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A 71-year-old man was transferred urgently to our hospital after collapsing near his home post the first shot of the BNT162b2 coronavirus disease 2019 vaccine (Pfizer-BioNTech, Comirnaty®). Immediately after arrival at our hospital, cardiac arrest due to complete atrioventricular block with no ventricular escaped beats was observed on electrocardiogram. Echocardiography showed preserved left ventricular ejection fraction, however, diffuse severe hypokinesia was revealed after 3 weeks, and he died 3 months after admission because of worsening heart failure. An autopsy examination revealed eosinophilic myocarditis or hypersensitivity myocarditis with extensive fibrosis and widespread myocardial dropout throughout the heart.
Learning objective
1. Severe myocarditis occurs extremely rarely after mRNA coronavirus disease 2019 (COVID-19) vaccination. 2. Myocarditis after mRNA COVID-19 vaccination might cause complete atrioventricular block, followed by a course of decreased left ventricular ejection fraction. 3. Histologically, severe myocarditis after mRNA COVID-19 vaccination seems to present as fulminant necrotizing eosinophilic myocarditis or hypersensitivity myocarditis.
The BNT162b2 (Pfizer-BioNTech, Comirnaty®) is a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine for the prevention of the novel coronavirus disease 2019 (COVID-19) infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [
]. In Japan, the vaccine was approved by the Pharmaceutical Affairs Bureau on February 14, 2021, and vaccination began on February 17, 2021. A large-scale report on myocarditis after mRNA vaccination was published, although the frequency was extremely rare [
Herein, we report a case of severe myocarditis wherein complete atrioventricular (AV) block was observed a few hours after the first dose of the BNT162b2 mRNA COVID-19 vaccine, and left ventricular ejection fraction (LVEF) decreased after approximately 3 weeks.
Case report
A 71-year-old man with type 2 diabetes mellitus and essential hypertension who was receiving medication from his primary care physician was transferred to our hospital after he was found collapsed following the administration of the first dose of BNT162b2 COVID-19 vaccine. He presented with no apparent cold symptoms before the vaccination. It was estimated from the inoculation record that approximately 4–5 h had passed since the vaccination. On the arrival of the emergency team, he was ambiguous but able to follow through. However, immediately after arrival at our hospital, long cardiac arrest due to complete AV block without ventricular escaped beats was observed on electrocardiogram (ECG) (Fig. 1a ). Cardiopulmonary resuscitation was started immediately, and the patient's heartbeat resumed after adrenaline administration (Fig. 1b). Further, a temporary pacemaker was implanted. An ECG obtained by his family physician 9 months earlier showed no findings suggestive of chronic AV conduction impairment (Fig. 1c). He presented with low-grade fever (37.2 °C); however, COVID-19 antigen test results from the nasopharynx samples were negative. Blood samples showed significantly increased white blood cell counts [WBCs, 161 × 102/μL (neutrophils, 56.90 %; lymphocytes, 34.90 %; eosinophils, 0.40 %; basophils, 0.20 %; and monophils, 7.60 %)], C-reactive protein (CRP, 11.5 mg/dL), creatine kinase (CK, 5353 U/L; CK-MB, 107 U/L), and troponin T (1.610 ng/mL) levels, whereas the renal function was almost normal (serum creatinine, 0.94 mg/dL; estimated glomerular filtration rate, 61.1 mL/min/1.73m2) and the left ventricular wall motion and LVEF were normal (65 %).
Fig. 112-lead electrocardiogram (ECG). (a) Complete atrioventricular block with no ventricular escaped beats observed immediately after arrival at our hospital, (b) ECG after resumption of own heartbeat after adrenaline administration, (c) ECG 9 months before admission by the patient's family doctor, (d) sinus tachycardia after hospitalization.
