated myocarditis and pericarditis considering the known symptoms, diagnosis, management, treatment, and pathogenesis of disease that has been gleaned from clinical research and animal models. Sex differences in the immune response to COVID-19 are discussed, and theories for how mRNA vaccines could lead to myocarditis/pericarditis are proposed. Additionally, gaps in our understanding that need further research are raised.

Vaccination-Associated Myocarditis and Myocardial Injury.

SARS-CoV-2 vaccine-associated myocarditis/myocardial injury should be evaluated in the contexts of COVID-19 infection, other types of viral myocarditis, and other vaccine-associated cardiac disorders. COVID-19 vaccine-associated myocardial injury can be caused by an inflammatory immune cell infiltrate, but other etiologies such as microvascular thrombosis are also possible. The clinical diagnosis is typically based on symptoms and cardiac magnetic resonance imaging. Endomyocardial biopsy is confirmatory for myocarditis, but may not show an inflammatory infiltrate because of rapid resolution or a non-inflammatory etiology. Myocarditis associated with SARS-COVID-19 vaccines occurs primarily with mRNA platform vaccines, which are also the most effective. In persons aged >16 or >12 years the myocarditis estimated crude incidences after the first 2 doses of BNT162b2 and mRNA-1273 are approximately 1.9 and 3.5 per 100 000 individuals, respectively. These rates equate to excess incidences above control populations of approximately 1.2 (BNT162b2) and 1.9 (mRNA-1273) per 100 000 persons, which are lower than the myocarditis rate for smallpox but higher than that for influenza vaccines. In the studies that have included mRNA vaccine and SARS-COVID-19 myocarditis measured by the same methodology, the incidence rate was increased by 3.5-fold over control in COVID-19 compared with 1.5-fold for BNT162b2 and 6.2-fold for mRNA-1273. However, mortality and major morbidity are less and recovery is faster with mRNA vaccine-associated myocarditis compared to COVID-19 infection. The reasons for this include vaccine-associated myocarditis having a higher incidence in young adults and adolescents, typically no involvement of other organs in vaccine-associated myocarditis, and based on comparisons to non-COVID viral myocarditis an inherently more benign clinical course.

A Comparison of COVID-19 and Influenza-Associated Myocarditis: A Nationwide Study in the United States.

We aimed to compare the characteristics and outcomes of adult patients hospitalized with myocarditis and either concomitant corona virus disease 2019 (COVID-19) or influenza, and elucidate clinical predictors associated with adverse outcomes in both groups. The study used the national inpatient sample (NIS) from 2019 to 2020 to identify 27,725 adult myocarditis hospitalizations, of which 5840 had concomitant COVID-19 and 1045 had concomitant influenza. After propensity score matching, the in-hospital mortality from myocarditis was significantly higher in COVID-19 compared to influenza. Patients with myocarditis and COVID-19 were more likely to have cardiovascular comorbidities and be older than those with influenza-associated myocarditis. Predictors of mortality were also different in both groups.

Incidence and risk factors of myocarditis in hospitalized patients with COVID-19.

Myocarditis as cardiac involvement in coronavirus disease 2019 (COVID-19)-infection is well known. Real-world data about incidence in hospitalized COVID-19-patients and risk factors for myocarditis in COVID-19-patients are sparse. We used the German nationwide inpatient sample to analyze all hospitalized patients with confirmed COVID-19-diagnosis in Germany in 2020 and stratified them for myocarditis. Overall, 176 137 hospitalizations (52.3% males, 53.6% aged ≥70 years) with confirmed COVID-19-infection were coded in Germany in 2020 and among them, 226 (0.01%) had myocarditis (incidence: 1.28 per 1000 hospitalization-cases). Absolute numbers of myocarditis increased, while relative numbers decreased with age. COVID-19-patients with myocarditis were younger (64.0 [IQR: 43.0/78.0] vs. 71.0 [56.0/82.0], p < 0.001). In-hospital case-fatality was 1.3-fold higher in COVID-19-patients with than without myocarditis (24.3% vs. 18.9%, p = 0.012). Myocarditis was independently associated with increased case-fatality (OR: 1.89 [95% CI: 1.33-2.67], p < 0.001). Independent risk factors for myocarditis were age <70 years (OR: 2.36 [95% CI: 1.72-3.24], p < 0.001), male sex (1.68 [95% CI: 1.28-2.23], p < 0.001), pneumonia (OR: 1.77 [95% CI: 1.30-2.42], p < 0.001), and multisystemic inflammatory COVID-19-infection (OR: 10.73 [95% CI: 5.39-21.39], p < 0.001). The incidence of myocarditis in hospitalized COVID-19-patients in Germany was 1.28 cases per 1000 hospitalizations in 2020. Risk factors for myocarditis in COVID-19 were young age, male sex, pneumonia, and multisystemic inflammatory COVID-19-infection. Myocarditis was independently associated with increased case-fatality.

