Cardiac Adverse Events after Vaccination—A Systematic Review

The Vaccine Adverse Event Reporting System database has been used to report adverse events following several vaccines. We studied the patient population predisposed to such reactions and how these reactions differ with respect to the vaccine type. We searched the electronic databases PubMed, EMBASE, and Scopus up to 9 July 2021 for any study describing cardiac adverse events attributed to the vaccination. A total of 56 studies met the criteria comprising 340 patients. There were 20 studies describing cardiac adverse events following smallpox vaccination, 11 studies describing adverse events after influenza vaccination, and 18 studies describing adverse events after COVID-19 vaccination. There was a total of six studies describing cardiac adverse events after the pneumococcal vaccine, tetanus toxoid, cholera vaccine, and rabies vaccine. Adverse events following influenza vaccination occurred more commonly in older females within an average duration of four days from vaccination. Pericardial involvement was the most reported adverse event. Adverse events following COVID-19 vaccination happened at a mean age of 42.7 years, more commonly in males, and mostly after a second dose. Adverse events following smallpox vaccination occurred more commonly in younger males, with an average onset of symptoms from vaccination around 16.6 days. Adverse events were mostly myopericarditis; however, the acute coronary syndrome has been reported with some vaccines.


Introduction
Vaccination has remained an integral part of primary care medicine for preventing common and life-threatening diseases for decades. Vaccination has been associated with minor injection site reactions, fever, fatigue, and lymphadenopathy; however, serious neurological and cardiac adverse events (AEs) have been known to occur [1]. The Vaccine Adverse Event Reporting System (VAERS), a passive surveillance database, provides information on reports of AEs after vaccination with approved vaccines in the United States (2). Through this passive reporting, the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) conduct post-licensure vaccine safety monitoring [2]. A study on the VAERS database from 1990 to 2018 showed 0.1% (708) myopericarditis cases out of the 620,195 reports of possible adverse events to VAERS [3]. At the end of 2019, a novel coronavirus now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the cause of pneumonia cases in Wuhan, China [4]. It rapidly spread, resulting in a global pandemic affecting 400 million people worldwide and has taken approximately 6 million lives till now. In order to fight this infection, there was an emergent authorization of several vaccines by the World Health Organization all over the world. Two of them are Coronavirus disease (COVID-19) mRNA vaccines: BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) and mRNA-1273 (Moderna COVID-19 vaccine), three are adenoviral vector vaccines:
The median age for developing cardiac AEs following vaccination was 43.79 ± 21.2 years. Most of the patients described were males (84%) and rest were females (Table 1).
A total of 34 patients were included in cardiac AEs following influenza vaccination, with the mean age of patients being 68.55 ± 18.23 years. Fifty-five percent of cases described were female. Myocarditis/pericarditis/myopericarditis developed in 29 patients, and Takotsubo cardiomyopathy was described in two cases. The average time of symptom onset from vaccination was 4.7 ± 4 days. Anti-inflammatory treatment was used in 66% of patients, and one patient required an extracorporeal membrane oxygenator. Steroids were used on one patient. All patients recovered (Table 2).
A total of 67 patients developed cardiac AEs following COVID-19 vaccination. Overall, 35 cases reported AEs after BNT162b2 (Pfizer), 26 cases developed cardiac AEs after mRNA-1273, four cases developed cardiac AEs after AZD1222, and two cases developed cardiac AEs after receiving CoronaVac and JNJ-78436735. The average age for these patients was 42.7 years (SD = 19.6), with 59 (88%) patients being male gender. Most patients (69.6%) developed a reaction after the second dose. Myocarditis/pericarditis/myopericarditis developed in 35 patients. Acute coronary syndrome (ACS) was described in six patients. There was one case of myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) and one stress-induced cardiomyopathy. The average time of symptom onset from vaccination was 2.34 days (SD = 1.83 days). Moreover, 15 cases received anti-inflammatory treatment, and the same number of patients received colchicine. All patients recovered except one (Table 3).
A total of 232 developed adverse events following smallpox vaccination with a mean age of 29.48 ± 8.9 years. Most of these AEs (82.75%) were described in male patients. Most patients (212) developed myocarditis/myopericarditis or pericarditis. Twenty-six patients had ACS, and there were two cases of arrhythmias. The average duration of symptom onset from the time of vaccination was 16.6 days (SD = 14). For treatment, nine cases described the use of NSAIDs, and three patients received colchicine. Most patients developed AE following the first dose, but 30 patients developed a reaction after the second dose. There were three cases with mortality. Endomyocardial biopsy (EMB)was performed in eight cases, and four cases had eosinophilic infiltration (Table 4).
Cardiac AEs were also described with the pneumococcal vaccine, mostly in the elderly age group. Myopericarditis was also reported with tetanus toxoid in three males with an average age of 25 years. All three patients recovered, and a biopsy in one case showed eosinophilic infiltration. There was also one case of ACS reported after a cholera vaccination and myocarditis after a rabies vaccination (Table 5). The median age for developing cardiac AEs following vaccination was 43.79 ± 21.2 years. Most of the patients described were males (84%) and rest were females (Table 1).

