Myocarditis and coronavirus disease 2019 vaccination: A systematic review and meta-summary of cases

Vaccination is significant to control, mitigate, and recover from the destructive effects of coronavirus disease 2019 (COVID-19). The incidence of myocarditis following COVID-19 vaccination has been an increasing and growing public concern; however, little is known about it. This study aimed to systematically review myocarditis following COVID-19 vaccination. We included studies containing individual patient data of myocarditis following COVID-19 vaccination published between January 1, 2020 and September 7, 2022 and excluded review articles. Joanna Briggs Institute critical appraisals were used for risk of bias assessment. Descriptive and analytic statistics were performed. A total of 121 reports and 43 case series from five databases were included. We identified 396 published cases of myocarditis and observed that the majority of cases were male patients, happened following the second dose of mRNA vaccine administration, and experienced chest pain as a symptom. Previous COVID-19 infection was significantly associated with the risk of myocarditis following the administration of the first dose (p < 0.01; OR, 5.74; 95% CI, 2.42–13.64), indicating that its primary mechanism is immune mediated. Moreover, 63 histopathology examinations were dominated by non-infective subtypes. Electrocardiography and cardiac marker combination is a sensitive screening modality. However, cardiac magnetic resonance is a significant non-invasive examination to confirm myocarditis. Endomyocardial biopsy may be considered in confusing and severe cases. Myocarditis following COVID-19 vaccination is relatively benign, with a median length of hospitalization of 5 days, intensive care unit admission of <12%, and mortality of <2%. The majority was treated with non-steroidal anti-inflammatory drugs, colchicine, and steroids. Deceased cases had characteristics of being female, older age, non-chest pain symptoms, first-dose vaccination, left ventricular ejection fraction of <30%, fulminant myocarditis, and eosinophil infiltrate histopathology. Systematic review registration: PROSPERO (CRD42021271806).


Introduction
Since first identified and reported in China in late 2019, coronavirus disease 2019 (COVID-19) has rapidly and extensively spread among countries, escalating into a pandemic. The COVID-19 pandemic has severely affected economic, social, political, and cultural sectors [1] and has persisted in attracting worldwide attention.
To control, mitigate, and recover from the destructive effects of COVID-19, vaccination is critical. Recent evidence regarding the ineffectiveness of COVID-19 vaccines for some strains. However, COVID-19 vaccination may pose beneficial effects, particularly, for high-risk populations, including older adults and individuals with multiple comorbidities [2]. To support international vaccination coverage, the World Health Organization (WHO) issued authorization for COVID-19 vaccine emergency use [3] in combination with government regulation to accelerate [4] COVID-19 vaccination up to 12 billion doses, which continues to increase globally [5]. With the rapid increase in vaccination shots comes several reported adverse events complained by patients, ranging from minor to major events [6].
Therefore, to provide appropriate information and a standing position for the public and clinicians, including myocarditis following COVID-19 vaccination, any vaccination-related issues should be thoroughly investigated. However, most reports on myocarditis following COVID-19 vaccination were case reports and case series, and little is known regarding the nature and characteristics of this phenomenon. Therefore, this systematic review aimed to describe the characteristics of myocarditis following COVID-19 vaccination by collecting detailed individual patient data (IPD) from those available reports and literature to create a systematic review and meta-summary of cases of myocarditis following COVID-19 vaccination.

Materials and methods
This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 [11] and was registered and can be accessed in the PROSPERO database (CRD42021271806). No ethical approval was required as we only analyzed secondary data from published literature.

Eligibility criteria
The following study types were included in this review: case reports, case series, and observational studies (crosssectional, case-control, and cohort studies). Screening of eligible studies was based on the following inclusion criteria: (1) patients of all ages with myocarditis following any COVID-19 vaccination type as participants according to the definition from European Society of Cardiology (ESC) guidelines for myocarditis [12] or Centers for Disease Control and Prevention (CDC) updates on myocarditis following COVID-19 vaccination [13]; (2) individual-specific patient data were available; (3) all COVID-19 vaccine types (mRNA and non-mRNA vaccines); and (4) reported in English. Diagnosis of myocarditis was based on the combination of clinical signs, electrocardiography (ECG), cardiac markers, echocardiography/angiocardiography, cardiac magnetic resonance (CMR), and, if available, histopathologic examination (autopsy or endomyocardial biopsy) according to the ESC [12] and CDC updates on myocarditis [13].
We excluded nonscientific articles (popular magazines), randomized-controlled trials, reviews, unavailable text, duplication, and studies that report unclear populations (e.g., pericarditis without myocardial involvement or heart failure and myocardial injury instead of myocarditis). Myocarditis that was not due to COVID-19 was excluded. If needed, we contacted the authors to ask for additional patient information.

