Response to: Szuster‐Ciesielska, letter to the editor regarding ‘Autopsy findings in cases of fatal COVID‐19 vaccine‐induced myocarditis’

COVID‐19 vaccines have been linked to myocarditis, which, in some circumstances, can be fatal. This systematic review aims to investigate potential causal links between COVID‐19 vaccines and death from myocarditis using post‐mortem analysis. We performed a systematic review of all published autopsy reports involving COVID‐19 vaccination‐induced myocarditis through 3 July 2023. All autopsy studies that include COVID‐19 vaccine‐induced myocarditis as a possible cause of death were included. Causality in each case was assessed by three independent physicians with cardiac pathology experience and expertise. We initially identified 1691 studies and, after screening for our inclusion criteria, included 14 papers that contained 28 autopsy cases. The cardiovascular system was the only organ system affected in 26 cases. In two cases, myocarditis was characterized as a consequence from multisystem inflammatory syndrome. The mean age of death was 44.4 years old. The mean and median number of days from last COVID‐19 vaccination until death were 6.2 and 3 days, respectively. We established that all 28 deaths were most likely causally linked to COVID‐19 vaccination by independent review of the clinical information presented in each paper. The temporal relationship, internal and external consistency seen among cases in this review with known COVID‐19 vaccine‐induced myocarditis, its pathobiological mechanisms, and related excess death, complemented with autopsy confirmation, independent adjudication, and application of the Bradford Hill criteria to the overall epidemiology of vaccine myocarditis, suggests that there is a high likelihood of a causal link between COVID‐19 vaccines and death from myocarditis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced myocarditis is a rare but well-documented complication in young males. The increased incidence of sudden death among athletes following vaccination has been reported and requires further investigation. Whether the risk of myocarditis, a known major cause of sudden death in young male athletes, also increases after coronavirus disease 2019 (COVID-19) infection is unknown. The severity and implications of these critical adverse effects require a thorough analysis to elucidate their key triggering mechanisms. The present review aimed to evaluate whether there is a justification to hypothesize that catecholamines in a “hypercatecholaminergic” state are the key trigger of SARS-CoV-2 mRNA vaccine-induced myocarditis and related outcomes and whether similar risks are also present following COVID-19 infection. A thorough, structured scoping review of the literature was performed to build the hypothesis through three pillars: detection of myocarditis risk, potential alterations and abnormalities identified after SARS-CoV-2 mRNA vaccination or COVID-19 infection and consequent events, and physiological characteristics of the most affected population. The following terms were searched in indexed and non-indexed peer review articles and recent preprints (<12 months): agent, “SARS-CoV-2” or “COVID-19”; event, “myocarditis” or “sudden death(s)” or “myocarditis+sudden death(s)” or “cardiac event(s)”; underlying cause, “mRNA” or “spike protein” or “infection” or “vaccine”; proposed trigger, “catecholamine(s)” or “adrenaline” or “epinephrine” or “noradrenaline” or “norepinephrine” or “testosterone”; and affected population, “young male(s)” or “athlete(s).” The rationale and data that supported the hypothesis were as follows: SARS-CoV-2 mRNA vaccine-induced myocarditis primarily affected young males, while the risk was not observed following COVID-19 infection; independent autopsies or biopsies of patients who presented post-SARS-CoV-2 mRNA vaccine myocarditis in different geographical regions enabled the conclusion that a primary hypercatecholaminergic state was the key trigger of these events; SARS-CoV-2 mRNA was densely present, and SARS-CoV-2 spike protein was progressively produced in adrenal medulla chromaffin cells, which are responsible for catecholamine production; the dihydroxyphenylalanine decarboxylase enzyme that converts dopamine into noradrenaline was overexpressed in the presence of SARS-CoV-2 mRNA, leading to enhanced noradrenaline activity; catecholamine responses were physiologically higher in young adults and males than in other populations; catecholamine responses and resting catecholamine production were higher in male athletes than in non-athletes; catecholamine responses to stress and its sensitivity were enhanced in the presence of androgens; and catecholamine expressions in young male athletes were already high at baseline, were higher following vaccination, and were higher than those in non-vaccinated athletes. The epidemiological, autopsy, molecular, and physiological findings unanimously and strongly suggest that a hypercatecholaminergic state is the critical trigger of the rare cases of myocarditis due to components from SARS-CoV-2, potentially increasing sudden deaths among elite male athletes.

