The Aftermath of COVID-19: Exploring Long-Term Effects on the Organ Systems (preprint)

Background: Post-acute sequelae of SARS-CoV-2 infection (PASC) is a complicated disease that affects millions of people all over the world. Previous studies have shown that PASC impacts 10% of SARS-CoV-2 infected patients of which 50-70% are hospitalized. It has also been shown that 10-12% of those vaccinated against COVID-19 were affected with PASC and its complications. The severity and the later development of PASC symptoms is positively associated with the early intensity of the infection. Results: The generated health complications caused by PASC involve a vast variety of organ systems. Patients affected by PASC have been diagnosed with neuropsychiatric and neurological symptoms. Cardiovascular system also has been involved and several diseases such as myocarditis, pericarditis, and coronary artery diseases were reported. Chronic hematological problems such as thrombotic endothelialitis and hypercoagulability were described as a condition that could increase the risk of clotting disorders and coagulopathy in PASC patients. Chest pain, breathlessness, and cough in PASC patients were associated with respiratory system in long COVID-19 causing respiratory distress syndrome. The observed immune complications were notable, involving several diseases. Renal system also was impacted and result in raising the risk of diseases such as thrombotic issues, fibrosis, and sepsis. Endocrine gland malfunction can lead to diabetes, thyroiditis, and male infertility. Symptoms such as diarrhea, nausea, loss of appetite and taste were also among reported observations due to several gastrointestinal disorders. Skin abnormalities might be an indication of infection and long-term implications such as persistent cutaneous complaints were linked to PASC. Conclusions: Long COVID is a multidimensional syndrome with considerable public health implications, affecting several physiological systems and demanding thorough medical therapy as well as more study to address its underlying causes and long-term effects.

Improved diagnosis of COVID-19 vaccine-associated myocarditis with cardiac scarring identified by cardiac magnetic resonance imaging. (preprint)

BackgroundMyocarditis is a rare but potentially serious complication of COVID-19 vaccination. Cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) imaging can identify cardiac scar, which may improve diagnostic accuracy and prognostication. ObjectivesTo define the incidence of long-term LGE post COVID-19 vaccine-associated myocarditis (C-VAM) and to establish the additive role of CMR in the diagnostic work-up. MethodsPatients with Brighton Collaboration Criteria Level 1 (definite) or Level 2 (probable) C-VAM were prospectively recruited from the Surveillance of Adverse Events Following Vaccination In the Community (SAEFVIC) database to undergo CMR at least 12 months after diagnosis. As there were limited patients with access to baseline CMR, prior CMR results were not included in the initial case definition. The presence of LGE on follow-up CMR was then integrated into the diagnostic algorithm and the reclassification rate (definite vs. probable) was calculated. ResultsSixty-seven patients with C-VAM (mean age 30 {+/-} 13 years, 72% male) underwent CMR evaluation. Median time from vaccination to CMR was 548 (range 398-603) days. Twenty patients (30%) had persistent LGE, most frequently found in the basal inferolateral segment (n = 11). At diagnosis, nine patients (13%) were classified as definite and 58 (87%) as probable myocarditis. With integration of CMR LGE data, 16 patients (28%) were reclassified from probable to definite myocarditis. ConclusionPersistent LGE on CMR occurs in one third of patients with C-VAM. Without CMR at diagnosis, almost one third of patients are misclassified as probable rather than definite myocarditis.