Study selection
Titles and abstracts were independently screened for eligibility. Subsequently, studies with potentially eligible abstracts were reviewed for full-text articles according to previously determined inclusion and exclusion criteria. Any disagreements were resolved by consensus of those authors.

Data extraction
The following data were extracted from included studies: the number of cases; sex; age; region; comorbidities; previous COVID-19 infection; current COVID-19 infection status; vaccine types; vaccine doses; from the day(s) of vaccination to specific myocarditis symptoms; from the day(s) of vaccination to the emergency department (ED) admission; from the day(s) of specific symptom onset to ED from specific myocarditis symptoms; preceding symptoms; presenting symptoms; cardiac markers, including troponin I, high-sensitive troponin I (hsTnI), troponin T, high-sensitive troponin T (hsTnT), creatinine phosphokinase (CPK), creatinine kinase myocardial band (CKMB), brain natriuretic peptide (BNP), and Pro-BNP; D-dimer; white blood cells (WBCs); erythrocyte sedimentation rate (ESR); C-reactive protein (CRP); ECG/Holter stress test; echocardiography/angiography; CMR; cardiac histopathologic examination; length of hospitalization (LoH); management; and outcomes (deceased or recovery).
In the context of day(s) from the event (e.g., vaccination day) to the event (e.g., specific symptoms), the first event was determined as day one. The specific symptoms included chest pain, dyspnea, palpitation, syncope, or cardiac arrest [13], which led patients to the ED. Preceding symptoms were determined as any symptoms or signs that occurred before specific symptoms. CMR data were collected and mainly classified as edema, hyperemia, fibrosis/scar, and pericardial involvement [12], [14]. Patients were classified into probable and confirmed cases according to the CDC criteria [13], and their myocarditis score was also evaluated based on the ESC criteria [12]. All collected data were independently compared as pre-piloted forms, and any discrepancy was resolved through consensus.

Quality assessment
We independently analyzed and judged the risk of bias of included studies using the Joanna Briggs Institute (JBI) for case reports and case series critical appraisal instruments [15]. The JBI critical appraisal for case reports consists of eight questions, whereas JBI critical appraisal for case series consists of ten questions. However, we combined questions number 4 and 5 in the JBI appraisal as they represent the same domain (bias selection of participants into the study), and we did not include question number 10, considering statistical analysis is not an appropriate characteristic in this context. This critical appraisal consists of yes/no/unclear answers for each question [16]. The studies were classified as low, medium, and high risks of bias according to the total "yes" answers of ≥74%, 50%-74%, and ≤49% of total questions, respectively.

Statistical analysis
All collected IPD from the included study were combined in a meta-summary. Patients with confirmed cases were compared with probable cases. A p-value threshold of 0.05 was considered statistically significant. The Shapiro-Wilk test was used to determine the normality distribution of the data [17]. Categorical variables were presented as frequencies and percentages. Continuous variables were presented as means and standard deviations; otherwise, median and range (minimum-maximum) were considered. As indicated, categorical data were compared using Chi-square or Fisher's exact test [18]. Moreover, normally distributed data were compared by employing the independent T-test. Otherwise, the Mann-Whitney test would be used when the data were abnormally distributed by the Shapiro-Wilk test. We identified demographic and comorbid factors that may contribute to the occurrence of myocarditis following the first COVID-19 vaccination by multivariate analysis (logistic regression). Only variables with a p-value of <0.25 were included in the multivariate analysis [19]. The Spearman or Pearson correlation test was used to evaluate the correlation between clinical parameters and outcomes by considering data distribution. We used a statistical software, IBM SPSS Statistics for Windows, version 22 (IBM Corp., Armonk, NY, USA), during statistical analysis processes.

