The coronavirus disease 2019 (COVID-19) pandemic, which started in January 2020 has affected people worldwide. Rapid vaccine development has enabled COVID-19 prevention. Two mRNA COVID-19 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) demonstrated safety and efficacy in clinical trials, and were granted emergency use authorization by the US Food and Drug Administration in December 2020.12 As the number of people vaccinated against COVID-19 has increased, there have been multiple reports of myocarditis as an adverse event following immunization,3456789101112 which was not observed in clinical trials.

Myocarditis is histologically characterized by diffuse and/or focal inflammatory infiltrates within myocardial tissue, accompanied by myocyte damage without evidence of ischemia.13 Little is known about the histopathological characteristics of myocarditis following COVID-19 vaccination because endomyocardial biopsy is not a routine procedure for myocarditis and, due to its generally favorable prognosis,8 opportunities for autopsy studies are rare.10

We recently observed a case of sudden cardiac death in a young male six days after receiving the first dose of the BNT162b2 mRNA vaccine and report the distinctive clinical and pathological findings of this case.

The deceased was 22-year-old male military recruit. His blood pressure was elevated on physical examination 17 and 7 months before his death (156/94 mmHg and 128/74 mmHg, respectively), but he was otherwise healthy. On June 13, 2021, 5 days after the first dose of BNT162b2 mRNA vaccination, he complained to a colleague of chest pain at 1:00 AM, during a smoke break, and went to bed. At 8:00 AM, he was found unconscious hunched beside the bed. He was taken to an emergency department and was found to have ventricular fibrillation on electrocardiography. Cardiopulmonary resuscitation was performed for two hours, but he could not be resuscitated.

An autopsy was performed 24 hours after his death. The deceased was well-nourished with no visible injuries on external examination. The heart weighed 470 g and had multiple petechiae on its surface. The pericardium was smooth with no fibrin deposition or exudate. The coronary arteries were patent, and the heart valves were unremarkable. The myocardium was of normal thickness and there was no dilation of the atria or ventricles. The myocardium was homogeneously brown with no obvious necrosis or fibrosis. On microscopic examination, diffuse inflammatory infiltration, with neutrophil and histiocyte predominance, was observed within the myocardium (Fig. 1A). Notably, the inflammatory infiltrates were dominant in the atria (Fig. 1A and B), and around the sinoatrial (SA) and atrioventricular (AV) nodes (Fig. 1C), whereas ventricular area displayed minimal or no inflammatory cells (Fig. 1D). Occasional myocyte necrosis or degeneration was found adjacent to the inflammatory infiltrates, without abscess formation or bacterial colonization. There was also scattered single-cell necrosis of myocytes without accompanying inflammation. Multiple scattered foci of contraction band necrosis (CBN) was identified throughout the myocardium, predominantly in the left ventricle. No other specific pathological changes were found in the lung, liver, kidney, spleen, pancreas, or brain on macroscopic or microscopic examination.

Masson's trichrome staining highlighted dense eosinophilic intracellular strips of myocytes, consistent with CBN (Fig. 1B and D). CD68 and CD3 immunostaining showed a moderate number of histiocytes and sparse lymphocytes in the inflammatory infiltrates (Fig. 2A and B). Degenerated or ischemic myocytes exhibited positive C4d immunoreactivity (Fig. 2C).

The cause of death was determined to be myocarditis. Given that the myocarditis showed a temporal relationship to vaccine administration and there was no other explanation for the sudden cardiac death, on July 26, 2021, Korea Centers for Disease Control and Prevention acknowledged that myocarditis and vaccination were “possibly related” in this case.

There were three main histological findings in the heart: 1) myocarditis predominantly involving the atrial wall, with neutrophil and histiocyte predominance; 2) non-inflammatory single-cell necrosis; and 3) diffuse CBN throughout the myocardium, predominantly in the left ventricle. These pathological findings were not evident on macroscopic examination. The only abnormal gross finding was cardiac enlargement, which may have been secondary to hypertension.

