Myocarditis and pericarditis are inflammatory conditions of the heart that present a range of symptoms, often including chest pain, fatigue, breathlessness and palpitations that may be irregular due to cardiac rhythm disturbances. Myocarditis has been proposed to account for a fraction of cardiac injury among patients infected with SARS-CoV-2 and associated systemic inflammation; and it might be one of the reasons for the high mortality seen in COVID-19 patients. Furthermore, following vaccination with mRNA COVID-19 vaccines (ie, Comirnaty and Spikevax), myocarditis and pericarditis can develop within a few days of vaccination, particularly following the second dose. Based on recent reviewed data, the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have determined that the risk for both of these conditions is overall ‘very rare’ (~1 in 10 000 vaccinated people may be clinically affected), with the highest risk among younger males. Both EMA and FDA agree that the benefits of all authorised COVID-19 vaccines continue to outweigh their risks, given the threat of serious COVID-19 illness and related complications. Since myocarditis has a very wide clinical spectrum, ranging from mild to fulminant life-threatening disease, we present in this review a sum of the latest findings and considerations for the proper diagnosis and management of affected patients.

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Acute myocarditis caused by COVID-19 disease and following COVID-19 vaccination

Myocarditis and pericarditis have been reported after COVID‐19 vaccine administration in children and adolescents, raising the concern about their possible association with these vaccines. The objective was to explore the incidence, clinical presentation, and association of myocarditis and pericarditis with COVID‐19 vaccines in children and adolescents. We conducted a systematic literature search on three databases, that is, Cochrane, MEDLINE/PubMed, and EMBASE from inception till March 2022. A total of three case reports, four case series, and six observational studies were included in the review. For case reports and case series, the mean age of the patients was 17.4 years, with 96.9% being male. Chest pain (n = 31, 93.9%), fever (n = 18, 54.5%), myalgias (n = 15, 45.4%) and headache (n = 9, 27.2%) were the most common presentations. Out of 33 patients, 32 (96.9%) of patients received Pfizer‐BioNTech whereas only one (3.03%) received Moderna (mRNA 1273). Clinical investigations revealed ST elevation (n = 32, 97%), and elevated CRP (n = 9, 27.2%) and cardiac troponin (n = 29, 87.8%). The pooled incidence of myocarditis and pericarditis from observational studies was (0.00063%) and (0.000074%) %, respectively. Myocarditis and pericarditis in children and adolescents after the COVID‐19 vaccines were more prevalent among males and more commonly observed after the second dose of Pfizer. Though the overall incidence was low, however, the clinicians should consider myocarditis and pericarditis as probable diagnosis when encountering young patients, with a history of vaccine administration, presenting with suggestive findings.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/clc.23965

Development of myocarditis and pericarditis after COVID‐19 vaccination in children and adolescents: A systematic review

Antibody-dependent enhancement (ADE) has been shown previously for SARS-CoV-1, MERS-CoV, and SARS-CoV-2 infection in vitro. In this study, the first monoclonal antibody (mAb) that causes ADE in a SARS-CoV-2 in vivo model was identified. mAb RS2 against the SARS-CoV-2 S-protein was developed using hybridoma technology. mAb RS2 demonstrated sub-nanomolar affinity and ability to neutralize SARS-CoV-2 infection in vitro with IC50 360 ng/mL. In an animal model of SARS-CoV-2 infection, the dose-dependent protective efficacy of mAb RS2 was revealed. However, in post-exposure prophylaxis, the administration of mAb RS2 led to an increase in the viral load in the respiratory tract of animals. Three groups of blood plasma were examined for antibodies competing with mAb RS2: (1) plasmas from vaccinated donors without COVID-19; (2) plasmas from volunteers with mild symptoms of COVID-19; (3) plasmas from patients with severe COVID-19. It was demonstrated that antibodies competing with mAb RS2 were significantly more often recorded in sera from volunteers with severe COVID-19. The results demonstrated for the first time that in animals, SARS-CoV-2 can induce antibody/antibodies that can elicit ADE. Moreover, in the sera of patients with severe COVID-19, there are antibodies competing for the binding of an epitope that is recognized by the ADE-eliciting mAb.