Study selection
In the primary search, 6370 studies were identified after the removal of 2941 irrelevant research articles by the automation feature of each search engine and 1426 duplications. A total of 6184 articles were excluded during the title and abstract screening, leaving 186 studies for full-text reviews. Subsequently, 24 studies were excluded, while 164 studies consisted of 121 case reports  and 43 case series , with a total of 396 cases included ( Figure 1) in this meta-summary. Some studies, such as those by Diaz et al. [179] and Montgomery et al. [180] fulfilled the inclusion criteria and consisted of several participants. However, we excluded them because specific individual data could not be extracted. We only included patients who fulfilled the myocarditis criteria, such as in the case series reported by Patel et al. [178].
Meta-summary of cases IPD from 396 cases was included in this systematic review (Table S2). The basic data and comparison of demographic, clinical characteristics, and management between probable and confirmed cases are presented in Table 1.
Notably, not all cases describe all variables and that made each variable have a different number of reported cases. For example, reported data on age, sex, and previous COVID-19 infection are available in 370, 384, and 167 cases, respectively. That also applies to other variables, which are subsequently named as reported cases in Table 1. Furthermore, due to different reported cases in each variable, the numbers of probable and confirmed cases (which act as the denominator for each group) are different in each variable. The number of probable and confirmed cases for each variable is not shown.

Demographic characteristics
The majority of reported myocarditis was mRNA-type vaccines, including BNT162b2 (68.5%) and mRNA-1273 (23.9%). Moreover, we observed myocarditis following the administration of viral vector-based vaccine (6%, consisting of 8, 14, and 1 cases of Ad26.COV2.S, AZD1222, and rAd26-rAd5, respectively), inactivated virus vaccine (3 cases), and recombinant protein vaccine (1 case of NVX-CoV2373). The median age was 22 (range 12-88) years, and the majority (87.6%) were male patients. There were 121 cases of children under 18 years old, with eight cases of children under 13 years old. According to WHO regional area, the majority of reported articles were from Europe (40.5), America (39.2%), and Western Pacific (15.2%). Less than 10% of reports were from Asian and African regions.
The median of vaccination day to the presence of specific symptoms and from the vaccination day to the ED admission was 3 (1-90) and 4 (1-90) days, respectively. Meanwhile, most cases reported that the patients came to the ED on the day of specific symptom onset. The confirmed group had a significantly shorter interval of the day(s) of vaccination to specific symptoms and day(s) of specific symptoms to the ED (p < 0.01 and p < 0.03, respectively) than the probable group (Table 1).

Laboratory examination
In this meta-summary, all inflammatory markers, except for WBC (40%), were increased in more than half of the cases: CRP (78.2%), D-Dimer (54.5%), and ESR (52.2%). No differences in inflammatory marker abnormality between the probable and confirmed groups were noted (Table 1).
Of 286 CMR examinations, 259 (90%) revealed abnormal results. Based on ESC and CDC recommendations for CMR in myocarditis, the prevalence of fibrosis/scar (late gadolinium enhancement [LGE]), myocardial edema (increased global or regional myocardial signal intensity), and hyperemia (early gadolinium enhancement) in this meta-summary were 84.6%, 44.1%, and 4.2%, respectively. LGE was the most common typical myocarditis sign on CMR examination. Pericardial involvement was observed in 7.3% of CMR examinations.  From vaccination to specific symptoms (days)

Diagnosis and management
According to the CDC classification of myocarditis, 312 and 84 cases were classified as confirmed and probable groups, respectively (Table S2). Based on the ESC score for myocarditis, an ESC score of 3 (39.7%) was the most common, followed by 2 (29.5 %), 4 (18.4%), 1 (8.6%), and 5 (3.8%). The confirmed group had a significantly higher ESC score than the probable group (p = 0.00).