Cardiac safety after AstraZeneca COVID-19 vaccination: A cohort observational study (preprint)

Background Vaccination is a well-established part of preventive and public health medicine but is not without risk. Most of the side effects related to COVID-19 vaccines are minor including local symptoms at the injection site and some systemic symptoms, such as fatigue, headache, and fever. Some preliminary reports mentioned a more serious side effect; myocarditis seen after certain COVID-19 vaccines. The purpose of this study was to reveal any decrease in left ventricular systolic function in patients receiving the AstraZeneca COVID-19 vaccine compared to healthy individuals who did not receive the vaccine.Methods This study included 150 people divided into two equal groups; the case group included individuals who received AstraZeneca COVID-19 vaccines, and the sex- and age-matched control group included healthy individuals who did not receive any of the COVID-19 vaccines. Echocardiographic parameters for assessment of systolic function were evaluated after full vaccination.Results By the end of the study, no difference was found between the case and control groups regarding the left ventricular ejection fraction (LVEF), the S' wave of the mitral valve, or the global longitudinal strain (GLS).Conclusions AstraZeneca COVID-19 vaccination was not associated with myocardial damage, as evaluated by 2D echocardiography, tissue Doppler, and speckle tracking echocardiography.

Real-world Nuvaxovid COVID-19 vaccine safety profile after first 100,000 doses in Australia, 2022-2023 (preprint)

Introduction Nuvaxovid became available in Australia from February 2022, a year later than the first COVID-19 vaccines were released. It was a much-anticipated alternative vaccine for people that had either suffered an adverse event to and/or were hesitant to receive one of the mRNA or adenovirus based COVID-19 vaccines. Although safety from clinical trials was reassuring, small trial population size, relatively low administration rates worldwide and limited post-licensure intelligence meant potential rare adverse events were underinformed. Methods We conducted a retrospective observational analysis of adverse events following immunisation (AEFI) spontaneously reported to SAFEVAC, the integrated vaccine safety surveillance system used by Victoria and Western Australia, Australia. Reports received from 14 Feb 2022 to 30 June 2023 were analysed by vaccinee demographics, reported reactions and COVID-19 vaccine dose received and compared as reporting rates (RR) per 100,000 doses administered. Results 356 AEFI reports were received, following 102,946 Nuvaxovid doses administered. Rates were higher post dose 1 than dose 2 (rate ratio 1.5, p=0.0008); primary series than booster (rate ratio 2.4, p<0.0001); in females than males (rate ratio 1.4, p<0.01), especially those aged 30-49 years (RR=1.6, p=0.002). Serious AEFI included 76 chest pain (RR=73.8), two myocarditis (RR=1.9) and 20 pericarditis (RR=19.4). No cases of Guillain Barre or thrombosis with thrombocytopaenia syndromes were reported and no deaths attributable to vaccination. Conclusion The shared SAFEVAC platform enables pooling of clinically reviewed data across jurisdictions, increasing the safety profile evidence base of novel vaccines like Nuvaxovid and improving the odds for identification and description of rare events across all vaccines.

Comparative safety and effectiveness of Pfizer BA.4-5 versus Sanofi during the spring 2023 COVID-19 booster vaccination programme in England: a matched cohort study in OpenSAFELY-TPP (preprint)