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Antibodies Capable of Enhancing SARS-CoV-2 Infection Can Circulate in Patients with Severe COVID-19

The widespread use of Covid-19 mRNA vaccines has highlighted the need to address rare but concerning side effects. Systemic off-target gene expression has been identified as a primary cause of acute adverse reactions and side effects associated with nucleoside-modified mRNA vaccines. In this study, we incorporated the permanent cationic lipid Dotap component into the mRNA-LNP formula associated with the FDA-approved mRNA vaccine Comirnaty to create a novel positively charged LNP carrier for mRNA vaccine delivery. Using the optimized LNP formula to prepare SARS-Cov-2 Spike mRNA vaccines for immunogenicity testing, Balb/c mice exhibited improved immunogenicity kinetics with initial antibody titers being lower but showing a continuous upward trend, ultimately reaching levels comparable to those of control mRNA vaccines 8 weeks after boost immunization. The mRNA vaccines encapsulated in the modified LNPs have demonstrated a superior safety profile in respect to systemic delivery of LNP constituents, off-target gene expression, and the systemic pro-inflammatory stimulation. Consequently, it may represent a safer alternative of conventional mRNA-LNP vaccines.

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Improving mRNA vaccine safety and efficiency with cationized lipid nanoparticle formula

More than 3 years have passed since the emergence of COVID-19. On 8 May 2023, COVID-19 in Japan was downgraded to Category 5 by the Infectious Disease Control Law. In Japan, at the beginning of the COVID-19 pandemic in 2020, cases of infection and deaths from severe disease were few compared with those in Western countries. However, in the medical field, screening for COVID-19 was given top priority, resulting in confusion and proving disadvantageous for many patients. The overreaction to COVID-19 as the most important issue in society can be attributed largely to statements by infectious disease experts. In addition, the mRNA vaccine emerged in 2021, and most of the population was vaccinated up to two times within a short period of less than 1 year because infectious disease experts strongly promoted vaccination. After 2022, when vaccination progressed and the Omicron strain, which is an attenuated strain, became the mainstay of SARS-CoV-2, the number of severe cases of COVID-19 decreased significantly; however, the number of infected people increased dramatically instead. A significant portion of the population is thought to have hybrid immunity due to vaccination plus natural infection and maintains high antibody titer levels. Henceforth, additional vaccination should be given preferentially to those who will benefit most from it. Conversely, measures against COVID-19 caused serious damage to the economy and society. Policies that not only address countermeasures against infection, but also those that encompass the economy and society as a whole, are necessary.

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COVID-19 and the COVID-19 Vaccine in Japan—A Review from a General Physician’s Perspective

Myocarditis is now recognized as a rare complication of coronavirus disease 2019 (COVID-19) mRNA vaccination, particularly in adolescent and young adult males. Since the authorization of the Pfizer-BioNTech™ and Moderna™ mRNA vaccines targeting the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein, the Centers for Disease Control and Prevention (CDC) has reported 1175 confirmed cases of myocarditis after COVID-19 vaccination in individuals ages 30 years and younger as of January 2022. According to CDC data in June 2021, the incidence of vaccine-mediated myocarditis in males ages 12-29 years old was estimated to be 40.6 cases per million second doses of COVID-19 mRNA vaccination administered. Individuals with cases of COVID-19 vaccine-mediated myocarditis typically present with acute chest pain and elevated serum troponin levels, often within one week of receiving the second dose of mRNA COVID-19 vaccination. Most cases follow a benign clinical course with prompt resolution of symptoms. Proposed mechanisms of COVID-19 vaccine myocarditis include molecular mimicry between SARS-CoV-2 spike protein and self-antigens and the triggering of preexisting dysregulated immune pathways in predisposed individuals. The higher incidence of COVID-19 vaccine myocarditis in young males may be explained by testosterone and its role in modulating the immune response in myocarditis. There is limited data on long-term outcomes in these cases given the recency of their occurrence. The CDC continues to recommend COVID-19 vaccination for everyone 5 years of age and older given the greater risk of serious complications related to natural COVID-19 infection including hospitalization, multisystem organ dysfunction, and death. Further study is needed to better understand the immunopathology and long-term outcomes behind COVID-19 mRNA vaccine-mediated myocarditis.

