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.

Acute myopericarditis and left shoulder capsulitis following second dose of mRNA SARS-CoV-2 Moderna vaccination.

Vaccination against mRNA SARS-CoV-2 has been administered on a very large scale and various side effects have been described. The increased risk of myopericarditis is known, and only a few cases of shoulder capsulitis have been reported after vaccination. These two pathologies have never been reported in the same patient after vaccination. Our article presents the history of a man in his 40s who presented with myopericarditis a few days after vaccination against SARS-CoV-2 with mRNA(Messenger RNA) Moderna® vaccine and who at the same time developed shoulder capsulitis. His cardiovascular symptoms resolved rapidly, and his shoulder symptoms improved/resolved within 1 year. This case should make physicians aware of the possibility of several concomitant side effects following vaccination against SARS-CoV-2.

Myocarditis and autoimmunity.

INTRODUCTION: Autoimmune myocarditis may develop due to heterogeneous causes. Myocarditis is often caused by viral infections, but it can also be caused by systemic autoimmune diseases. Immune checkpoint inhibitors and virus vaccines induce immune activation, and they can cause the development of myocarditis, as well as several immune-related adverse events. The development of myocarditis is dependent on the genetic factors of the host, and the major histocompatibility complex (MHC) may be an important determinant of the type and severity of the disease. However, non-MHC immunoregulatory genes may also play a role in determining susceptibility. AREA COVERED: This review summarizes the current knowledge of the etiology, pathogenesis, diagnosis, and treatment of autoimmune myocarditis with a particular focus on viral infection, autoimmunity, and biomarkers of myocarditis. EXPERT OPINION: An endomyocardial biopsy may not be the gold standard for the diagnosis of myocarditis. Cardiac magnetic resonance imaging is useful in diagnosing autoimmune myocarditis. Recently identified biomarkers of inflammation and myocyte injury are promising for the diagnosis of myocarditis when measured simultaneously. Future treatments should focus on the appropriate diagnosis of the etiologic agent, as well as on the specific stage of the evolution of immune and inflammatory processes.

Epigenomic landscape exhibits interferon signaling suppression in the patient of myocarditis after BNT162b2 vaccination.

After the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a novel mRNA vaccine (BNT162b2) was developed at an unprecedented speed. Although most countries have achieved widespread immunity from vaccines and infections, yet people, even who have recovered from SARS-CoV-2 infection, are recommended to receive vaccination due to their effectiveness in lowering the risk of recurrent infection. However, the BNT162b2 vaccine has been reported to increase the risk of myocarditis. To our knowledge, for the first time in this study, we tracked changes in the chromatin dynamics of peripheral blood mononuclear cells (PBMCs) in the patient who underwent myocarditis after BNT162b2 vaccination. A longitudinal study of chromatin accessibility using concurrent analysis of single-cell assays for transposase-accessible chromatin with sequencing and single-cell RNA sequencing showed downregulation of interferon signaling and upregulated RUNX2/3 activity in PBMCs. Considering BNT162b2 vaccination increases the level of interferon-α/γ in serum, our data highlight the immune responses different from the conventional responses to the vaccination, which is possibly the key to understanding the side effects of BNT162b2 vaccination.

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.

Evaluation of Autoantibody Binding to Cardiac Tissue in Multisystem Inflammatory Syndrome in Children and COVID-19 Vaccination-Induced Myocarditis.

Importance: Cardiac dysfunction and myocarditis have emerged as serious complications of multisystem inflammatory syndrome in children (MIS-C) and vaccines against SARS-CoV-2. Understanding the role of autoantibodies in these conditions is essential for guiding MIS-C management and vaccination strategies in children. Objective: To investigate the presence of anticardiac autoantibodies in MIS-C or COVID-19 vaccine-induced myocarditis. Design, Setting, and Participants: This diagnostic study included children with acute MIS-C or acute vaccine myocarditis, adults with myocarditis or inflammatory cardiomyopathy, healthy children prior to the COVID-19 pandemic, and healthy COVID-19 vaccinated adults. Participants were recruited into research studies in the US, United Kingdom, and Austria starting January 2021. Immunoglobulin G (IgG), IgM, and IgA anticardiac autoantibodies were identified with immunofluorescence staining of left ventricular myocardial tissue from 2 human donors treated with sera from patients and controls. Secondary antibodies were fluorescein isothiocyanate-conjugated antihuman IgG, IgM, and IgA. Images were taken for detection of specific IgG, IgM, and IgA deposits and measurement of fluorescein isothiocyanate fluorescence intensity. Data were analyzed through March 10, 2023. Main Outcomes and Measures: IgG, IgM and IgA antibody binding to cardiac tissue. Results: By cohort, there were a total of 10 children with MIS-C (median [IQR] age, 10 [13-14] years; 6 male), 10 with vaccine myocarditis (median age, 15 [14-16] years; 10 male), 8 adults with myocarditis or inflammatory cardiomyopathy (median age, 55 [46-63] years; 6 male), 10 healthy pediatric controls (median age, 8 [13-14] years; 5 male), and 10 healthy vaccinated adults (all older than 21 years, 5 male). No antibody binding above background was observed in human cardiac tissue treated with sera from pediatric patients with MIS-C or vaccine myocarditis. One of the 8 adult patients with myocarditis or cardiomyopathy had positive IgG staining with raised fluorescence intensity (median [IQR] intensity, 11 060 [10 223-11 858] AU). There were no significant differences in median fluorescence intensity in all other patient cohorts compared with controls for IgG (MIS-C, 6033 [5834-6756] AU; vaccine myocarditis, 6392 [5710-6836] AU; adult myocarditis or inflammatory cardiomyopathy, 5688 [5277-5990] AU; healthy pediatric controls, 6235 [5924-6708] AU; healthy vaccinated adults, 7000 [6423-7739] AU), IgM (MIS-C, 3354 [3110-4043] AU; vaccine myocarditis, 3843 [3288-4748] AU; healthy pediatric controls, 3436 [3313-4237] AU; healthy vaccinated adults, 3543 [2997-4607] AU) and IgA (MIS-C, 3559 [2788-4466] AU; vaccine myocarditis, 4389 [2393-4780] AU; healthy pediatric controls, 3436 [2425-4077] AU; healthy vaccinated adults, 4561 [3164-6309] AU). Conclusions and Relevance: This etiological diagnostic study found no evidence of antibodies from MIS-C and COVID-19 vaccine myocarditis serum binding cardiac tissue, suggesting that the cardiac pathology in both conditions is unlikely to be driven by direct anticardiac antibody-mediated mechanisms.

