March 25, 2024

To: Dr. Genevieve Engle, PharmD, BCMAS

From: Danielle Snyder, PharmD Candidate
CC: Dr. Zachary Fricker, PharmD
Re: COVID-19 and Myocarditis
__________________________________________________________________________

In response to your request regarding the incidence of myocarditis occurring with the COVID-19
infection and the Covid vaccine, with a possible mechanism of action, the following information
is provided.

Response and Recommendation:

Studies suggest that the incidence of myocarditis ranges from 0.01% to 7.7% in patients
diagnosed with COVID-19.1
The incidence of myocarditis related to the COVID-19 vaccination is thought to be between 20
to 30 patients out of every million.2
The mechanism of action is unknown, however there are a few theories that have been
proposed suggesting it is caused by either direct damage to the myocardium, a viral-induced
myocarditis, or an overactivation of the host immune response.2,3

Analysis and Synthesis:

The following information was collected using a thorough literature search.

Incidence of myocarditis occurring with diagnosis of COVID-19

Route A, et al. discussed the occurrence of myocarditis as a complication of both a COVID-19
diagnosis and the mRNA vaccine.1 Authors performed a literature search using PubMed,
EMBASE, medRxiv, and Cochrane electronic medical databases containing reports of
COVID-19 myocarditis or its vaccine-related myocarditis from December 2019 to May 2022.
MeSH terms included COVID-19, SARS-CoV-2, myocarditis, myopericarditis, myocardial injury,
inflammation, cardiomyopathy, cardiovascular complication, COVID-19 vaccination, mRNA
COVID-19 vaccine, troponin, and cardiac magnetic resonance.

Table 1: Myocarditis incidence in patients with COVID-191

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Study Total COVID-19 patients Myocarditis incidence (%)
Boehmer et al. 2021 1,452,773 0.146
Buckley et al. 2021 718,365 5.0
Barda et al. 2021 173,106 0.01
Annie et al. 2021 259,352 0.2
Murk et al. 2021 70,288 0.1
Linschoten et al. 2020 3,011 0.1
Jalali et al. 2021 196 7.7
Sang III et al. 50 4
Kunal et al. 2020 108 2.8
Bhatia et al. 2021 644 0.31
Daniels et al. 2021 1,597 2.3

Table 2: Myocarditis incidence in patients with COVID-19 vaccine1

Study Type of vaccine Total COVID-19 vaccine Myocarditis incidence
patients
a
Simone et al. BNT162b2 or 2,392,924 15
2021 mRNA-1273b
Patone et al ChAdOx1c, ChAdOx1: 20,615,911; ChAdOx1: 226
BNT162b2a, or BNT162b2: 16,993,389; BNT162b2: 158
mRNA-1273b mRNA-1273: 1,006,191 mRNA-1273: 9
a
Mevorach et al. BNT162b2 5,442,696 136
2021
Witberg et al. BNT162b2a 2,558,421 54
2021
Diaz et al. 2021 BNT162b2a or 2,000,287 20
mRNA-1273b
Husby et al. BNT162b2a or 4,155,361 269
2021 mRNA-1273b
a: Pfizer vaccine. b: Moderna vaccine. c: Chimpanzee adenoviral vaccine developed by the University of Oxford, AstraZeneca

Route A, et al conclude that given all of the data they have reviewed, the benefits of the vaccine
outweigh the risks significantly in all populations and remains the mainstay of prevention despite
this incidence of myocarditis today.1

Bailey, et al aimed to review current literature on the patient populations with mild-to-moderate
COVID-19 infection to determine if there is a significant cardiac risk in this population, relative to

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those who experienced a more severe COVID-19 disease.4 It is important to note that the
authors did not discuss their specific methods, search terms, or the inclusion and exclusion
criteria in their discussion. It is known that those with comorbidities, especially diabetes,
hypertension, heart failure, and other chronic illnesses, have more severe COVID-19 symptoms
and have more cardiovascular specific comorbidities. It was also noted that even those who
were previously healthy or presented with mild or asymptomatic COVID-19 infection still
developed myocarditis. While this review article does not directly impact the answer to this
question, it is important to note that the results of this review, listed in Table 3, suggest that a
mild infection is not a reason to consider that myocardial involvement is less likely as there was
still cardiac involvement in previously healthy individuals. Further research is needed to
determine the true, long term cardiac effects of the COVID-19 infection.