Outcomes
Seven cases (<2%) were deceased (4 females and 3 males, respectively), whereas the other 98% recovered. BNT162b2 (4 cases) [42,53,125,145] was the most common vaccine type in deceased cases, followed by Ad26.COV2.S (2 cases) [106,113] and mRNA-1273 (1 case) [70]. Four of the seven deceased cases were older than the age of 55. All deaths occurred following the Table 2. Continued *Diffuse ST-segment elevation is the most common type and is observed in 71 reported cases (36% of the total ST-segment elevation). a Available ECG refers to the number of cases that reported ECG examination. Its percentage is derived from the number of cases divided by the total cases (396 cases). The number of cases serves as the denominator for ECG finding/abnormality; b Available cardiac marker refers to the number of cases that reported cardiac marker examination. Its percentage is derived from the number of cases divided by the total cases (396 cases). The number of cases serves as the denominator for cardiac marker abnormality; c Available echocardiography/angiography refers to the number of cases that reported echocardiography/angiography examination. Its percentage is derived from the number of cases divided by the total cases (396 cases). The number of cases serves as the denominator for echocardiography/angiography findings/abnormality; d Available CMR refers to the number of cases that reported CMR examination. Its percentage is derived from the number of cases divided by the total cases (396 cases). The number of cases serves as the denominator for CMR findings/abnormality; e Available CMR refers to the number of cases that reported CMR examination. Its percentage is derived from the number of cases divided by the total cases (396 cases). The number of cases serves as the denominator for CMR findings/abnormality; f Available histopathology examination refers to the number of cases that reported histopathology examination. Its percentage is derived from the number of cases divided by the total cases (396 cases). The number of cases serves as the denominator for histopathology examination findings/abnormality. BBB: Bundle branch block; AVD: Atrioventricular dissociation; JER: Junctional escape rhythm; CMR: Cardiac magnetic resonance; LGE: Late gadolinium enhancement; EGE: Early gadolinium enhancement. first dose of vaccination except for one case [145]. The LVEF was <30% in all deceased cases except for one case [125]. All cases had no significant comorbidity except for one case [106]. All the available data showed that the patients went to the ED on the same day of symptom onset (chest pain, 2 cases [42,53]; hypotension, 1 case [145]; shortness of breath, 1 case; fever, 1 case [125]; palpitation, 1 case [113]; and cardiac arrest, 1 case [70]). Five of the seven cases that reported histopathology examination revealed abnormal findings (including one case that revealed normal findings in endomyocardial biopsy although revealed fulminant myocarditis in autopsy) [70]. Three of the five cases had fulminant appearance myocarditis, whereas extensive inflammation or necrotic eosinophil was noted in all cases [42,53,70,106,113,125,145].
Bivariate and multivariate analyses of factors affecting myocarditis following the first-dose vaccination compared with second/third vaccinations We analyzed demographic and comorbidity associated with myocarditis following the first dose of COVID-19 vaccination compared with the second and third doses of vaccination. Bivariate analysis showed that older age (p < 0.01), female sex (p < 0.01), and previous COVID-19 infection (p < 0.001) were significantly associated with the risk of myocarditis following the first dose of vaccination (  (Table 3).