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 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.

Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis.

Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination. Contrary to early hypotheses, patients did not demonstrate features of hypersensitivity myocarditis, nor did they have exaggerated SARS-CoV-2-specific or neutralizing antibody responses consistent with a hyperimmune humoral mechanism. We additionally found no evidence of cardiac-targeted autoantibodies. Instead, unbiased systematic immune serum profiling revealed elevations in circulating interleukins (IL-1ß, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, and TIMP1). Subsequent deep immune profiling using single-cell RNA and repertoire sequencing of peripheral blood mononuclear cells during acute disease revealed expansion of activated CXCR3+ cytotoxic T cells and NK cells, both phenotypically resembling cytokine-driven killer cells. In addition, patients displayed signatures of inflammatory and profibrotic CCR2+ CD163+ monocytes, coupled with elevated serum-soluble CD163, that may be linked to the late gadolinium enhancement on cardiac MRI, which can persist for months after vaccination. Together, our results demonstrate up-regulation in inflammatory cytokines and corresponding lymphocytes with tissue-damaging capabilities, suggesting a cytokine-dependent pathology, which may further be accompanied by myeloid cell-associated cardiac fibrosis. These findings likely rule out some previously proposed mechanisms of mRNA vaccine--associated myopericarditis and point to new ones with relevance to vaccine development and clinical care.

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.

Cardiovascular Complications of Coronavirus Disease-2019.

Cardiovascular complications associated with the severe acute respiratory syndrome coronavirus 2 infection are common and lead to high mortality in the acute phase and high morbidity in the chronic phase impacting an individual's quality of life and health outcomes. Patients afflicted with coronavirus disease-2019 (COVID-19) infection display an increased risk for myocarditis, dysrhythmia, pericarditis, ischemic heart disease, heart failure, and thromboembolism. Although cardiovascular complications are reported across all patients with COVID-19, hospitalized patients with severe infection are most vulnerable. The underline pathobiology remains poorly defined albeit complex. Following current guidelines in decision-making for evaluation and management in addition to the beginning or returning exercise is recommended.

Diagnosis of Acute Myocarditis Following mRNA Vaccines against SARS-CoV-2: A Methodological Review.

The occurrence of acute myocarditis following the administration of mRNA vaccines against SARS-CoV-2 remains relatively rare, and it is associated with a very low mortality rate. The incidence varied by vaccine type, sex, and age and after the first, second, or third vaccination dose. However, the diagnosis of this condition often remains challenging. To further elucidate the relationship between myocarditis and SARS-CoV-2 mRNA vaccines, starting with two cases observed at the Cardiology Unit of the West Vicenza General Hospital located in the Veneto Region, which was among the first Italian areas hit by the COVID-19 pandemic, we performed a review of the available literature to highlight the clinical and diagnostic elements that could contribute to suspicion of myocarditis as an adverse event of SARS-CoV-2 immunization.

Acute heart failure due to COVID-19 related myocardial injury and de novo hypertensive cardiomyopathy: a challenging diagnosis.

We report a COVID-19 case with acute heart and kidney failure in a healthy young male. Echocardiography showed severe systolic and diastolic left ventricle dysfunction, with diffuse myocardial thickening. Cardiac MRI showed aspects of focal myocarditis, and hypertensive cardiomyopathy. Renal biopsy demonstrated limited acute tubular injury, and hypertensive kidney disease. Coronary angiography excluded critical stenoses. Unlike what we initially suspected, myocardial inflammation had a limited extent in our patient; severe hypertension causing cardiomyopathy and multi-organ damage, not diagnosed before, was primarily responsible for severe illness. Correct diagnosis and guidelines-directed treatment allowed a favorable course.