Table 3: Studies detailing myocarditis in asymptomatic COVID194

Source Population size Suspected or Patients with Patients with
confirmed myocarditis and myocarditis and
myocarditis and asymptomatic mild symptoms
COVID19+
Eiros, et al 139 24 (17%) 6 (25%) 0
Clark, et al 146 (59 2 (3%) 2 (100%) 0
COVID19+, 60
athlete controls,
27 healthy
controls)
Starekova et 145 2 (1.4%) 1 (50%) 1 (50%)
al
Rajpal et al 26 4 (15%) 2 (50%) 2 (50%)

Jaiswal V, et al composed a systematic review to collate evidence about demographics,

symptomatology, diagnostic techniques, and clinical outcomes of COVID-19 infected patients
with myocarditis.5 The literature search was done using PubMed, Google Scholar, Cochrane
CENTRAL, and Web of Science database until August 31, 2021. The search terms were
“SARS-CoV-2” and/or “COVID-19” and/or “myocarditis.” The eligibility criteria for including
studies included: patients with confirmed myocarditis in association with COVID-19, age >18
years of age, they had to be cohorts, case series, or a case report. The data that was extracted
includes publication characteristics, demographics including age, gender, and comorbidities,
and clinical characteristics along with laboratory findings. They also included features of imaging

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and the management of the patient pertaining to both the COVID-19 infection and myocarditis,
as well as complications and final clinical outcomes.
The data analysis included 54 case reports and 5 cohorts comprising 215 adult patients in total.5
- Presenting symptoms on admission were noted from 139 of the 215 patients, and these
symptoms included cough, shortness of breath, chest pain, diarrhea, fatigue, myalgia,
dyspnea, hypoxia, syncope, tachycardia, hypotension, tachypnea, malaise, and
vomiting.
- Inflammatory markers were reported in 185 of 215 patients, and they were elevated in
181 (97.8%) of those patients.
- Cardiac markers were documented in 212 patients, and 201 (94.8%) of those were
elevated.
- In the radiographic imaging studies, 120 individuals had documented imaging studies
and the most common feature was cardiomegaly, reporting in 32.5% of patients.
- Electrocardiography (ECG) findings were obtained for 96 patients, of which only 2%
were normal. Other patients had various findings including ST segment elevation
(44.8%), T wave inversion (7.3%), ST depression (5.2%), sinus tachycardia (11.5%),
atrial fibrillation (3.1%), and ventricular tachycardia (2%).
- Echocardiography findings were noted for 175 patients, where 9 (5.14%) patients
showed a normal ejection fraction, and 55 (31.4%) of patients demonstrated a reduced
ejection fraction with a mean EF of 35%.
- Cardiovascular magnetic resonance (CMR) imaging is the non-invasive gold-standard
test for diagnosing, and it was identified that 42 patients underwent CMR imaging with
36 of them diagnosed with myocarditis.

Table 4: Comorbidities5
Comorbidity Number (%)
Hypertension 92 (51.7%)
Diabetes mellitus type 2 6 (3.4%)
Obesity 5 (2.8%)
Ischemic stroke 2 (1.1%)

The diagnosis of myocarditis in a patient with COVID-19 infection may be difficult as the
symptoms can overlap with COVID-19 and the diagnosis of myocarditis can be challenging.5
The most common comorbidity in patients with COVID-19 and myocarditis was hypertension,
however diabetes mellitus type 2, obesity, and ischemic stroke were all noted as well. Because

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of the incidence of inflammatory markers, it is thought that myocarditis may be a result of the
cytokine storm that happens in the COVID-19 infection. Myocarditis in its simplest terms is the
inflammation of the myocardium, and it is thought that COVID-19 may have more of an impact
on the cardiac system than researchers originally thought. With COVID-19 traveling to the
myocardium, the cytokine release can result in direct cardiac damage when trying to treat the
infected cardiomyocytes. Because of the elevated cardiac enzymes and cardiac imaging
resulting with abnormalities among these patients, it is thought that COVID-19 could be directly
damaging the cardiac cells, as well, which results in myocarditis.

Incidence of myocarditis occurring with the COVID-19 vaccination

The Vaccine Adverse Event Reporting System (VAERS) was accessed and the events were
reported by vaccine in Table 4.6 Of note, VAERS only includes self-reported adverse events and
cannot be used alone to determine the incidence of adverse events from vaccines. This is a
voluntary process and may include information that is incomplete, inaccurate, coincidental, or
unverifiable. Another limitation to this data is that it is not possible to know the total number of
patients vaccinated, so the table shows the total number of myocarditis events reported
compared to the total number of all events reported broken down by vaccine type.