Discussion
Myocarditis is characterized by inflammation of the heart, and in resource-abundant countries, viral infections are the most frequently presumed cause of myocarditis [63]. Often pericarditis and myocarditis are observed in tandem; hence the term myopericarditis being recognized by the European Society of Cardiology (ESC). The annual incidence of myocarditis in the United States is estimated to be 1 to 10 per 100,000 of the population [44]. Vaccine-associated myocarditis is a rare event that was recognized as an adverse event after the mass revaccination against the smallpox virus began in military personnel. The new guidelines by ESC have now recognized inflammatory cardiomyopathy into four groups based on EMB results: inflammation-negative, virus-negative; inflammation-positive, virus-negative; inflammation-negative, virus-positive; and inflammation-positive, viruspositive [64]. Vaccine-associated cardiomyopathy usually falls into the virus-negative category. Characteristics of predisposed patients and treatment strategies remain to be defined.
The incidence of myopericarditis rose from 0.08 per 1000 to 0.11 per 1000 after the resumption of smallpox vaccination in 2002 [37]. Recent vaccination against the deadly COVID-19 virus has raised similar concerns of myopericarditis with an absolute rate of 1.7 per 1,000,000 vaccinated individuals as described by Husby et al. in a Denmark-based cohort study. However, these rates are much lower than the incidence rate described for viral myocarditis (10 to 22 per 100,000 individuals) [65]. Thus, there should be no vaccine hesitancy based on these cardiac AEs; however, physicians should be cautious about the development of these AEs, and care should not be delayed if suspicion arises.
Su et al.'s study on the VAERS database from 1990 to 2018 showed that most patients developing myopericarditis from vaccination were 19-49 years old, and 90% of this age group were male with symptom onset 8-14 days after vaccination [3]. The vaccines frequently associated with these AEs in order of frequency were smallpox, anthrax, typhoid, and inactivated influenza. Cardiac AEs from hepatitis B, zoster vaccine, hepatitis A, varicella, hemophilus, influenza, polio, and pneumococcal vaccine were also reported. We tried to study how these reactions differ with respect to the type of vaccine.
AEs following smallpox vaccination are the most studied among all vaccines. A prospective study by Engler et al. in military personnel saw an increased incidence of new-onset cardiac symptoms following smallpox and trivalent inactivated influenza with a relative risk difference of 16.11 between vaccinated and non-vaccinated populations [37]. Thus, vaccinia-associated inflammatory disease was defined as any cardiac inflammatory syndrome occurring within 30 days of vaccination without another identifiable cause [66]. Reif et al. described that the hyperactivation of inflammatory response from the variola virus in the smallpox vaccine is responsible for these AEs following smallpox vaccination. The study identified increased monocyte recruitment followed by upregulation of intercellular adhesion molecule 1 in patients developing adverse events. The activated macrophages then produce cytokine interleukin-10 (IL-10), which along with certain genotypes of IL-4, leads to increased production of granulocyte stimulating factor-3, a cytokine produced by activated T cells, macrophages, and endothelial cells to increase production of neutrophils for inflammatory reactions [67].
Influenza vaccination has been associated with a decrease in all-cause mortality in heart failure patients [68]. A literature search in 2017 described seven cases of pericarditis in patients above 60 years of age following influenza vaccination, as was seen in our analysis [12]. In a case series of 84 pericarditis cases by Zanettini et al., 23 cases were thought to be due to influenza vaccination in elderly females [18]. The mean time of symptom onset was seven days, as was seen in our analysis [12]. The mechanisms of systemic immunologic reactivity for pericarditis remain to be proven because of its rarity. Following influenza vaccination, there is a systemic inflammatory reaction, and it is postulated that the AEs, particularly TTC, may be due to this increased sympathetic discharge [15].
The first reports of AEs following COVID-19 vaccination came from Israel's Health Ministry, which reported heart inflammation in cases who received the Pfizer vaccine [69]. Soon after, a CDC advisory committee on immunization practices identified a likely associ-ation between the COVID-19 mRNA vaccines and cases of myocarditis and pericarditis [70]. Based on data from the VAERS, the CDC has estimated that the incidence of myocarditis after COVID-19 vaccination is 0.48 cases per 100,000 overall and 1.2 cases per 100,000 among vaccine recipients between the ages of 18 and 29 years. However, based on the study by Witberg et al. on the Israel database incidence of myocarditis, it was estimated that there were 2.13 cases per 100,000 vaccinated persons in the 42 days after the first vaccine dose [71]. It is important to consider these case reports within the broader context of the COVID-19 pandemic, which has caused tremendous morbidity and mortality throughout the world.