Public Interest in Myocarditis during the SARS-CoV-2 Pandemic.

OBJECTIVE: Public interest in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has been rising with regard to associated myocarditis. Thus, the objective of our study was to assess trends in public interest in myocarditis during the course of the pandemic and the SARS-CoV-2 vaccine rollout in the United States. METHODS: We conducted a longitudinal assessment of public interest in myocarditis, and its association with actual coronavirus disease 2019 (COVID-19) -related myocarditis during the first wave of the pandemic and SARS-CoV-2 vaccine-related myocarditis following vaccine rollout. To complete this objective, we used data from 3 sources: a report from the Morbidity and Mortality Weekly Report, the Vaccine Adverse Event Reporting database, and from Google Trends. RESULTS: Results show that Relative Search Interest (RSI) was low before and during the initial phase of the pandemic and peaked in April 2021, during the initial vaccine push. The ratio of myocarditis related to the SARS-CoV-2 vaccines was considerably lower than the ratio of myocarditis from natural infection. CONCLUSIONS: Search interest in myocarditis was low until SARS-CoV-2 vaccines were rolled out, in which media coverage intensely focused on a relatively small number of cases. This study highlights both the benefits of COVID-19 vaccine uptake and the impact of the media on public interest.

Adjudicated myocarditis and multisystem illness trajectory in healthcare workers post-COVID-19.

BACKGROUND: We investigated the associations of healthcare worker status with multisystem illness trajectory in hospitalised post-COVID-19 individuals. METHODS AND RESULTS: One hundred and sixty-eight patients were evaluated 28-60 days after the last episode of hospital care. Thirty-six (21%) were healthcare workers. Compared with non-healthcare workers, healthcare workers were of similar age (51.3 (8.7) years vs 55.0 (12.4) years; p=0.09) more often women (26 (72%) vs 48 (38%); p<0.01) and had lower 10-year cardiovascular risk (%) (8.1 (7.9) vs 15.0 (11.5); p<0.01) and Coronavirus Clinical Characterisation Consortium in-hospital mortality risk (7.3 (10.2) vs 12.7 (9.8); p<0.01). Healthcare worker status associated with less acute inflammation (peak C reactive protein 48 mg/L (IQR: 14-165) vs 112 mg/L (52-181)), milder illness reflected by WHO clinical severity score distribution (p=0.04) and shorter duration of admission (4 days (IQR: 2-6) vs 6 days (3-12)).In adjusted multivariate logistic regression analysis, healthcare worker status associated with a binary classification (probable/very likely vs not present/unlikely) of adjudicated myocarditis (OR: 2.99; 95% CI (1.01 to 8.89) by 28-60 days postdischarge).After a mean (SD, range) duration of follow-up after hospital discharge of 450 (88) days (range 290, 627 days), fewer healthcare workers died or were rehospitalised (1 (3%) vs 22 (17%); p=0.038) and secondary care referrals for post-COVID-19 syndrome were common (42%) and similar to non-healthcare workers (38%; p=0.934). CONCLUSION: Healthcare worker status was independently associated with the likelihood of adjudicated myocarditis, despite better antecedent health. Two in five healthcare workers had a secondary care referral for post-COVID-19 syndrome. TRIAL REGISTRATION NUMBER: NCT04403607.

A population-based assessment of myocarditis after messenger RNA COVID-19 booster vaccination among adult recipients.