Table 5: Summary of events reported through VAERS to date6

Vaccine type Myocarditis events reported Total events reported
Janssen 274 99,281
Moderna 4,087 561,598
Novavax 1 476
Pfizer-Biontech 13,397 982,010
Unknown 95 14,711
Moderna bivalent 23 17,377
Pfizer-Biontech bivalent 42 24,083
TOTAL 17,919 1,700,159

Power JR, et al reviewed the incidence and potential mechanisms of myocarditis associated
with the COVID-19 vaccine and discussed some of the management principles of myocarditis.2
It is important to note that the methods, search terms for the literature search, and the inclusion
and exclusion criteria were not discussed. Authors discussed that prior to the COVID-19
pandemic, the 2019 Global Burden of Cardiovascular Disease suggested that the annual
incidence of myocarditis was 6.1 cases in men and 4.4 cases in women per 100,000 subjects

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 aged 35-39, but this incidence can be as high as 10-20 cases per 100,000 in the studies
referenced by Tschope C et al and Bozkurt B et al. Through an analysis of the Vaccine Adverse
Event Reporting System (VAERS), there was an association between the vaccine and
myocarditis however VAERS relies on passive reporting and is dependent on both the
recognition and reporting of true events. These results estimated an incidence of 0.48 events
per 100,000 recipients in the general population and 1.2 events per 100,000 in subjects
between the ages of 18 and 20. It is noted that this report found that adolescent males are the
most affected subpopulation and typically report symptoms of chest pain, shortness of breath,
and palpitations about one week after the second vaccination.

Table 6: Incidence of myocarditis after COVID-19 vaccination2

Study Type of Vaccine Total Cases of Cases of Incidence overall
Population Myocarditis myocarditis after
2nd dose
Klein et al BNT 162b2a 57% 6,200,000 34 - 13.2 per 100,000
MRNA-1273b 43% person-years
Witberg et al BNT 162b2a 100% 2,558,421 54 - 2.13 per 100,000
persons
Mevorach et al BNT 162b2a 100% 9,289,765 136 86 5.34 (incidence ratio)
Simone et al BNT 162b2a 50% 2,392,924 15 86.7 0.08 per 100,000 first
MRNA-1273b 50% doses
0.58 per 100,000
second doses
Montgomery et BNT 162b2a 1,745,000 23 87 0.82 per 100.000
al MRNA-1273b doses
Diaz et al BNT 162b2a 52.6% 2,000,287 20 80 1.0 per 100,000
MRNA-1273b 44.1% persons
Ad26.COV2.S 3.1%
Perez et al BNT 162b2a 175,472 7 - 55.4 per 100,000
MRNA-1273b person-years
a: Pfizer vaccine. b: Moderna vaccine

Overall, data reviewed in this article suggest an estimated incidence of 20-30 cases per million
patients, and the incidence is higher with COVID-19 vaccines that use mRNA technology than
vaccines that use the traditional viral vector approach.2 It is proposed that the male population
has a higher incidence compared to females due to the differential effects of sex hormones on
cytokine production.The above mentioned limitations to estimated the overall incidence
combined with the evolving nature of COVID-19 and shorter follow-up times suggest that the
estimated incidence of COVID-19 vaccine-associated myocarditis is underestimated.

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Despite the limitations in reporting the incidence of COVID-19 vaccine-associated myocarditis,
this review article discusses a few proposed mechanisms for how this adverse effect is
possible.2 It is thought that the cytokine released secondary to the direct viral infection of the
cardiomyocytes causes direct cardiac damage to the myocardium tissues, which is one
proposed mechanism. Another theory is that molecular mimicry could be driving an autoimmune
myocarditis after vaccines. There is a shared molecular pattern between SARS-CoV-2 viral
proteins and the self antigens that exceeds that of other coronaviruses, which would explain the
characteristic inflammatory effects of COVID-19. Another idea is that there is an adaptive
immune response to the vaccine, resulting in an innate immune overactivation specifically to the
mRNA vaccine.

Ishisaka Y, et al conducted a systematic review and meta-analysis to discuss the incidence and
clinical outcomes of myocarditis in the COVID-19 infection, vaccination, and control group which
included non-COVID-19 causes of myocarditis.7
● COVID-19 infected group: 2.76 per thousand (95% CI, 0.85-8.92)
● COVID-19 mRNA vaccine group: 19.7 per million (95% CI, 12.3-31.6)
● Control group: 0.861 per million (95% CI, 0.0045-16.7)
This study could not discuss the statistical significance between frequency or mean values
between the three study arms because it was not a direct comparison, and some of the studies
did not clarify the clinical diagnostic criteria for myocarditis. However the summary of what they
were able to find suggests that myocarditis could be a side effect of both the COVID-19 infection
and the vaccine. They were able to determine that the severity of symptoms of myocarditis was
much less severe in the COVID-19 vaccine patients when compared to the COVID-19 infection
patients.