Discussion
This is a meta-summary of myocarditis following COVID-19 vaccination from current literature. Of note, this is not the first systematic review of the relevant topic. However, most published articles mainly investigated demographic characteristics or were limited to abstract conferences. This pooled 396 IPD provides more data for analysis (Table 1). Hyperimmunity or immune-mediated process is suspected as one of the principal mechanisms of myocarditis following vaccination [181] through the activation of aberrant immune responses to produce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies that cross-react with structurally similar cardiac-self antigens, including α-myosin heavy chain, actin [181], or even myocardial cell-expressed spike protein [151]. The nature of the higher antigenicity of mRNA vaccine in producing spike antibodies than that of other vaccine types [182] may explain our finding with higher myocarditis incidence following COVID-19 mRNA vaccination than that of other observed vaccine forms ( Table 1).
The studies included in this systematic review report cases from different populations worldwide, suggesting that the risk of myocarditis following COVID-19 vaccination is not population specific. Since we noted a higher incidence of this myocarditis in male than that in female patients (Table 1), there may be influences of hormonal differences between sex groups as the previous study explains the roles of testosterone that promotes a more aggressive immune response by inducing CD4+ cells and inhibiting anti-inflammatory immune cells, whereas estrogen suppresses pro-inflammatory lymphocytes [183]. The slightly higher proportion of female patients who developed myocarditis following the first vaccine shot than that of male patients may be because of a marginal effect (Table 3). Moreover, we reported that the median age was 22 years (Table 1). The fact that myocarditis following COVID-19 vaccination had a high incidence in the young population may also indicate the theory of hyperimmune mechanism; however, further research is needed to confirm this. Younger populations were observed to have more potent immune responses than older populations [184].
Moreover, young age was a valuable finding for diagnosing myocarditis following COVID-19 vaccination as cardiovascular disease is commonly associated with older age [12], whereas more than 60% of cases were below the age of 30. Previous COVID-19 infection may sensitize the immune system, producing a stronger immune response, even on the first vaccination dose. Our study observed that previous COVID-19 infection possessed a six-fold odd of having myocarditis following the first COVID-19 vaccine compared with the group without a previous history of COVID-19 infection (Table 3). A previous meta-analysis reported that Takotsubo cardiomyopathy, which may have similar symptoms to myocarditis, is more prevalent in female patients following the first dose of vaccination than that in young male patients following the second dose of COVID-19 vaccination [185].
The results in Table 1 indicate that comorbidities are present in less than half the number of cases. The most common comorbidity is autoimmune or inflammatory disorders, including asthma, hypothyroidism, and vitiligo. They constitute one-third of cases with comorbidities. One of the possible explanations is the aberrant immune response of patients with autoimmune-related diseases contributes to myocarditis [186]. Surprisingly, psychiatric or functional disorders, particularly attention deficit hyperactivity disorder (ADHD) and depression, constitute the second (14%) most common comorbidities, which may be related to current evidence that depression [187,188] and ADHD [189,190] are associated with autoimmune disorders.
Moreover, patients with a history of myocarditis constitute 11% of comorbid cases. Although those numbers were slightly smaller than the number of hypertensive cases, they could be considered high as hypertension prevalence was higher than that of myocarditis. Immune-response sensitization may contribute to recurrent myocarditis [186]. None of the studies reported myocarditis following COVID-19 vaccination in pregnancy. Pregnancy seems neither a risk factor for developing myocarditis nor it is a protective factor. Regarding immune mediation as the basic mechanism, the immune system suppression state in pregnancy [191,192] may diminish the aberrant immune response to COVID-19 vaccination.
The preceding symptoms of myocarditis following COVID-19 vaccination were not specific (e.g., fever, myalgia, and chill) and only occurred in approximately half of the cases (Table 1). Chest pain should be the first specific clue of myocarditis following COVID-19 vaccination diagnosis and the main reason nearly all patients (80.0%) came to the ED ( Table 1). Considering that cardiovascular comorbidities are relatively high, it is mandatory to distinguish chest pain between myocarditis and other cardiovascular diseases [12]. Chest pain was commonly felt less than four days following the vaccine shot, and most patients came to the ED on the same day of specific symptom onset (Table 1). Interestingly, confirmed patients tended to seek help in the ED faster than probable patients ( Table 1).