In this case, the myocarditis was histologically different from viral or immune-mediated myocarditis in that the inflammatory infiltrates were predominantly neutrophils and histiocytes, rather than lymphocytes. Multinucleated giant cells were not observed. The area of myocarditis was confined to the atrial wall, but the ventricles were free of cellular infiltration. Inflammatory cells were also present in the SA and AV nodes. Myocyte necrosis or degeneration was observed adjacent to the inflammatory infiltrates. Neutrophil infiltration of the myocardium is an uncommon histological type of myocarditis, and is generally observed in immunocompromised patients with bacterial infection.14 The deceased was previously healthy and there were no signs of infective myocarditis. Dissemination of infective endocarditis and pneumonia were also excluded. The underlying mechanism of myocardial injury in this case is unclear, but it may have involved cytokine-mediated or histiocyte-linked immunologic injury to the myocardium. Isolated atrial myocarditis is very rare and thus is an unfamiliar disease entity to pathologists. To our knowledge, only two case reports of sudden cardiac death caused by isolated atrial myocarditis have been published previously.1516 Previous reports noted that atrial myocarditis may be overlooked on postmortem examination because sampling of atrium is not routinely performed. In the present case, extensive myocardial sampling enabled accurate diagnosis. A total of 35 sections were examined (25 sections of ventricular and atrial myocardium and 10 sections of the conduction system) and 9 sections had evidence of myocarditis. Myocarditis is usually not apparent on gross examination. Even if the heart is grossly unremarkable, pathologists should examine a sufficient number (≥ 10) of atrial and ventricular sections in order not to overlook or misdiagnose the cause of death, especially if the deceased had myocarditis symptoms and a recent mRNA vaccination history.

Notably, single-cell necrosis (or single-cell ischemia) of myocytes without inflammation was observed in multiple sites throughout the atria. Several autopsy studies of the cardiovascular pathological findings of individuals who died of COVID-19 have also found single-cell necrosis, and this might be a distinctive pathological characteristic of COVID-19.171819 Thus, myocardial injury due to COVID-19 vaccination may histologically present not only as myocarditis, but also as scattered single-cell necrosis, similar to myocardial lesions of COVID-19.

Another major histological finding was abundant CBN throughout the myocardium, especially in the left ventricle. CBN is usually observed after irreversible myocyte injury and is associated with ischemic heart disease or a catecholamine excess state.20 The CBN in this case was extensive throughout the ventricular myocardium and we are cautious about drawing a conclusion about the causality. The association between the CBN and COVID-19 vaccination is unclear. The CBN may have occurred as a result of ventricular fibrillation or catecholamine administration during resuscitation. There was no evidence of coronary atherosclerosis or microthrombosis, which could explain the presence of CBN.

We were able to find only one previously published case report of a death due to myocarditis after COVID-19 vaccination with a comprehensive clinicopathological analysis. Verma et al.10 reported the case of a 42-year-old man, who presented with chest pain and dyspnea 2 weeks after the second dose of mRNA-1273 vaccination, and died 3 days after symptom onset. On microscopic examination, myocyte damage with a mixed inflammatory infiltrate of macrophages, lymphocytes, and eosinophils was observed in the myocardium of both ventricles, whereas the atria showed no evidence of myocarditis. In contrast, our case patient developed symptoms 5 days after the first dose of the BNT162b2 mRNA vaccine and died 7 hours later, and showed isolated atrial myocarditis with neutrophil and histiocyte predominance. The histopathological features described in Verma et al.'s report10 did not include CBN or single-cell necrosis of myocytes. This suggests that myocarditis after COVID-19 mRNA vaccination is heterogenous, both clinically and histologically.

The demographic and clinical characteristics of myocarditis after mRNA vaccination in previous reports are summarized in Table 1. Vaccine-associated myocarditis has been reported predominantly in young males after the second vaccination. Myocarditis was mainly diagnosed clinically based on elevated serum troponin and cardiac magnetic resonance imaging, and all patients except our and the patient reported by Verma et al.10 recovered after receiving supportive care. The patient in this case showed similar clinical features, which supports a potential association between vaccination and myocarditis. However, given that other reported myocarditis cases were generally mild and the symptoms usually developed after the second vaccination, the clinical course of our case (sudden death 6 days after the first vaccination) is an extremely rare event. Considering the short time interval between the onset of the deceased patient's symptoms and his sudden death, the immediate cause of death was possibly an arrhythmia, rather than heart failure.

This is the first case in South Korea that the Korea Centers for Disease Control and Prevention acknowledged the causality of COVID-19 vaccination and myocarditis. This unique case provides an example of a serious adverse event following COVID-19 mRNA vaccination. It is unknown whether this case is related to the vaccine type or to a specific vaccine component. It is also unclear whether the location (atrium), type of inflammation (neutrophils and histiocytes), CBN, and single-cell necrosis without inflammation are specific characteristics of COVID-19 vaccine-associated myocarditis. Comprehensive clinical and pathological evaluation of additional cases is needed to clarify the relationship between COVID-19 vaccination and myocarditis.