Mechanism of action
The American College of Cardiology (ACC) held a roundtable in May of 2021 and documented
their discussion to address caring for adults with cardiac symptoms after SARS-CoV-2 infection,
the guideline was reviewed for the evaluation and discussion on the mechanism of myocarditis
after COVID-19.3 They recognized that COVID-19 may have short- and long-term impacts on
the cardiovascular system, which is where the term “Long COVID” came into play. These
guidelines recognize myocarditis as a rare, but serious side effect of the infection and the
COVID-19 mRNA vaccination There was also mention of other abnormal cardiac findings that
have been found on cardiac magnetic resonance imaging, even without having any cardiac

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Nashville, TN 37212
symptoms. To understand the incidence, the ACC provided a few proposed mechanisms for
why myocarditis is associated with COVID-19 infection and the vaccine.

There are several mechanisms of cardiovascular injury discussed in this guideline.3 Case
reports with COVID-associated myocarditis are rare, but they follow the pathway of viral-induced
myocarditis. It is typically described in a three-phase process:
1. Acute viral exposure with an innate immune response (<1 week)
2. Activation of an acquired immune response with cytokine and chemokine release (1-4
weeks)
3. Disease progression with clearance of the virus and development of fibrosis, remodeling,
and cardiomyopathy (>4 weeks)
For some individuals with myocarditis, there may be an elevation of cardiac enzymes or
abnormalities on CMR early after infection, however there is often a delayed onset of any of
these findings.3 This delay lines up with the normal pathway of viral-induced myocarditis, but the
variation in this presentation which may suggest other mechanisms may be responsible for the
association. Other proposed mechanisms include direct virus invasion with an overactive host
inflammatory response, which includes an excessive activation of innate immune pathways, a
surge of proinflammatory cytokines, and molecular mimicry to induce an autoimmune response
on cardiac tissue. Some baseline comorbidities with cardiac involvement may potentiate any of
these responses, however it is known that cardiac involvement can happen even in the absence
of any comorbidities.

To answer this question, the following search terms were used:

Database Search Term
"COVID-19"[Mesh] AND "Myocarditis"[Mesh]
PubMed
“COVID-19 Vaccine”[Mesh] AND “Myocarditis”[Mesh]
Medline “COVID-19”[Mesh] AND “Myocarditis”[Mesh] AND “Incidence” [Mesh]
Ultimate “COVID-19 vaccine”[Mesh] AND “Myocarditis”[Mesh]
Embase “COVID-19”[Emtree] AND “Myocarditis”[Emtree]
Google
“Incidence of myocarditis”[keyword] AND “COVID-19”[keyword]
Scholar

Thank you for contacting the Christy Houston Foundation Drug Information Center at the
Belmont University College of Pharmacy. Please do not hesitate to contact the Drug Information
Center at 615-460-8382 or druginfo@belmont.edu with any additional questions.

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References:
1. Rout A, Suri S, Vorla M, Kalra DK. Myocarditis associated with COVID-19 and its
vaccines - a systematic review. Prog Cardiovasc Dis. 2022;74:111-121.
doi:10.1016/j.pcad.2022.10.004
2. Power JR, Keyt LK, Adler ED. Myocarditis following COVID-19 vaccination: incidence,
mechanisms, and clinical considerations. Expert Rev Cardiovasc Ther.
2022;20(4):241-251. doi:10.1080/14779072.2022.2066522
3. Writing Committee, Gluckman TJ, Bhave NM, et al. 2022 ACC expert consensus
decision pathway on cardiovascular sequelae of COVID-19 in adults: myocarditis and
other myocardial involvement, post-acute sequelae of SARS-CoV-2 infection, and return
to play: a report of the american college of cardiology solution set oversight committee. J
Am Coll Cardiol. 2022;79(17):1717-1756. doi:10.1016/j.jacc.2022.02.003
4. Bailey E, Frishman WH. Mild-to-moderate COVID-19 infection and myocarditis: a review.
Cardiol Rev. 2023;31(3):173-175. doi:10.1097/CRD.0000000000000458
5. Jaiswal V, Sarfraz Z, Sarfraz A, et al. COVID-19 infection and myocarditis: a
state-of-the-art systematic review. J Prim Care Community Health.
2021;12:21501327211056800. doi:10.1177/21501327211056800
6. Vaccine adverse event reporting system (VEARS) public dashboard. Updated February
23, 2024. Accessed March 15, 2024.
7. Ishisaka Y, Watanabe A, Aikawa T, et al. Overview of SARS-CoV-2 infection and vaccine
associated myocarditis compared to non-COVID-19-associated myocarditis: a
systematic review and meta-analysis. Int J Cardiol. 2024;395:131401.
doi:10.1016/j.ijcard.2023.131401

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