Coronary angiography revealed no significant organic stenosis of the coronary arteries. He was complicated with bacterial pneumonia and required antimicrobial therapy. A contrast-enhanced cardiac magnetic resonance imaging (MRI) scan was performed at the time of temporary pacemaker replacement on the fifth day. However, we could not obtain the accurate evaluation because the MRI images were suboptimal quality due to the patient's body motion. After insertion of the temporary pacemaker, AV conduction recovered, although quite wide QRS complex with first degree AV block (complete right bundle block, and left-axis deviation) remained, and the patient showed sinus tachycardia with a heart rate of 100–150 beats per min. (Fig. 1d). However, AV conduction was at an unstable state that occasionally and suddenly became ventricular-pacing dependent using a temporary pacemaker. Furthermore, the inflammatory reaction on blood test showed high levels of WBC and CRP, despite the selection of appropriate antimicrobial agents based on the sputum culture for pneumonia findings, and the CK levels also remained high. A permanent pacemaker was implanted on the 22nd day.
On the 24th day, urine output decreased and blood samples of the patient showed an elevated level of transaminases. Despite normal LVEF in the 2nd week of admission, the patient had diffuse wall motion loss and an LVEF of 33 % on the 24th day. Intra-aortic balloon pumping (IABP) was inserted for cardiogenic shock and the left ventricular myocardial biopsy was performed at the same time on the 27th day, and the pathology results confirmed the diagnosis of myocarditis (Fig. 2). Therefore, steroid pulse therapy [methylprednisolone (1 g × 3 days)] was performed. These intensive treatments improved the patient's circulatory failure. Troponin T level in blood samples before the intensive care was as high as 1.34 ng/mL, but it kept relatively low level at 0.18 ng/mL one week, therefore we did not decide that additional immunosuppressive therapy was given. Subsequent intensified heart failure medication and cardiac rehabilitation did not improve LVEF, which decreased to the 20 % range. An IABP was reinserted on day 61 after admission when the heart failure worsened again and troponin T level was again elevated at 1.42 ng/mL. Therefore, we tried a second steroid pulse therapy, however, the therapy had limited effect. On the 78th day, a urinary tract infection caused worsening heart failure and rapid progression of multiple organ dysfunction syndrome, and the patient died on the 83rd day.
Fig. 2Endomyocardial biopsy. Hematoxylin–eosin stains of heart tissue specimens obtained via left ventricular endomyocardial biopsy on the 27th day of admission. Images of the hematoxylin–eosin stains were obtained using 100× and 600× objectives. Arrows indicate eosinophils.
The left ventricular myocardial biopsy was performed on the 27th day (Fig. 2). Cardiomyocytes were largely necrotic and replaced by fibrotic material, with moderate degrees of lymphocytic and eosinophilic infiltration. No granulomas were found. The diagnosis of acute necrotizing eosinophilic myocarditis or severe form of hypersensitivity myocarditis was made.
Autopsy findings
Autopsy was performed after obtaining the consent from the patient's family. Pulmonary, hepatic, and renal congestion were observed, which were probably caused by circulatory failure. No notable findings were found in the brain. Approximately 50 % of the myocardium was replaced by fibrotic material throughout the heart (430 g) (Fig. 3a ). Eosinophilic myocarditis persisted, although with milder activity than that of the biopsy performed on the 27th day (Fig. 3b). The AV node and proximal His bundle were found to be intact (Fig. 3c); however, complete AV block was fully explicable by the heavily inflamed and necrotic myocardium surrounding the His bundle.
Fig. 3Autopsy findings of the ventricular septum. (a) Macroscopic view of the ventricular septal region and Masson trichrome stained images (10×) and (b) strongly magnified image (600×) with hematoxylin–eosin staining. The arrow in (b) indicates eosinophils. (c) The atrioventricular (AV) node is indicated using hematoxylin–eosin staining (600×).