OBJECTIVES: We aimed to estimate the rate of myocarditis after the messenger RNA (mRNA) COVID-19 booster vaccination by vaccine type, age, and sex. METHODS: We used data from the British Columbia COVID-19 Cohort, a population-based cohort surveillance platform. The exposure was a booster dose of an mRNA vaccine. The outcome was diagnosis of myocarditis during hospitalization or an emergency department visit within 7-21 days of booster vaccination. RESULTS: The overall rate of myocarditis was lower for the booster dose (6.41, 95% confidence interval [CI]: 3.50-10.75) than the second dose (17.97, 95% CI: 13.78-23.04); (Rate ratiobooster vs dose-2 = 0.34, 95% CI: 0.17-0.61). This difference was more apparent for the mRNA-1273 vaccine type. After the second dose, the myocarditis rate in males was significantly lower for BNT162b2 than mRNA-1273 overall and among those aged 18-39 years. In contrast, after the booster dose, no significant differences between myocarditis and vaccine type was observed overall or within the specific age groups among males or females. CONCLUSION: Myocarditis after mRNA COVID-19 vaccines is a rare event. A lower absolute risk of myocarditis was observed after a booster dose of mRNA vaccine than the primary series second dose.

Myocarditis or Pericarditis Events After BNT162b2 Vaccination in Individuals Aged 12 to 17 Years in Ontario, Canada.

Importance: The risk of myocarditis or pericarditis after COVID-19 messenger RNA vaccines varies by age and sex, and there is some evidence to suggest increasing risk with shorter intervals between dose 1 and 2 (ie, interdose interval). Objective: To estimate the incidence of reported myocarditis or pericarditis after BNT162b2 vaccine among adolescents and to describe the clinical information associated with these events. Design, Setting, and Participants: This was a population-based cohort study using passive vaccine safety surveillance data linked to the provincial COVID-19 vaccine registry. Included in the study were all adolescents aged 12 to 17 years in Ontario, Canada, who received 1 or more doses of BNT162b2 vaccine between December 14, 2020, and November 21, 2021, and reported an episode of myocarditis or pericarditis. Data were analyzed from December 15, 2021, to April 22, 2022. Exposure: Receipt of BNT162b2 (Comirnaty [Pfizer-BioNTech]) vaccine. Main Outcomes and Measure: Reported incidence of myocarditis or pericarditis meeting level 1 to 3 of the Brighton Collaboration case definition per 100 000 doses of BNT162b2 administered by age group (12-15 years vs 16-17 years), sex, dose number, and interdose interval. All clinical information associated with symptoms, health care usage, diagnostic test results, and treatment at the time of the acute event were summarized. Results: There were approximately 1.65 million doses of BNT162b2 administered and 77 reports of myocarditis or pericarditis among those aged 12 to 17 years, which met the inclusion criteria during the study period. Of the 77 adolescents (mean [SD] age, 15.0 [1.7] years; 63 male individuals [81.8%]), 51 (66.2%) developed myocarditis or pericarditis after dose 2 of BNT162b2. Overall, 74 individuals (96.1%) with an event were assessed in the emergency department, and 34 (44.2%) were hospitalized (median [IQR] length of stay, 1 [1-2] day). The majority of adolescents (57 [74.0%]) were treated with nonsteroidal anti-inflammatory drugs only, and 11 (14.3%) required no treatment. The highest reported incidence was observed among male adolescents aged 16 to 17 years after dose 2 (15.7 per 100 000; 95% CI, 9.7-23.9). Among those aged 16 to 17 years, the reporting rate was highest in those with a short (ie, ≤30 days) interdose interval (21.3 per 100 000; 95% CI, 11.0-37.2). Conclusions and Relevance: Results of this cohort study suggest that there was variation in the reported incidence of myocarditis or pericarditis after BNT162b2 vaccine among adolescent age groups. However, the risk of these events after vaccination remains very rare and should be considered in relation to the benefits of COVID-19 vaccination.

Diagnosis and Treatment of Acute Myocarditis: A Review.

