Correspondence
Temporal relation between second dose
BNT162b2 mRNA Covid-19 vaccine and cardiac
involvement in a patient with previous
SARS-COV-2 infection
Coronavirus disease (COVID)-19 caused by severe acute respiratory
syndrome coronarvirus (SARS-COV)-2 infection has been
demonstrated to be associated with cardiac injury [1–3]. Cases of
acute myocarditis have been reported, even in patients with
COVID-19 in the absence of significant lung involvement, suggesting
a viral triggered immune-mediated injury [4]. The modified
RNA vaccines, the BNT162b2 and mRNA-1273, that encode the
prefusion SARS-COV-2 spike glycoprotein, have shown to confer
94–95% protection against COVID-19 with a safe profile [5,6].
Although these vaccines can counteract the COVID-19 pandemic,
there is apprehension for patients who experienced previous
SARS-COV-2 infection, as these subjects have not been tested in
the trials [5]. Systemic reactogenicity, leading to systemic adverse
events often occurred after dose 2 and within 2 days after vaccination
[5]. The present report describes a case of cardiac involvement
in a patient with previous SARS-COV-2 infection within days of the
second dose of BNT162b2 mRNA vaccine.
An otherwise healthy 56-year-old man presented to the emergency
department complaining of acute onset of chest pain 3 days
after the second dose of BNT162b2 mRNA COVID-19 vaccine. He
did not report fever, systemic symptoms or cutaneous rash after
the first and second dose of the vaccine. He had no history of
allergy. Nine months earlier he experienced mild signs of
COVID-19 infection with fever lasting for 3 days and cough for
1 week, but he did not complain of chest pain or dyspnea.
He was not hospitalized, and he took only acetaminophen.
Nasopharyngeal swabs by real-time reverse-transcriptase–
polymerase-chain-reaction (rRT-PCR) assay, had been persistently
positive for 1 month while he did not undergo any blood tests during
that period. One month later, anti-SARS-COV-2 serology
demonstrated presence of IgG anti S1 and S2 proteins (titer of 60
AU/mL with positive threshold above 15).
On arrival at the emergency department arterial blood pressure
was 165/95 mmHg, heart rate 81 beats per minute, oxygen saturation
99% while breathing ambient air and body temperature
36.2 °C. Electrocardiogram (ECG) showed sinus rhythm, and minimal
ST elevation on precordial leads, with peaked T waves. The
chest x-ray was unremarkable (Supplemental Fig. 1A-B). Laboratory
tests revealed elevated levels of biomarkers of myocardial
necrosis, i.e. high-sensitivity (hs) troponin T 289 ng/L, and
C-reactive protein 2.9 mg/L with normal blood cell counts, without
evidence of peripheral eosinophilia (Table 1). Urgent coronary
angiography carried out to rule out an acute coronary syndrome
(Fig. 1A-B). Cardiac ventriculography showed preserved global left
ventricular function. Chest pain resolved spontaneously within 4 h
of admission. The patient was therefore transferred to the cardiology
ward with a diagnosis of suspected acute myocarditis. He
underwent nasopharyngeal swabbing and the specimens were
tested for common respiratory viruses by RT-PCR and resulted all
negative. As expected, anti-SARS-COV-2 serology revealed a
high-titer of IgG anti S1 and S2 proteins (titer > 400 AU/mL), and
positive anti-nucleocapsid antibodies due to previous exposure.
Hs-troponin T and CK-MB peaked on day 1 with values of
515 ng/L and 27 mg/L, respectively. No specific anti-inflammatory
or steroidal therapy was administered, and CK-MB normalized at
day 5 while hs-troponin T normalized within 7 days. Cardiac MRI
showed non-dilated ventricles with preserved left (63%) and right
ejection fraction (60%). There was focal subepicardial-intramyocardial
(non-ischemic pattern) late gadolinium enhancement (LGE)
involving the basal and apical segments of the infero-lateral wall,
colocalized with signs suggestive for edema on T2 weighted
images (Fig. 1C-1D), consistent with the diagnosis of acute
myocarditis [7]. No pericardial effusion was observed. During hospital
stay no further episodes of chest pain and no arrhythmias
were observed on ECG monitoring. Due to increased levels of
d-dimer, a CT angiography of the chest was performed and ruled
out pulmonary embolism. The patient was discharged on day 7.