Introduction: The spring 2023 COVID-19 booster vaccination programme in England used both Pfizer BA.4-5 and Sanofi vaccines. All people aged 75 years or over and the clinically vulnerable were eligible to receive a booster dose. Direct comparisons of the effectiveness of these two vaccines in boosting protection against severe COVID-19 events have not been made in trials or observational data. Methods With the approval of NHS England, we used the OpenSAFELY-TPP database to compare effectiveness of the Pfizer BA.4-5 and Sanofi vaccines during the spring 2023 booster programme, between 1 April and 30 June 2023. We investigated two cohorts separately: those aged 75 or over (75+); and those aged 50 or over and clinically vulnerable (CV). In each cohort, vaccine recipients were matched on date of vaccination, COVID-19 vaccine history, age, and other characteristics. Effectiveness outcomes were COVID-19 hospital admission, COVID-19 critical care admission, and COVID-19 death up to 16 weeks after vaccination. Safety outcomes were pericarditis and myocarditis up to 4 weeks after vaccination. We report the cumulative incidence of each outcome, and compare safety and effectiveness using risk differences (RD), relative risks (RR), and incidence rate ratios (IRRs). Results 492,642 people were 1-1 matched in the CV cohort, and 673,926 in the 75+ cohort, contributing a total of 7,423,251 and 10,173,230 person-weeks of follow-up, respectively. The incidence of COVID-19 hospital admission was higher for Sanofi than for Pfizer BA.4-5. In the CV cohort, 16-week risks per 10,000 people were 22.3 (95%CI 20.4 to 24.3) for Pfizer BA.4-5 and 26.4 (24.4 to 28.7) for Sanofi, with an IRR of 1.19 (95%CI 1.06 to 1.34). In the 75+ cohort, these were 17.5 (16.1 to 19.1) for Pfizer BA.4-5 and 20.4 (18.9 to 22.1) for Sanofi, with an IRR of 1.18 (1.05-1.32). These findings were similar across all pre-specified subgroups. More severe COVID-19 related outcomes (critical care admission and death), and safety outcomes at 4 weeks, were rare in both vaccines so we could not reliably compare effectiveness of the two vaccines. Conclusion This observational study comparing effectiveness of Pfizer BA.4-5 and Sanofi vaccine during the spring 2023 programme in England in the two main eligible cohorts - people aged 75 and over and in clinically vulnerable people - found some evidence of superior effectiveness against COVID-19 hospital admission for Pfizer BA.4-5 compared with Sanofi within 16 weeks after vaccination.

Beyond the Virus: QTc Interval Changes in COVID-19 Survivors (preprint)

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme-2 receptors on host cells to enter the cells. These receptors are expressed on heart muscle tissue and the tissues of other major organs, which supports the primary accepted theory for the direct cardiac cell injury of coronavirus disease 2019 (COVID-19) and the associated cardiorespiratory manifestations. The SARS-CoV-2 infection leads to unstable myocardial cell membranes due to hypoxia, myocarditis, myocardial ischemia, and abnormal host immune response. This is the main reason behind arrhythmia and electrocardiogram (ECG) changes during COVID-19. However, the specific effect on QTc after Covid 19 infection has not been studied well. Therefore, this study aimed to examine the association between post COVID-19 infection and QTc changes.Objectives: Examine the association between post COVID-19 infection and QTc changes.Materials and Methods: This is a case control study conducted on middle age of either sex involves 50 adult patients with post-COVID-19 infections (eight were defaulted from the study because they were not cooperative), 23 females and 19 males with mean age (36.98 ± 12.2 years) who were non-vaccinated against Covid 19 after one month to two years of an acute episode of COVID-19 (confirmed by positive real-time reverse-transcription polymerase chain reaction (RT-PCR)) test according to the World Health Organization (WHO) selected randomly from those attending to the adult Holter and Echocardiography lab in Al-Zahraa Hospital/ Al-Hussein Medical City/ Karbala Province after being referred by Internist during the period from the 12th of October 2022 to the end of January 2024 and divided in to three groups : non hospitalize, hospitalize and admitted to intensive care while control group consisted of 40 healthy persons 23 females and 17 males with mean age (33.28 ± 9.58 years), whom referred by Internist for ECG with no Hx of the previous infection of covid 19. All of them have electrocardiographic evaluation by taking ECG.Conclusion That post COVID-19 patients had prolonged QT and QTc intervals increase the risk for cardiac arrhythmias.

Risk of Adverse Events Following Monovalent Third or Booster Dose of COVID-19 mRNA Vaccination in U.S. Adults Ages 18 Years and Older (preprint)