COVID-19 vaccine-associated myocarditis

There is a growing evidence of cardiovascular complications in coronavirus disease 2019 (COVID-19) patients. As evidence accumulated of COVID-19 mediated inflammatory effects on the myocardium, substantial attention has been directed towards cardiovascular imaging modalities that facilitate this diagnosis. Cardiac magnetic resonance imaging (CMRI) is the gold standard for the detection of structural and functional myocardial alterations and its role in identifying patients with COVID-19 mediated cardiac injury is growing. Despite its utility in the diagnosis of myocardial injury in this population, CMRI's impact on patient management is still evolving. This review provides a framework for the use of CMRI in diagnosis and management of COVID-19 patients from the perspective of a cardiologist. We review the role of CMRI in the management of both the acutely and remotely COVID-19 infected patient. We discuss patient selection for this imaging modality; T1, T2, and late gadolinium enhancement imaging techniques; and previously described CMRI findings in other cardiomyopathies with potential implications in COVID-19 recovered patients.

Role of cardiac magnetic resonance imaging in the diagnosis and management of COVID-19 related myocarditis: Clinical and imaging considerations.

Myocarditis is now recognized as a rare complication of coronavirus disease 2019 (COVID-19) mRNA vaccination, particularly in adolescent and young adult males. Since the authorization of the Pfizer-BioNTech™ and Moderna™ mRNA vaccines targeting the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein, the Centers for Disease Control and Prevention (CDC) has reported 1175 confirmed cases of myocarditis after COVID-19 vaccination in individuals ages 30 years and younger as of January 2022. According to CDC data in June 2021, the incidence of vaccine-mediated myocarditis in males ages 12-29 years old was estimated to be 40.6 cases per million second doses of COVID-19 mRNA vaccination administered. Individuals with cases of COVID-19 vaccine-mediated myocarditis typically present with acute chest pain and elevated serum troponin levels, often within one week of receiving the second dose of mRNA COVID-19 vaccination. Most cases follow a benign clinical course with prompt resolution of symptoms. Proposed mechanisms of COVID-19 vaccine myocarditis include molecular mimicry between SARS-CoV-2 spike protein and self-antigens and the triggering of preexisting dysregulated immune pathways in predisposed individuals. The higher incidence of COVID-19 vaccine myocarditis in young males may be explained by testosterone and its role in modulating the immune response in myocarditis. There is limited data on long-term outcomes in these cases given the recency of their occurrence. The CDC continues to recommend COVID-19 vaccination for everyone 5 years of age and older given the greater risk of serious complications related to natural COVID-19 infection including hospitalization, multisystem organ dysfunction, and death. Further study is needed to better understand the immunopathology and long-term outcomes behind COVID-19 mRNA vaccine-mediated myocarditis. Original article: Morgan MC, Atri L, Harrell S, Al-Jaroudi W, Berman A. COVID-19 vaccine-associated myocarditis. World J Cardiol. 2022;14(7):382-391. DOI: 10.4330/wjc.v14.i7.382. The article was translated into Russian and published under the terms of the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license.

COVID-19 vaccine-associated myocarditis (Russian translation)

Background: As part of a curricular change, an academic medical center implemented a medical student telemedicine clinical experience for first-year medical students in October 2020. This research is a process evaluation of the implementation of a preclerkship medical student telemedicine clinical experience. Methods: Patients with two or more chronic diseases were recruited from affiliated primary care practices. We monitored the recruitment and retainment of patients throughout the curriculum. We used surveys to evaluate patient, student, and primary care overall experience with the program. We tracked referrals to higher levels of care and assessed skills students' felt they practice with each encounter. We followed progression of notes through chart review as the year progressed. Results: Of the 408 patients contacted, 150 agreed to participate in this program (36%). Of 1,053 scheduled visits, 686 (65%) were successfully completed. Seventy-five percent of patients were seen two or more times. Nearly 70% of surveyed patients felt that the clinical experience enhanced their communication with their primary care provider, and nearly 90% stated that students were "somewhat" or "extremely" professional. The majority (97%) of students reported an "excellent" or "good" view of the medical student telemedicine clinical experience. Qualitative measures of student performance, such as note writing, showed improvement over the course of the curriculum. Conclusions: Our data suggest that patients, students, and primary care providers were widely accepting of the curriculum, patients were successfully recruited and retained, and students successfully practiced key clinical skills on a telemedicine platform.

Lavannya Atri

Papers

COVID-19 vaccine-associated myocarditis

Role of cardiac magnetic resonance imaging in the diagnosis and management of COVID-19 related myocarditis: Clinical and imaging considerations.

COVID-19 vaccine-associated myocarditis (Russian translation)

Implementation of a Telemedicine Student Clinical Experience.

S2369 Rare Chest Pain Presentation of Esophageal Intramural Pseudodiverticulosis in AIDS Patient