This case highlights a potential relation between the second
dose of a COVID-19 vaccine and mild cardiac involvement, compatible
with acute myocarditis in an otherwise healthy patient with a
previous exposure to SARS-COV-2 infection. Pharmacovigilance on
cardiac injury is of paramount importance in this initial phase of
massive COVID-19 campaigns with the aim to identify specific
populations at increased risk and the target organs of adverse
events. Even if no causal relationship can be demonstrated in this
case report between the second dose of BNT162b2 mRNA
COVID-19 vaccination and acute myocarditis, the timing of the
onset and the inflammatory nature of the event make the relationship
plausible. Of interest, among the 4 related serious events in
the BNT162b2 vaccine trial, a paroxysmal ventricular arrhythmia
was observed [5]. Ventricular arrhythmias can occur as consequence
of an inflammatory cardiac injury [8,9], and they were frequently
observed in patients with COVID19 and cardiac injury [3].
Two deaths were documented during the trial and were judged as
unrelated, although in one case a cardiac arrest occurred [5]. No
reports of acute myocarditis were observed in the BNT162b2
mRNA and mRNA-1273 trials. Acute myocarditis can be underestimated
in clinical trials. Myocarditis must be actively searched as
observed in anticancer agent studies involving immune checkpoints
inhibitors [10,11]. The expected long-term prognosis of
the patient we reported is good [12]. Acute myocarditis can occur
following vaccination [13], and smallpox vaccination has been
https://doi.org/10.1016/j.ijcha.2021.100774
2352-9067/Ó 2021 The Author(s). Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
IJC Heart & Vasculature 34 (2021) 100774
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Table 1
Clinical Laboratory findings.
Measure Reference Range Emergency Department Hospital Day 1 Hospital Day 2 Hospital Day 3 Hospital Day 4 Hospital Day 5 Hospital Day 6 Hospital Day 7
Cardiac biomarkers:
hs-Troponin T (ng/L) 0–14 289* 515* 413* 457* – 19.7* – 12.8
CK-MB (mg/L) <4.9 – 27.4* 21.0* 5.2* – 1.7 – 1.6
NT-pro-BNP (ng/L) 0–210 – – – – – – – 20
Inflammatory biomarkers:
C-reactive protein (mg/dL) <0.5 2.9* – 2.1* – – – – 0.4
ESR (mm/h) 2–10 – – – – – – – 16*
Ferritin (ng/mL) 30–400 – – 370 – – – – 457*
Whole blood count:
White-cell count (per ml) 4,000–10,000 5,500 – 7,700 5,870 – – – 7,120
Lymphocytes (absolute count per mL) 900–4,000 1,330 – 1,460 1,830 – – – 1,760
Lymphocytes (%) 20.0–50.0 24.2 – 18.8 31.2 – – – 24.7
Eosinophilis (absolute count per mL) 0–450 60 – 80 120 – – – 150
Eosinophilis (%) 0–4.5 1.1 – 1.0 2.0 – – – 2.1
Hemoglobin (g/dl) 14.0–18.0 16.6 – 15.2 15.7 – – – 15.2
Hematocrit (%) 32.0–52.0 47.9 – 45.3 47.4 – – – 44.5
Platelet count (per ml) 140,000–440,000 249,000 – 207,000 237,000 – – – 288,000
Hepatic biomarkers:
ALT (U/L) 3–45 35 – 33 – – – – 39
GGT (U/L) 2–50 – – 41 – – – – 35
Bilirubin (mg/dL) 0.25–1 0.34 – 0.86 – – – – 0.57
Proteins (g/dL) 6.4–8.5 – – 6.5 – – – – 6.5
Total cholesterol (mg/dL) – – 203 – – – – 154
Triglycerides (mg/dL) – – 126 – – – – 82
INR 0.86–1.13 0.98 – – – – – – 0.98
Renal function:
Creatinine (mg/dL) y 0.67–1.17 0.90 – 0.82 0.84 – – – 0.99
Others:
LDH (U/L) 135–225 – – – – – – – 186
CK (U/L) 30–200 235 356* – – – – – 78
Amilase (U/L) 28–100 – – 43 – – – – 53
Glucose (mg/dL) 70–100 99 – 90 – – – – 85
Sodium (mmol/L) 132–143 140 – 141 142 – – – 139
Potassium (mmol/L) 3.4–5.2 3.78 – 4.12 4.29 – – – 5.1
D-dimer (mg/mL) 0.0–0.57 – – – – – – – 1.99*
TSH (mg/mL) 0.27–4.20 – – – – – – – 0.30
* The value in the patient was above normal.