Importance: Acute myocarditis, defined as a sudden inflammatory injury to the myocardium, affects approximately 4 to 14 people per 100 000 each year globally and is associated with a mortality rate of approximately 1% to 7%. Observations: The most common causes of myocarditis are viruses, such as influenza and coronavirus; systemic autoimmune disorders, such as systemic lupus erythematosus; drugs, such as immune checkpoint inhibitors; and vaccines, including smallpox and mRNA COVID-19 vaccines. Approximately 82% to 95% of adult patients with acute myocarditis present with chest pain, while 19% to 49% present with dyspnea, and 5% to 7% with syncope. The diagnosis of myocarditis can be suggested by presenting symptoms, elevated biomarkers such as troponins, electrocardiographic changes of ST segments, and echocardiographic wall motion abnormalities or wall thickening. Cardiac magnetic resonance imaging or endomyocardial biopsy are required for definitive diagnosis. Treatment depends on acuity, severity, clinical presentation, and etiology. Approximately 75% of patients admitted with myocarditis have an uncomplicated course, with a mortality rate of approximately 0%. In contrast, acute myocarditis that is complicated by acute heart failure or ventricular arrhythmias is associated with a 12% rate of either in-hospital mortality or need for heart transplant. Approximately 2% to 9% of patients have hemodynamic instability, characterized by inability to maintain adequate end-organ perfusion, and require inotropic agents, or mechanical circulatory devices, such as extracorporeal life support, to facilitate functional recovery. These patients have an approximately 28% rate of mortality or heart transplant at 60 days. Immunosuppression (eg, corticosteroids) is appropriate for patients who have myocarditis characterized by eosinophilic or giant cell myocardial infiltrations or due to systemic autoimmune disorders. However, the specific immune cells that should be targeted to improve outcomes in patients with myocarditis remain unclear. Conclusions and Relevance: Acute myocarditis affects approximately 4 to 14 per 100 000 people per year. First-line therapy depends on acuity, severity, clinical presentation, and etiology and includes supportive care. While corticosteroids are often used for specific forms of myocarditis (eg, eosinophilic or giant cell infiltrations), this practice is based on anecdotal evidence, and randomized clinical trials of optimal therapeutic interventions for acute myocarditis are needed.

Clinically Suspected and Biopsy-Proven Myocarditis Temporally Associated with SARS-CoV-2 Infection.

We review current data on clinically suspected [European Society of Cardiology (ESC) 2013 criteria] and biopsy-proven [ESC and World Health Organization (WHO) criteria] myocarditis that is temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ESC/WHO etiological diagnosis of viral myocarditis is based on histological and immunohistological evidence of nonischemic myocyte necrosis and monolymphocytic infiltration, i.e., myocarditis, plus the identification of a specific cardiotropic virus by molecular techniques, in particular polymerase chain reaction (PCR)/in-situ hybridization, on endomyocardial biopsy (EMB)/autopsy tissue. There is not yet definitive EMB/autopsy proof that SARS-CoV-2 causes direct cardiomyocyte damage in association with histological myocarditis. Clinical epidemiology data suggest that myocarditis is uncommon for both SARS-CoV-2-positive and -negative PCR cases. We hypothesize that the rare virus-negative biopsy-proven cases may represent new-onset immune-mediated or latent pre-existing autoimmune forms,triggered or fostered by the hyperinflammatory state of severe COVID-19. We recommend the application of the ESC/WHO definitions and diagnostic criteria in future reports to avoid low-quality scientific information leading to an inaccurate estimate of myocarditis incidence based on misdiagnosis.

One-Year Risk of Myocarditis After COVID-19 Infection: A Systematic Review and Meta-analysis.

