The etiology of perimyocarditis can be categorized as infectious or non-infectious. In the developed world, viral infections remain the most common cause for developing both myocarditis and pericarditis [1]. The occurrence of perimyocarditis from a viral infection is secondary to direct cytotoxicity from the virus, impacting both the pericardium and myocardium. Within the subcategory of non-infectious causes, medications, immune-mediated diseases, and vaccine-associated myocarditis have been reported [1, 2].

Vaccine-associated myopericarditis involves signs and symptoms of myopericarditis within 30 days of a vaccine in the absence of other pathology [2]. Most cases of vaccine-associated myopericarditis have been reported following smallpox vaccination; however, isolated case reports have linked myopericarditis to the Tdap vaccine, varicella vaccine, and the influenza vaccine [3, 4].

Our patient developed acute perimyocarditis three days after receiving his first dose of the Moderna vaccine. The emergency use authorization for the Moderna vaccine was issued in December, 2020. Clinical trials have demonstrated 94.1% efficacy of the vaccine in preventing COVID-19 illness, including severe disease with a strong safety profile [5].

The mRNA-1273 vaccine is composed of a modified mRNA encoding the spike protein of SARS-CoV-2, and when incorporated, directs the cell to synthesize spike protein. Immune cells then detect the COVID spikes and develop protective antibodies to prevent viral replication [5]. While this represents a newer vaccine approach, mRNA vaccines do not cause COVID-19 as the mRNA breaks down quickly in the cell and the vaccine encodes only a part of the complete virion. However, in the absence of a prior large-scale mRNA vaccine utilization, adverse events are difficult to predict. Isolated cases have been reported which described predominately young, healthy males who developed acute myocarditis following COVID-19 mRNA vaccination. Patients typically developed symptoms within days of receiving the second dose of their vaccine or, as seen in our case, the first dose in patients who were previously infected with COVID-19 [6,7,8]. Fortunately, the disease course of these patients was mild and recovered without major complications.

Our patient denied any hypersensitivity reactions to previous vaccines. However, his immune system may have been primed from his earlier SARS-CoV-2 exposure during mild COVID-19 disease, which may have precipitated his clinical presentation. An ongoing clinical study comparing reactogenicity between patients previously infected with SARS-CoV-2 versus naïve individuals found that the former experienced systemic side effects (i.e., fatigue, headache, and chills) with higher frequency. SARS-CoV-2 spike IgG titers before and after first dose of an mRNA vaccine (either Moderna or Pfizer) was also studied. Sampling found that patients with previous COVID-19 disease had antibody titers 10 to 45 times higher compared to those without previous infection [9]. The ZOE Covid Symptom Study, a smartphone application, also has a dataset where participants log their symptoms from COVID-19 itself to symptoms post-vaccination. They found participants previously infected with COVID-19 experienced more systemic adverse effects than naïve participants (33 % vs. 19 %) [10].

The pathophysiology of vaccine-associated myocarditis is not well defined. However, in COVID-19 myocardial inflammation, SARS-CoV-2 utilizes the spike protein to bind to a membrane-bound form of angiotensin-converting enzyme 2 (ACE2), facilitating intracellular uptake. Cardiovascular tissues express a large proportion of ACE2 receptors and therefore become a target for viral replication and direct viral injury [11, 12]. Naive T lymphocytes can be subsequently primed through viral antigens, and potentially self proteins released from damaged cardiomyocytes, via antigen-presenting cells. Uncommonly, this can lead to primed T-lymphocyte migration to cardiovascular tissues, cell-mediated cytotoxicity, and lymphocytic myocarditis [13]. Pro-inflammatory cytokines are then released which augments T-lymphocyte activation and furthers damage [11]. We propose that our patient’s initial SARS-CoV-2 infection primed T-lymphocytes against both SARS-CoV-2 proteins and cardiac antigens released during sub-clinical myocardial inflammation during his initial infection. His first dose of the Moderna vaccine may have reactivated this intrinsic immune response, subsequently resulting in myocardial injury. It’s also worth noting early serologic data found patients with prior natural infection developed higher antibody titers following first dose of an mRNA vaccine. This could represent an alternative vaccine related immune mechanism which could predispose patients with prior COVID-19 infection to a higher incidence of myocarditis compared to naïve patients. Obviously, the mechanism of COVID-19 vaccine associated myocarditis will require further study for conclusive definition.

As our patient remained clinically stable, he did not require endomyocardial biopsy during his hospitalization. He was treated with aspirin and colchicine as anti-inflammatory therapy remains the cornerstone of treatment for acute pericarditis [14]. His imaging showed no signs of ventricular dysfunction so he was not started on guideline-directed medical therapy for heart failure. In the setting of his acute myocarditis we elected to start metoprolol to help prevent heart failure, life-threatening arrythmias, and also limit ‘mechanical inflammation’ [15]. In addition, we recommended abstinence from strenuous activity to decrease risk of remodeling and sudden death as well [16]. While the benefits of vaccination are substantial, given the hypersensitivity myocarditis he suffered following the first dose of the Moderna vaccine and lack of information available at the time, after a patient-centered discussion he elected to forego the second dose of the vaccine.