y To convert the values for creatinine to micromoles per liter, multiply by 88.4.
ESR indicates erythrocyte sedimentation rate.
Furthermore, anti-ANA, -ENA and -nDNA tests were negative, rheumatoid factor, and complement C3 and C4 levels were within the normal ranges.
E.Ammirati,C.Cavalotti,A.Milazzoetal.IJCHeart&Vasculature34(2021)100774
2
frequently associated with eosinophilic myocarditis [14]. In the
present case, no peripheral eosinophilia and no signs suggesting
a hypersensitivity reaction (rush and fever) were observed, thus
eosinophilic myocarditis appears unlikely. As a potential explanation
of myocarditis, it is possible that molecular mimicry between
viral proteins of SARS-CoV-2 and cardiac structures can explain at
least partially the high incidence of cardiac injury observed during
COVID-19. Thus, in predisposed individuals, also an immune
response against the viral spike glycoprotein could confer a risk
for immune-mediated organ injury. Alternatively, the cardiac
injury could derive from a nonspecific inflammatory response secondary
to vaccination [15]. Hypothetically, both mechanisms
might explain the observed acute myocarditis. In conclusion, our
case report suggests that pharmacovigilance on cardiac injury
could be considered, especially with suspected or confirmed previous
history of COVID-19 aimed to actively search for acute
myocarditis when chest pain or discomfort is reported.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared
to influence the work reported in this paper.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.ijcha.2021.100774.
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Fig. 1. Coronary angiography and cardiac MRI. (A) The right coronary artery only had a mild plaque (<30% luminal diameter) in the mid portion, while (B) left main stem, left
anterior descending artery and circumflex artery had no evidence of coronary plaques. (C) T2- weighted 3-chamber view on cardiac MRI, showing focal areas of edema
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presence of non-ischemic myocardial lesions in the basal and apical segments of the infero-lateral wall (arrows) consistent with acute myocarditis.
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Enrico Ammirati
⇑
Cristina Cavalotti
Angela Milazzo
Patrizia Pedrotti
Francesco Soriano
‘‘De Gasperis” Cardio Center, Niguarda Hospital, Milan, Italy
⇑ Corresponding author at: Niguarda Hospital, Piazza Ospedale
Maggiore 3, 20162 Milano, Italy.
E-mail address: enrico.ammirati@ospedaleniguarda.it (E. Ammirati)
Jan W. Schroeder
Unit of Allergology and Immunology, Niguarda Hospital, Milan, Italy
Nuccia Morici
‘‘De Gasperis” Cardio Center, Niguarda Hospital, Milan, Italy
Cristina Giannattasio
‘‘De Gasperis” Cardio Center, Niguarda Hospital, Milan, Italy
Department of Health Sciences, University of Milano-Bicocca, Monza,
Italy
Maria Frigerio
‘‘De Gasperis” Cardio Center, Niguarda Hospital, Milan, Italy
Marco Metra
Institute of Cardiology, Department of Medical and Surgical Specialties,
Radiological Sciences, and Public Health, University of Brescia, c/o
Spedali Civili, Piazzale Spedali Civili 1, Brescia, Italy
E-mail addresses: metramarco@libero.it
Paolo G. Camici 1
IRCCS San Raffaele Hospital and Vita Salute University, Milano, Italy
Fabrizio Oliva
‘‘De Gasperis” Cardio Center, Niguarda Hospital, Milan, Italy
Received 28 March 2021
Accepted 28 March 2021
Available online 31 March 2021
E. Ammirati, C. Cavalotti, A. Milazzo et al. IJC Heart & Vasculature 34 (2021) 100774
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