We report a case of myocarditis following COVID-19 vaccination. This case has three discrepancies from recent large-scale reports on mRNA COVID-19 vaccine-associated myocarditis [
]. First is that our patient was relatively older. Secondly, the vaccine was the first injection for the patient and adverse events occurred within a few hours of vaccine administration. And finally, the clinical course was extremely severe and progressive. This case in particular had an interesting clinical course over a period of three months. On admission, the patient had extensive wide QRS rhythms with elevation of CK and troponin T, while left ventricular wall motion was preserved at least until 2 weeks after admission. Therefore, we assumed that the myocardium damage was limited to the side near the conduction system in incipient stage, and speculated that complete AV block without escape beat as the initial manifestation was caused by the myocardial damage. After left ventricular dysfunction manifested after three weeks of admission, myocardial biopsy revealed severe cardiomyocytes necrosis with moderate degrees of lymphocytic and eosinophilic infiltration. We considered that inflammation of the myocardium might have progressed from a localized to an overall condition in this case. If myocardial biopsy had been performed at the earlier stage with limited inflammatory cell infiltration and the steroids or other anti-inflammatory drugs had started, the subsequent clinical course might have been different. Also, if initial resuscitation had been delayed, this patient would have been managed as an unknown cause sudden death. The severity of myocarditis after mRNA COVID-19 vaccination may differ from case to case, however, since severe cases have rarely been reported, their pathophysiology remains unclear. The one reason for the occurrence of the above discrepancies with previous reports might be explained by extensibility of inflammation [
], no known reports exist on mRNA COVID-19 vaccine-associated myocarditis that initially started with complete AV block and was followed by irreversible myocardial damage.
There are limited reports on autopsy following myocarditis after the administration of mRNA COVID-19 vaccine [
First identified case of fatal fulminant eosinophilic myocarditis following the initial dose of the Pfizer-BioNTech mRNA COVID-19 vaccine (BNT162b2, Comirnaty): an extremely rare idiosyncratic hypersensitivity reaction.
]. In these reports, the histological examination of the heart sections showed fulminant necrotizing eosinophilic myocarditis. This reaction may represent an overly exuberant immune response, and the myocardial injury may be mediated by similar immune mechanisms, such as cytokine storms, as observed in COVID-19 infection by SARS-CoV-2. Fulminant necrotizing eosinophilic myocarditis is an extremely rare hypersensitivity syndrome caused by various drugs and vaccines. Further, in approximately 25 % of cases of fulminant necrotizing eosinophilic myocarditis, no eosinophilia is found in the blood or other organs [
]. In this case, myocardial histology was accompanied by a prominent eosinophilic infiltrate, which was extremely different from that of a typical viral cardiomyopathy [
]. In addition, no elevated levels of eosinophils in the peripheral blood and no histological findings of eosinophilic vasculitis were found at autopsy. After reviewing previous reports on mRNA COVID-19 vaccine-associated myocarditis, it seemed likely that hypersensitivity myocarditis was caused by the BNT162b2 COVID-19 vaccine [
First identified case of fatal fulminant eosinophilic myocarditis following the initial dose of the Pfizer-BioNTech mRNA COVID-19 vaccine (BNT162b2, Comirnaty): an extremely rare idiosyncratic hypersensitivity reaction.
Even if myocarditis occurs after mRNA COVID-19 vaccination, most cases are mild, and the benefits of vaccination are reported to outweigh the disadvantages of nonvaccination [
]. However, a small percentage of severe cases may occur, and its frequency is unknown at present. We experienced a case that is instructive in considering myocarditis after mRNA COVID-19 vaccination. Additional evidence is required because of the limited information on the mRNA COVID-19 vaccine.
Patient permission/consent statement
We warmly thank the patient's family for permitting the publication of his case.
CRediT authorship contribution statement
Naoaki Onishi wrote the manuscript and Kazuaki Kaitani critically revised it. Yuki Konishi, Toshiyuki Kaneko, Naohiro Maekawa, Akihira Suenaga, Shinnosuke Nomura, Takayasu Kobayashi, Shokan Kyo, Marie Okabayashi, Hirooki Higami, Maki Oi, Nobuya Higashitani, Sayaka Saijo, Fumiko Nakazeki, Naofumi Oyamada, and Toshikazu Jinnai critically read the manuscript, especially in the description of the clinical course part. Tomoko Okuno and Tomoyuki Shirase critically revised the manuscript especially in the description of the pathology part.
First identified case of fatal fulminant eosinophilic myocarditis following the initial dose of the Pfizer-BioNTech mRNA COVID-19 vaccine (BNT162b2, Comirnaty): an extremely rare idiosyncratic hypersensitivity reaction.
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