Background: The U.S. FDA authorized the monovalent third primary series or booster doses of COVID-19 mRNA vaccines in August 2021 for persons 18 years and older. Monitoring of outcomes following updated authorizations is critical to evaluate vaccine safety and can provide early detection of rare adverse events (AEs) not identified in pre-licensure trials. Methods We evaluated the risk of 17 AEs following third doses of COVID-19 mRNA vaccines from August 2021 through early 2022 among adults aged 18-64 years in three commercial databases (Optum, Carelon Research, CVS Health) and adults aged >65 years in Medicare Fee-For-Service. We compared observed AE incidence rates to historical (expected) rates prior to the pandemic, estimated incidence rate ratios (IRRs) for the Medicare database and pooled IRR across the three commercial databases. Analyses were also stratified by prior history of COVID-19 diagnosis. Estimates exceeding a pre-defined threshold were considered statistical signals. Results Four AEs met the threshold for statistical signals for BNT162b2 and mRNA-1273 vaccines including Bells Palsy and pulmonary embolism in Medicare, and anaphylaxis and myocarditis/pericarditis in commercial databases. Nine AEs and three AEs signaled among adults with and without prior COVID-19 diagnosis, respectively. Conclusions This early monitoring study identified statistical signals for AEs following third doses of COVID-19 mRNA vaccination. Since this method is intended for screening purposes and generates crude results, results do not establish a causal association between the vaccines and AEs. FDAs public health assessment remains consistent that the benefits of COVID-19 vaccination outweigh the risks of vaccination.

Myocarditis and Pericarditis Following the COVID-19 Vaccination: A Single-Centre Case Seriese (preprint)

The Surveillance of rare adverse events following vaccination, particularly related to COVID-19 vaccines, requires thorough examination. This paper investigates vaccine-associated myocarditis and/or pericarditis (VAMPS), presenting insights into clinical manifestations, management, and outcomes. Conducted at the Prince Sultan Cardiac Center in Saudi Arabia from March 2021 to May 2022, this retrospective case series comprises 20 patients with an average age of 27.9 ± 14.0 years, predominantly males (70%). Pfizer-BioNTech, AstraZeneca, and Moderna vaccines were administered in 74%, 21%, and 5% of cases, respectively, with 53% receiving the second dose, 26% the booster, and 21% the initial dose. Common symptoms included shortness of breath (60%), chest pain (50%), palpitations (40%), premature ventricular contractions (35%), and fever (25%). Cardiac magnetic resonance imaging revealed preserved left ventricular function (80%), subepicardial and/or mid-wall late gadolinium enhancement (65%), and lateral (39%), anterolateral (15%), inferolateral (15%), and anteroseptal (15%) segments affected. Myocarditis, pericarditis, and myopericarditis were diagnosed in 40%, 20%, and 40% of cases, respectively. C-reactive protein was elevated in two-thirds of patients. Recovery was achieved with anti-inflammatory medications, primarily colchicine (72%), aspirin(39%), and ibuprofen (33%). While no fatalities occurred, 30% experienced severe complications, and 15% had minor complications. In conclusion, VAMPS exhibits distinct characteristics and may lead to serious complications. Cardiologists should consider VAMPS in the differential diagnosis for symptomatic patients recently vaccinated against COVID-19, emphasizing the importance of ongoing surveillance and understanding of rare adverse events.

COVID-19 vaccination was a rare potential etiology for cause of death after medicolegal autopsy. A Finnish nationwide study. (preprint)

COVID-19 vaccinations began globally at the end of 2020. By the end of 2021, 9.8 million doses were given in Finland. Regarding safety, most vaccine-related adverse reactions have been mild, but serious and lethal ones have also occurred. Autopsies in post vaccination deaths may give insight to the extent of fatal health conditions with potential COVID-19 vaccine etiology and provide new hypotheses of possible causalities between vaccination and severe health conditions. We searched the complete documentation on all medicolegal autopsies in Finland between December 2020 and December 2021 to assess how often the basis for autopsy was a suspected fatal adverse reaction to COVID-19 vaccination, and whether vaccination remained a potential etiology for any health condition determined as a cause of death after the autopsy. We linked register-based data on individual COVID-19 vaccination course and pre-existing health conditions. We found 428 autopsy cases with a mention of COVID-19 vaccination, and prior to autopsy, vaccination was suspected to play a part in 76 deaths. Post autopsy, a forensic pathologist considered vaccination as a potential etiology in five underlying and seven contributory causes of death. These included seven thromboembolisms, two diabetic ketoacidoses, one myocarditis, one acute pancreatitis, and one eosinophilic granulomatosis with polyangiitis. In relation to the number of vaccinations within Finland, a suspicion of vaccine-related serious adverse reaction was rarely an indication for medicolegal autopsy. Even less frequently was vaccination considered to play a part in the process leading to death, although considerable doubt remains in the accuracy of individual considerations, and autopsy cannot definitively confirm causality between vaccination and death. Regarding vaccination safety, continuing evaluation of suspected vaccine-related deaths is essential, and an autopsy should be part of the investigation when such a suspicion arises.