To the editor, We read with interest the letter by Dr. Gül and Dr. Öztürk, 1 which comments about the previous letter by Dr. Polykretis. 2 The letter by Dr. Polykretis aimed to underline the differences between the genetic vaccines against COVID‐19 and vaccines based on inactivated or attenuated viruses in terms of immunization mechanism. Moreover, and most importantly, it sought to emphasize the necessity of biodistribution studies in front of the numerous publications reporting on a variety of serious adverse events among vaccinees. 2 Considering that some pharmaceutical companies, such as Pfizer/BioNTech, had ‘to move at the speed of science, to really understand what is taking place in the market’ to release the vaccines (as declared later on by Janine Small, President of International Developed Markets, to the European Parliament on Monday, October 10th, 2022), there is nothing of scientifically despicable or misleading in seeking for the collection of more accurate data about biodistribution. Dr. Gül and Dr. Öztürk accuse the letter by Dr. Polykretis of being ‘misinforming’ and of containing some ‘basic errors’, arguing on the definitions of genetic vaccines and autoimmunity. We would like to address on both cases. Regarding the definition of genetic vaccines, the letter by Dr. Polykretis is not misleading, as scientific literature reports that: ‘gene vaccines are a new approach to immunization and immunotherapy in which, rather than a live or inactivated organism (or a subunit thereof), one or more genes that encode proteins of the pathogen are delivered’. 3 As concerns the term autoimmunity, the Merriam‐Webster medical dictionary it defines it as: ‘a condition in which the body produces an immune response against its own tissue constituents’. Therefore, it is not misinforming or erroneous to define autoimmune reaction the response of the immune system against human cells that intake the lipid nanoparticles (LNPs) and translate the spike protein (in case of the mRNA vaccines), or that get infected by the adenovirus and express and translate the spike protein (in case of the adenovirus‐based vaccines). Regarding the fact that even the ‘traditional vaccines’ cause the immune system to respond by attacking self‐cells during the immunization process, there are some fundamental aspects that should be underlined: (i) The vaccines based on inactivated or killed viruses involve principally presentation to antigen presenting cells (APCs) including macrophages, monocytes, B cells and dendritic cells that phagocytose the virus particles and present the viral antigens to CD4+ T‐cells. The aforementioned classes of cells carry out this specific role within the organism, making them somewhat expendable, as there is a continuous turnover of such cells. (ii) The attenuated viruses have a reduced virulence and thus, the resulting infection involves a minor number of human cells. Instead, several sources of histopathological evidence demonstrate that the genetic vaccines exhibit an off‐target distribution in tissues, which are terminally differentiated and subject to symptomatic injury. These include the heart and brain, which may sustain a massive production of spike protein which elicits a strong autoimmunological inflammatory response. 4 , 5 The above mentioned histopathological findings confirm exactly the mechanism previously theorized by Dr. Polykretis: “For instance, if the mRNA contained in the LNPs would get internalized by cardiac myocytes, and such cells would produce the spike protein, the resulting inflammation would likely lead to the necrosis of the myocardium, with an extent proportional to the number of involved cells”. 2 An independent secondary analysis of serious adverse events reported in phase III clinical trials of Pfizer and Moderna, found that the mRNA vaccines combined were associated with an excess risk of serious adverse events of 1 per 800 vaccinated individuals. 6 Nevertheless, indiscriminate COVID‐19 vaccination has been expanded to include age groups and naturally immune with minimal chance of suffering major complications due to COVID‐19. In these groups COVID‐19 vaccination is not clinically indicated nor medically necessary. According to a large‐scale risk‐benefit analysis, between 31 207 and 42 836 young adults aged 18‐29 years would need to receive a third mRNA vaccine dose to prevent one COVID‐19 hospitalization over a course of six months. 7 The authors estimate that at least 18.5 serious adverse events could occur for every COVID‐19 hospitalization prevented. From January 2021 to the time of writing, 1598 athletes suffered cardiac arrest, 1101 of which with deadly outcome. 8 Notably, in a 38‐years timespan (1966‐2004), 1101 athletes under the age of 35 died (~29/years) due to various heart‐related conditions, 50% of whom had congenital anatomical heart disease and cardiomyopathies and 10% had atherosclerotic heart disease with early onset. 9 According to a study done on 301 teenagers between the ages of 13 and 18 who had received two doses of the Pfizer/BioNTech vaccine, 29.24% of participants experienced cardiovascular complications such tachycardia, palpitations and 2.33% suffered myopericarditis. 10 It is noteworthy, that no statistically significant increase in the incidence of myocarditis or pericarditis was observed in un‐vaccinated subjects after SARS‐CoV‐2 infection, in a large population study. 11 Since the end of 2021 and throughout 2022, young age excess mortality has substantially increased in many European countries (Figure 1), in concert with the vaccine program. 12 FIGURE 1 Graph showing the excess mortality in the age group 0–14 until week 2022–51, generated with data from 27 participating European countries (EuroMOMO 2022). In conclusion we thank our colleagues for advancing the discourse on the extremely concerning safety data after COVID‐19 vaccination, which prompt us to emphasize again and more firmly the need of biodistribution studies as well as of rational harm‐benefit assessments by age group. CONFLICT OF INTEREST The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.