BACKGROUND: Acute myocarditis has been described as a relatively rare cardiovascular complication of COVID-19 infection. However, data regarding the risk of myocarditis during the post-acute phase of COVID-19 are scant. We assess the risk of incident myocarditis in COVID-19 survivors within 1 year from the index infection by a systematic review and meta-analysis of the available data. METHODS: Data were obtained by searching Medline and Scopus for all studies published at any time up to September 1, 2022, and reporting the long-term risk of incident myocarditis in COVID-19 survivors. Myocarditis risk data were pooled using the Mantel-Haenszel random-effects models with hazard ratio (HR) as the effect measure with 95% confidence interval (CI). Heterogeneity among studies was assessed using the Higgins-Thompson I2 statistic. RESULTS: Overall, 20,875,843 patients (mean age 56.1 years, 59.1% male) were included in this analysis. Of them, 1,245,167 experienced (and survived) COVID-19 infection. Over a mean follow-up of 9.5 months, myocarditis occurred to 0.21 (95% CI 0.13-0.42) out of 1000 patients survived to COVID-19 infection compared with 0.09 [95% CI 0.07-0.12) out of 1000 control subjects. Pooled analysis revealed that recovered COVID-19 patients presented an increased risk of incident myocarditis (HR 5.16, 95% CI 3.87-6.89; P < 0.0001; I2 = 7.9%) within 1 year from the index infection. The sensitivity analysis confirmed yielded results. CONCLUSIONS: Our findings suggest that myocarditis represents a relatively rare but important post-acute COVID-19 sequelae.

A narrative review of vaccine pharmacovigilance during mass vaccination campaigns: Focus on myocarditis and pericarditis after COVID-19 mRNA vaccination.

Vaccines have had a tremendous impact on reducing the burden of infectious diseases; however, they have the potential to cause adverse events following immunization (AEFIs). Prelicensure clinical trials are limited in their ability to detect rare AEFIs that may occur in less than one per thousand individuals. While postmarketing surveillance systems have shown COVID-19 mRNA vaccines to be safe, they led to the identification of rare cases of myocarditis and pericarditis after COVID-19 vaccination that were not initially detected in clinical trials. In this narrative review, we highlight concepts of vaccine pharmacovigilance during mass vaccination campaigns and compare the approaches used in the context of myocarditis and pericarditis following COVID-19 vaccination to historical examples. We describe mechanisms of passive and active surveillance, their strengths and limitations, and how they interacted to identify and characterize the safety signal of myocarditis and pericarditis after COVID-19 mRNA vaccination. Articles were synthesized from a PubMed search using relevant keywords for articles published on vaccine surveillance systems and myocarditis and pericarditis after COVID-19 vaccination, as well as the authors' collections of relevant publications and grey literature reports. The global experience around the identification and monitoring of myocarditis and pericarditis after COVID-19 mRNA vaccination has provided important lessons for vaccine safety surveillance and highlighted its importance in maintaining public trust in mass vaccination programmes in a pandemic context.

Cardiovascular complications of COVID-19 vaccines: A review of case-report and case-series studies.

BACKGROUND: There are multiple reviews on cardiovascular aspects of COVID-19 disease on cardiovascular system in different population but there is lack of evidence about cardiovascular adverse effects of COVID vaccines. OBJECTIVES: The purpose of this study was to compare the cardiac complications of COVID19 vaccines, based on vaccine type (mRNA, vector-based, and inactivated vaccines). METHODS: A systematic search was performed covering PubMed for English case-reports and case-series studies, and finally 100 studies were included. RESULTS: Myocarditis (with overall rate around 1.62%) was shown to be the most common post-COVID19 immunization cardiac event. More than 90% of post-COVID19 vaccination myocarditis occurred after receiving mRNA vaccines (Moderna & Pfizer-BioNTech), but the report of this event was less in the case of vector-based vaccinations and/or inactivated vaccines. Myocarditis was reported more commonly in men and following the second dose of the immunization. Takotsubo cardiomyopathy (TTC) was reported after mRNA (more commonly) and vector-based vaccinations, with no case report after inactivated vaccines. When mRNA and vector-based vaccinations were used instead of inactivated vaccines, a greater frequency of vaccine-induced thrombotic thrombocytopenia (VITT) and pulmonary emboli (PE) was reported. Myocardial infarction/cardiac arrest was recorded in those beyond the age of 75 years. CONCLUSION: The personal and public health benefits of COVID-19 vaccination much outweigh the minor cardiac risks. Reporting bias, regarding more available mRNA vaccines in developed countries, may conflict these results.

Risk of myocarditis and pericarditis following coronavirus disease 2019 messenger RNA Vaccination-A nationwide study.