Long-term cardiovascular safety of COVID-19 vaccination according to brand, dose and combinations: Cohort study of 46 million adults in England (preprint)

Using longitudinal health records from 45.7 million adults in England followed for a year, our study compared the incidence of thrombotic and cardiovascular complications after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the first two years of the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA- 1273) These findings support the wide uptake of future COVID-19 vaccination programs.

COVID-related Constrictive Pericarditis Requiring Pericardiectomy: A Case Report (preprint)

Background The COVID-19 pandemic was primarily considered a respiratory malady in the early phases of the outbreak. However, as more patients suffer from this illness, a myriad of symptoms emerge in organ systems separate from the lungs. Among those patients with cardiac involvement, myocarditis, pericarditis, myocardial infarction, and arrhythmia were among the most common manifestations. Pericarditis with pericardial effusion requiring medical or interventional treatments has been previously reported in the acute setting. Notably, chronic pericarditis with pericardial thickening resulting in constriction requiring sternotomy and pericardiectomy has not been published to date.Case Presentation A patient with COVID-19-associated constrictive pericarditis three years after viral infection requiring pericardiectomy was reported. The COVID-19 infection originally manifested as anosmia and ageusia. Subsequently, the patient developed dyspnea, fatigue, right-sided chest pressure, bilateral leg edema, and abdominal fullness. Following recurrent right pleural effusions and a negative autoimmune work-up, the patient was referred for cardiothoracic surgery for pericardiectomy when radiographic imaging and hemodynamic assessment were consistent with constrictive pericarditis. Upon median sternotomy, the patient’s pericardium was measured to be 8 mm thick. Descriptions of the clinical, diagnostic, and therapeutic features are provided. Within the first week after the operation, the patient’s dyspnea resolved; one month later, leg edema and abdominal bloating were relieved.Conclusions Although an association between COVID-19 and cardiac complications has been established, this case adds another element of virus severity and chronic manifestations. The need for sternotomy and pericardiectomy to treat COVID-19-related constrictive pericarditis is believed to be the first reported diagnosis.

Treadmill Exercise Stress Echocardiography Exposes Impaired Left Ventricular Function in Patients Recovering from Hospitalization with COVID-19 Without Overt Myocarditis Versus Historical Controls (preprint)

Background: Usual clinical testing rarely reveals cardiac abnormalities persisting after hospitalization for COVID-19. Such testing may overlook residual changes responsible for increased adverse cardiac events post-discharge. Methods: To further elucidate long-term status, we performed exercise stress echocardiography (ESE) in 15 patients age 30-63 without myocarditis 3 to 31 months after hospital discharge. We compared patient outcomes to published data in healthy comparisons (HC) exercising according to the same protocol. Results: Patients' treadmill exercise (Bruce protocol), averaging 8.2 min, was halted by dyspnea or fatigue. Pre-stress baselines in recovering patients (RP) matched HC except for higher heart rate: mean 81 bpm for RP and 63 for HC (p<0.0001). At peak stress, RP had significantly lower mean left ventricular (LV) ejection fraction (67% vs 73%, p<0.0017) and higher peak early mitral inflow velocity/early mitral annular velocity (E/e', 9.1 vs 6.6, p<0.006) compared with HC performing equal exercise (8.5 min). Thus, when stressed, patients without known cardiac impairment showed modest but consistently diminished systolic contractile function and diastolic LV compliance during recovery vs HC. Peak HR during stress was significantly elevated in RP vs HC; peak SBP also trended higher. Average pulmonary artery systolic pressures among RP remained normal. Conclusions: Our measurements during ESE uniquely identified residual abnormality in cardiac contractile function not evident in the unstressed condition. This finding exposes a previously-unrecognized residual influence of COVID-19, possibly related to underlying autonomic dysfunction, microvascular disease, or diffuse interstitial changes after subclinical myocarditis; it may have long-term implications for clinical management and later prognosis.