As previously stated, myocardial inflammation is the primary underlying process and is expected to be depicted by laboratory examination results. We observed higher CRP levels in 78.2% of patients, whereas WBC and ESR increments were reported in approximately 40% of patients (Table 1). Indeed, inflammatory parameters may be less sensitive and specific. Cardiac-specific markers are considered far more sensitive and increased in most cases, particularly troponins (Tables 1 and 2). Natriuretic peptides were highly sensitive to rule out heart failure [193], whereas only a few cases posed symptoms. In addition to cardiac markers, admission ECG is an inexpensive and fairly sensitive examination. ST-segment abnormality could be observed in 70% of cases, mainly consisting of diffuse ST-segment elevation (Table 3). Diffuse ST-segment elevation is a specific sign of myocarditis. However, it only presented in half of the cases. The combination of cardiac markers and ECG was a sensitive early screening modality for ruling out myocarditis following COVID-19 vaccination. However, coronary angiography may be needed to rule out acute coronary syndrome since both would result in similar findings.
Histopathology examination revealed abnormal findings in 90% of cases (Table 2). Myocardial inflammation in myocarditis has a patchy nature [194], and a negative result may be because of inadequate sample collection or sampling bias during sample fixation, processing, or preparation [140,195]. Nonetheless, histopathology examination has an imperative standing position as the gold standard diagnosis modality, drawing possible etiology of myocarditis, and considering appropriate management [183]. Acute lymphocytic and lymphohistiocytic myocarditis are the commonest histopathology subtypes in this review (Table 2), and both of them seem to be associated with immune-mediated etiologies [195,196]. The immune-mediated mechanism is often associated with minimal inflammation or myocytolysis [195], which was also observed in this meta-summary [54,57,68,88,118,120,121,145,148,151]. In 9 of 15 patients, the cardiomyocytes expressed SARS-CoV-2 spike proteins [151] that may provoke cardiac tissue inflammation following COVID-19 mRNA vaccination. Although human data are limited, surprisingly, cardiomyocytes in mice also expressed spike proteins intracellularly following a vaccine shot [197]. In most cases, a shift from CD8+ T cells to CD4+ T cells was noted [151], wherein CD4+ T cell is one of the major drivers in immune-mediated myocarditis [198]. Human leukocyte antigen-DR (HLA-DR), an HLA class II region commonly observed in several immune-mediated diseases, was increasingly expressed in 11 of 14 patients following COVID-19 vaccination [151]. Additionally, perforin-mediated myocardial lysis associated with acute idiopathic [199] and viral myocarditis [200,201] was not observed in 15 patients who received a vaccine shot [151]. As the temporal association between vaccination is strong and the absence of other alternative causes (e.g., negative viral panel), the COVID-19 vaccine is probably the primary inducer of those complex immune-mediated processes.
Furthermore, infiltrating eosinophils were noted in 24% of all histopathology reports ( Table 3) and 100% of all deceased cases. Eosinophils are known as one of the effectors in hypersensitivity, and their activation promotes the secretion of their large granules to provoke inflammatory and cytotoxic effects [202], which may explain why the presence of eosinophils may be associated with higher mortality.
According to the latest ESC and CDC criteria, CMR is a significant alternative modality to EMB in myocarditis diagnosis. In this review, CMR sensitivity is similar to EMB (Table 3). CMR provides noninvasive tissue characterization, including inflammatory stages and patterns, which may be used to rule out the ischemic cause, a common etiology that mimics myocarditis [12]. In the present cohort, myocardial fibrosis or scar represented by LGE, followed by myocardial edema were the two most common typical findings to confirm the diagnosis of myocarditis following COVID-19 vaccination. Diagnosis should not rely on pleural involvement as it is not a specific sign of myocarditis and is only positive in 10% of cases.
In a recent study, the vast majority of patients were treated with NSAIDs, thereby accelerating the resolution of myocardial inflammation [203] (Table 1). However, its position remains inconclusive in myocarditis [12]. IVIGs were commonly used for ICU patients to modulate the immune system and inflammatory response [204], which is proposed as the basic pathophysiology of myocarditis following COVID-19 vaccination [183]. Colchicine seems promising in treating pericarditis [205] and decreasing inflammation in myocarditis [206]. Notwithstanding, more clinical trials are needed regarding the finding of its toxicity in a pre-clinical study [207]. The American Heart Association considers steroids in severe cases although steroid position was unclear as most cases of myocarditis following COVID-19 vaccination were mild to moderate. In summary, the chief management of myocarditis remains supportive, and specific guideline-based therapy was directed for common complications, such as heart failure and arrhythmia [12]. Nevertheless, to conclude the optimal management for myocarditis following mRNA vaccination, further research is needed.
The confirmed group had a longer LoH than the probable group ( Table 1). One of the possible explanations was that patients with CMR and EMB findings may be treated more carefully and appropriately or they tended to have severe clinical manifestations; therefore, they have longer LoH. Interestingly, LoH is correlated with cumulative ESC scores (Table 4). Patients with longer LoH tended to have older age and lower LVEF (Table 4). Generally, older age and lower LVEF are associated with more severe outcomes [208,209], including myocarditis following COVID-19 vaccination.