BACKGROUND: An extended interval between the two primary doses may reduce the risk of myocarditis/pericarditis after COVID-19 mRNA vaccination. Taiwan has implemented a two-dose regimen with a 12-week interval for adolescents. Here we present nationwide data of myocarditis/pericarditis following COVID-19 vaccinations. METHODS: Data on adverse events of myocarditis/pericarditis were from the Taiwan Vaccine Adverse Events Reporting System between March 22, 2021, and February 9, 2022. The reporting rates according to sex, age, and vaccine type were calculated. We investigated the rates among young individuals under different two-dose intervals and among those who received two doses of different vaccines. RESULTS: Among 204 cases who met the case definition of myocarditis/pericarditis, 75 cases occurred after the first dose and 129 after the second. The rate of myocarditis/pericarditis after COVID-19 vaccination varied across sex and age groups and was highest after the second dose in males aged 12-17 years (126.79 cases per million vaccinees) for the BNT162b2 vaccine and in males aged 18-24 years (93.84 cases per million vaccinees) for the mRNA-1273 vaccine. The data did not suggest an association between longer between-dose interval and lower rate of myocarditis/pericarditis among males and females aged 18-24 or 25-29 years who received two doses of the BNT162b2 or mRNA-1273 vaccine. Rates of myocarditis/pericarditis in males and females aged 18-49 years after receiving ChAdOx1-S - mRNA-1273 vaccination was significantly higher than after ChAdOx1-S - ChAdOx1-S vaccination. CONCLUSIONS: Myocarditis and pericarditis are rare following mRNA vaccination, with higher risk occurring in young males after the second dose.

Observed versus expected rates of myocarditis after SARS-CoV-2 vaccination: a population-based cohort study.

BACKGROUND: Postmarketing evaluations have linked myocarditis to SARS-CoV-2 mRNA vaccines. We sought to estimate the incidence of myocarditis after mRNA vaccination against SARS-CoV-2, and to compare the incidence with expected rates based on historical background rates in British Columbia. METHODS: We conducted an observational study using population health administrative data from the BC COVID-19 Cohort from Dec. 15, 2020, to Mar. 10, 2022. The primary exposure was any dose of an mRNA vaccine against SARS-CoV-2. The primary outcome was incidence of hospital admission or emergency department visit for myocarditis or myopericarditis within 7 and 21 days postvaccination, calculated as myocarditis rates per 100 000 mRNA vaccine doses, expected rates of myocarditis cases and observedto-expected ratios. We stratified analyses by age, sex, vaccine type and dose number. RESULTS: We observed 99 incident cases of myocarditis within 7 days (0.97 cases per 100 000 vaccine doses; observed v. expected ratio 14.81, 95% confidence interval [CI] 10.83-16.55) and 141 cases within 21 days (1.37 cases per 100 000 vaccine doses; observed v. expected ratio 7.03, 95% CI 5.92-8.29) postvaccination. Cases of myocarditis per 100 000 vaccine doses were higher for people aged 12-17 years (2.64, 95% CI 1.54-4.22) and 18-29 years (2.63, 95% CI 1.94-3.50) than for older age groups, for males compared with females (1.64, 95% CI 1.30-2.04 v. 0.35, 95% CI 0.21-0.55), for those receiving a second dose compared with a third dose (1.90, 95% CI 1.50-2.39 v. 0.76, 95% CI 0.45-1.30) and for those who received the mRNA-1273 (Moderna) vaccine compared with the BNT162b2 (Pfizer-BioNTech) vaccine (1.44, 95% CI 1.06-1.91 v. 0.74, 95% CI 0.56-0.98). The highest observed-to-expected ratio was seen after the second dose among males aged 18-29 years who received the mRNA-1273 vaccine (148.32, 95% CI 95.03-220.69). INTERPRETATION: Although absolute rates of myocarditis were low, vaccine type, age and sex are important factors to consider when strategizing vaccine administration to reduce the risk of postvaccination myocarditis. Our findings support the preferential use of the BNT162b2 vaccine over the mRNA-1273 vaccine for people aged 18-29 years.