Cardiac MRI as a Risk Stratification Tool in COVID -19 Myocarditis (preprint)

The aim of this retrospective study was to identify myocardial injury after COVID-19 inflamation and to explore whether myocardial damage could be a possible cause of the persistent symptoms following COVID-19 infection in previously healthy individuals. The study included 139 patients who were enrolled between January-June 2021, mean age 46.7±15.2 years, 68 were men, 71 were women without known cardiac or pulmonary diseases. All patients underwent clinical work up, lab. analyses, cardiac ultrasound, and CMR on 1.5 T scanner using a recommended protocol for morphological and functional assessment before and after contrast media application with multi-parametric sequences. In 39% of patients late gadolinium enhancement (LGE) was found as a sign of myocarditis. Fibrinogen was statistically significantly higher in patients with LGE than in those without LGE, (4.3±0.23 vs 3.2±0.14g/L, p<0.05; respectively), as well as D-dimer (1.8±0.3 vs 0.8±0.1 mg/L FEU). Also troponin was statistically significantly higher in patients with myocardial LGE (13.1±0.4ng/L) compared to those with normal myocardium (4.9±0.3ng/L, p<0.001). We demonstrated chest pain, fatigue and elevated troponin to be independent predictors for LGE. Septal LGE was shown to be predictor for arrhythmias. The use of CMR is a potential risk stratification tool in evaluating outcomes following COVID-19 myocarditis.

Safety Monitoring of Bivalent COVID-19 mRNA Vaccines Among Recipients 6 months and Older in the United States (preprint)

Importance Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes post-licensure. Objective To evaluate health outcomes following bivalent COVID-19 Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273.222) vaccination among individuals 6 months and older in the United States. Design Monthly monitoring of health outcomes from August 2022 to July 2023 in four administrative claims databases. Descriptive analyses monitored vaccine uptake, outcome counts and coadministration of bivalent COVID-19 and influenza vaccines. Sequential analyses tested for elevated risk of each outcome in a prespecified post-vaccination risk interval, or a period of hypothesized elevation based on clinical guidance, compared to a historical baseline. Participants and Exposures Persons 6 months and older who received a bivalent COVID-19 BNT162b2 or mRNA-1273.222 vaccine during the study period, with continuous enrollment in a medical insurance plan from the start of an outcome-specific clean interval to the COVID-19 vaccination date. Vaccines were identified using product-specific codes from medical coding systems. Health Outcomes Twenty outcomes were monitored in BNT162b2 vaccine recipients 6 months-4 years, and mRNA-1273.222 vaccine recipients 6 months-5 years. Twenty-one outcomes were monitored in BNT162b2 vaccine recipients 5-17 years and mRNA-1273.222 vaccine recipients 6-17 years. Eighteen outcomes were monitored in persons 18 years and older for both mRNA vaccines. Results Overall, 13.9 million individuals 6 months and older received a single bivalent COVID-19 mRNA vaccine. The statistical threshold for a signal was met for two outcomes in one database: anaphylaxis following bivalent BNT162b2 and mRNA-1273.222 vaccines in persons 18-64 years and myocarditis/pericarditis following bivalent BNT162b2 vaccines in individuals 18-35 years. There were no signals identified in young children. Conclusions Results were consistent with prior observations from published studies on COVID-19 vaccine safety. This study supports the safety profile of bivalent COVID-19 mRNA vaccines and the conclusion that the benefits of vaccination outweigh the risks.