Histopathology examination revealed that myocarditis following COVID-19 vaccination is associated with a relatively good prognosis. Dominant lymphocyte infiltration cells as the most common subtype observed in this meta-summary is associated with better outcomes than other subtypes [194], especially since the majority of cases showed minimal inflammation and cardiomyolysis. Moreover, negative perforin cells observed in myocarditis following COVID-19 vaccination were associated with better LVEF improvement [210] as in this review. These may explain why most myocarditis following COVID-19 vaccination had relatively benign characteristics.
Deceased cases are minor (<2%) and seem to have distinct characteristics (Table S2). Compared with overall cases, deceased cases seem likely to occur in female patients (67% vs 12%), those without previous COVID-19 infection who present following the first dose of vaccine shot (86% vs 23%), and in older age (70% death in patients aged >55 years). The geriatric population seems to have a higher mortality rate due to myocarditis since this may be because of the senescence physiologic state in the geriatric population during compensated hemodynamic collapses and other pathological conditions. Notably, all geriatric deaths had an LVEF of <30% (Table S2). Owing to unspecific symptoms, underdiagnosis may also occur and increase mortality [42]. Therefore, early warning and identification are needed.
We observed that the deceased cases have sudden and severe clinical manifestations, which may be because of the following reasons: (1) all of them went to the ED on the day of specific onset, (2) severely reduced LVEF (<30%) in 4 of 5 cases, (3) extensive myocardial damage in the majority of the cases, (4) progressive histopathology examination from normal to fulminant myocarditis, and (5) rapidly progressed disease to death in less than 2 days after admission in more than half of the cases. Several cases have been treated with heart failure drugs ( Table 1). As the majority of EMB following COVID-19 vaccination showed non-infectious myocarditis and the presence of eosinophil infiltrates in all deceased cases, early immunosuppressant drugs may be required in addition to heart failure and intensive therapy [12], particularly in fulminant myocarditis. However, EMB remains the gold standard for diagnosing and determining etiology and appropriate therapy in myocarditis [12,195].
The limitation of this meta-summary was that it consisted of case reports and case series, which are the lowest levels in the hierarchy of evidence and may lack reported data. However, Sampayo-Cordero et al. [211] reported that aggregating case reports or case series and quantitatively analyzing them showed similar results to the meta-analysis of clinical study. A meta-summary of case reports was helpful in the setting of scarce data [212,213]. We anticipated the bias by assessing the included articles. In the present meta-summary, no confirmed cases were diagnosed by histopathology examination; however, CMR was a recommended [13] and valuable noninvasive modality to confirm myocarditis following COVID-19 vaccination. This is not the first review of the relevant topic. Overall, the results of this systematic review were concordant with those of published reviews. For example, myocarditis following vaccination has a preponderance of young adolescents and males; occurs following the second dose of mRNA vaccine shot; and is characteristically manifested by chest pain, elevated cardiac markers, and benign outcomes [214][215][216][217][218]. However, almost all of the included articles did not gather the specific IPD and focused on the pooled prevalence of each variable. In this systematic review, we collected the IPD of each case. Therefore, this meta-summary of cases allowed for statistical analysis to evaluate the comparison (e.g., comparison between probable and definitive cases), correlation (e.g., the correlation between LVEF and LoH to potential prognostic variables), and association (e.g., multivariate analysis of cases with previous COVID-19 infection had a six-fold odds of myocarditis following the first dose of vaccine shot than those without COVID-19 history) that were scarcely observed in previous reviews. Furthermore, this systematic review quantitatively analyzed more variables, including from the day of specific pain to the ED admission and prodromal symptoms, which were not reported in other reviews. Lastly, the detailed variable description (Table S2 and S3), including 63 histopathology examinations, was one of the strengths of this systematic review.

Conclusion
Patients complaining of chest pain, particularly young males, following the second dose of mRNA COVID-19 vaccination should be suspected of myocarditis. Cases of myocarditis following the first vaccination dose are associated with previous COVID-19 infection and being female. Comorbidities are present in half of the cases, and half of them are dysregulated immune-associated diseases. More attention should be provided to older females who come to the ED following the first dose of COVID-19 vaccination, even when their comorbidities are not significant and they present non-chest pain symptoms, as those characteristics dominate most deceased cases. The combination of ECG and cardiac markers, particularly troponins, is a highly sensitive screening modality, and their normal values may be used to rule out myocarditis, whereas CMR is preferred as a non-invasive examination to confirm myocarditis. Histopathology examination has an imperative value as the gold standard modality to diagnose, determine possible etiology, and guide appropriate management, particularly in severe and confusing cases. Non-infective subtypes dominate histopathology examinations with eosinophil involvement. Histopathology and epidemiology evidence indicate that immune-mediated process is the underlying mechanism of myocarditis following COVID-19 vaccination. The management is mainly supportive.