COVID-19 vaccination, especially AstraZeneca, was also found to be temporally related to thrombosis, but causality could not be proved; hence the vaccine was suspended [26,72]. Myocardial infarction (MI), in particular, is one of the most dreaded cardiac complications, as was seen in our included studies. The initial data from clinical trials by FDA briefing documents demonstrated that the incidence of MI was 0.02% and 0.03%, respectively, in the vaccine group. Later, a study on an elderly age group, comparing vaccinated and unvaccinated patients, did not show any significant increase in any cardiovascular events such as stroke or pulmonary embolisms [73].
As described earlier, these cardiac AEs are rare and different mechanisms have been proposed for these reactions, including molecular mimicry between immunogens in vaccines and human cells [74,75]. There is also the possibility of interaction between the encoded viral spike protein, antibodies generated by the host, and a yet undetermined cardiac protein in susceptible hosts [75]. Although these mechanisms for AEs are still enigmatic, a preponderance for male gender and younger age was observed in the VAERS database and our review [76]. The association of myocarditis with male sex and younger age could be attributed to sex hormones which may account for a more intense inflammatory response [77]. As suggested by experimental studies on myocarditis in mice, testosterone may be implicated in the inhibition of anti-inflammatory cells and the stimulation of immune responses by mRNA vaccine [78]. The presentation of symptoms within approximately two days of receiving a second dose (68% of patients) of mRNA vaccination also suggests an immune-mediated reaction in the host. Furthermore, cases of Type 1 Kounis syndrome have been described after inactivated COVID-19 vaccine, indicating an allergic reaction to a vaccine component [32].
According to 2012 ESC, cardiac magnetic resonance imaging (CMR) is the noninvasive gold standard method for the diagnosis of myocarditis [65]. CMR findings, including regional dysfunction, late gadolinium enhancement, and elevated native T1 and T2, have been used in many of these cases for myocarditis diagnosis following COVID-19 vaccination [7,9,22]. EMB, which is the gold standard, was performed on five patients with myocarditis after smallpox vaccination and in one patient after COVID-19 vaccination [65]. Three of them showed eosinophilic infiltrate. Yamamoto et al. also described biopsyproven eosinophilic myocarditis following tetanus toxoid, which responded to high-dose corticosteroid treatment [59].
Specific guidelines for the management of vaccinia-associated myopericarditis have been outlined by the Department of Defense Vaccine Healthcare Center, and symptomatic patients should receive treatment with analgesics and/or NSAIDs as a first-line treatment [66]. Most cases in our study received colchicine and ibuprofen. In patients with persistent symptoms, steroids were advised [66]. The ESC guidelines advise immunosuppressive therapy for virus-negative myocarditis; however, the data are still unclear [79]. It is recommended that in patients refractory to standard therapy with no contraindications, treatment must be tailored on an individual basis [79]. Steroids were used for many patients in this review, which led to improvement.

Limitations
The review could not include all studies from the VAERS database. It was limited to full-text articles describing the patient and the cardiac AEs. The review also mostly comprised of case reports, case series, and retrospective studies with few prospective studies. Therefore, there is a potential risk of bias, and the results should be interpreted with some caution. Given the rarity of these events and the retrospective nature of the events, it is not possible to estimate the relative risk of these AEs. Lastly, most of the studies did not provide all the required information, particularly about the results of cardiac testing and management.

Conclusions
Although vaccination remains a pivotal pillar of our healthcare to fight against some of the deadliest infections, understanding vaccine-associated cardiac adverse events will improve our healthcare delivery to this subpopulation. The incidence of cardiac AEs from vaccination remains much lower than cardiac AEs from other causes, but providers should be cautious of these AEs after vaccination.