Adverse Events Following SARS-CoV-2 mRNA Vaccination in Adolescents: A Norwegian Nationwide Register-Based Study (preprint)

BackgroundVaccination of older adolescents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in the spring of 2021 and continued with younger adolescents throughout the summer and fall. We assessed risks of adverse events following immunization (AEFI) in adolescents aged 12-19 years following SARS-CoV-2 vaccination with a messenger RNA (mRNA) vaccine in Norway. Materials and MethodsThe study sample included 496,432 adolescents born in 2002-2009, residing in Norway, and unvaccinated against SARS-CoV-2 at the beginning of the age-specific waves of vaccination in 2021. The exposures under study were first- and second-dose SARS-CoV-2 mRNA vaccinations vs. no dose. We applied Poisson regression and self-controlled case series (SCCS) analysis to estimate incidence rate ratios (IRRs) of 17 preselected outcomes, with associated 95% confidence intervals (CIs), between vaccinated and unvaccinated subjects using predefined post-vaccination risk windows. ResultsMost outcome-specific numbers of cases were low. There were no statistically significant associations between first-dose vaccination and any of the outcomes. In the main Poisson regression, second-dose vaccination was associated with increased risks of anaphylactic reaction (adjusted IRR [aIRR]: 10.05; 95% CI: 1.22-82.74), lymphadenopathy (aIRR: 2.33; 95% CI: 1.46-3.72), and myocarditis and pericarditis (aIRR: 5.27; 95% CI: 1.98-14.05). We also observed increased incidence of acute appendicitis outside the 14-day risk window. When expanding the risk window to 42 days in a post-hoc analysis, there was increased incidence of acute appendicitis following both first-dose vaccination (aIRR: 1.39; 95% CI: 1.09-1.78) and second-dose vaccination (aIRR: 1.43; 95% CI: 1.07-1.91). Results of the SCCS analysis were similar to the Poisson regression. ConclusionsIn general, potential AEFI were rare among adolescents. We found increased risks of anaphylactic reaction, lymphadenopathy, and myocarditis and pericarditis following second-dose vaccination. There were also indications of increased acute appendicitis risk when applying longer risk windows.

Severe acute myositis and myocarditis upon initiation of six-weekly Pembrolizumab post-COVID-19 mRNA vaccination (preprint)

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within one month of receiving the initial cycle of the anti-PD-1 drug Pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognising viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.

Safety of Monovalent BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and NVX-CoV2373 (Novavax) COVID-19 Vaccines in US Children Aged 6 months to 17 years (preprint)

Importance Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes that may not be identified in prelicensure trials. Objective To conduct near-real-time monitoring of health outcomes following COVID-19 vaccination in the United States (US) pediatric population aged 6 months to 17 years. Design We evaluated 21 pre-specified health outcomes; 15 were sequentially tested through near-real-time surveillance, and 6 were monitored descriptively within a cohort of vaccinated children. We tested for increased rate of each outcome following vaccination compared to a historical comparator cohort. Setting This population-based study was conducted under the US Food and Drug Administration public health surveillance mandate using three commercial claims databases. Participants Children aged 6 months to 17 years were included if they received a monovalent COVID-19 vaccine dose before early 2023 and had continuous enrollment in a medical health insurance plan from the start of an outcome-specific clean window to the COVID-19 vaccination dose. Exposure Exposure was defined as receipt of a monovalent BNT162b2, mRNA-1273, or NVX-CoV2373 COVID-19 vaccine dose. The primary analysis evaluated dose 1 and dose 2 combined, and secondary analyses evaluated each dose separately. Follow-up time was censored at death, disenrollment, end of risk window, end of study period, or a subsequent dose administration. Main Outcomes Twenty-one prespecified health outcomes. Results The study included 4,102,016 enrollees aged 6 months to17 years. Thirteen of 15 outcomes sequentially tested did not meet the threshold for a statistical signal. In the primary analysis, myocarditis or pericarditis signals were detected following BNT162b2 vaccine in children aged 12-17 years old and seizures/convulsions signals were detected following vaccination with BNT162b2 and mRNA-1273 in children aged 2-4/5 years. However, in a post-hoc sensitivity analysis, the seizures/convulsions signal was sensitive to background rates selection and was not observed when 2022 background rates were selected instead of 2020 rates. Conclusions and Relevance Of the two signaled outcomes, the myocarditis or pericarditis signals are consistent with previously published reports. The new signal detected for seizures/convulsions among younger children should be further investigated in a robust epidemiological study with better confounding adjustment.

Evolution of Myocarditis Incidence at a Large Healthcare System Before and During COVID-19 Pandemic (preprint)

Background Myocarditis is a recognized complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Emerging studies further suggest an associated risk of myocarditis following administration of messenger RNA (mRNA) COVID-19 vaccinations. coronavirus disease 2019 (COVID-19) vaccinations. We investigated the incidence of myocarditis throughout the COVID-19 pandemic across a large healthcare system in the Washington, DC, metropolitan area. Methods This retrospective analysis of patients admitted from 2017-2022. Myocarditis cases were temporally divided into two cohorts based on year of admission (pre-pandemic 2017-2019; pandemic 2020-2022), which were compared for overall myocarditis incidence. The primary endpoint was in-hospital mortality. Results The cohort included 573 myocarditis patients (pre-pandemic=208, pandemic=365). From 2017-2019, the total number and rate of myocarditis cases was consistent. Overall cases of myocarditis increased during the pandemic (97, 126, 142 patients in 2020, 2021, 2022, respectively). Interestingly, the rate of myocarditis cases not related to COVID-19 or the vaccines stayed consistent (0.0674%, 0.0676%, 0.0807%), but the rate of myocarditis related to COVID-19 or the vaccines myocarditis increased each year (0.0210%, 0.0416%, 0.0480%). In-hospital mortality was similar between the two pre-pandemic and pandemic cohorts (5.35% versus 7.7%, 0.276). Conclusion Among hospitalized patients, during the COVID-19 pandemic, the incidence of myocarditis increased as compared to the pre-pandemic era. It appears this increase is associated with either the SARS-CoV-2 infection or COVID-19 vaccination. In-hospital outcomes did not differ during the pandemic, but ongoing research is needed to evaluate the long-term impact of myocarditis during the pandemic.

Heart-on-a-chip model of immune-induced cardiac dysfunction reveals the involvement of free mitochondrial DNA and therapeutic effects of endothelial exosomes (preprint)

Cardiovascular disease continues to take more human lives than all cancer combined, prompting the need for improved research models and treatment options. Despite a significant progress in development of mature heart-on-a-chip models of fibrosis and cardiomyopathies starting from induced pluripotent stem cells (iPSCs), human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip system with circulating immune cells to model SARS-CoV-2-induced acute myocarditis. Briefly, we observed hallmarks of COVID-19-induced myocardial inflammation in the heart-on-a-chip model, as the presence of immune cells augmented the expression levels of proinflammatory cytokines, triggered progressive impairment of contractile function and altered intracellular calcium transient activities. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the in vitro heart-on-a-chip model and then validated in COVID-19 patients with low left ventricular ejection fraction (LVEF), demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2 induced myocardial inflammation, we established that administration of human umbilical vein-derived EVs effectively rescued the contractile deficit, normalized intracellular calcium handling, elevated the contraction force and reduced the ccf- mtDNA and chemokine release via TLR-NF-kB signaling axis.

Autopsy Proven Fatal COVID-19 Vaccine-Induced Myocarditis (preprint)

Background: 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. Methods: We performed a systematic review of all published autopsy reports involving COVID-19 vaccination-related myocarditis through July 3rd, 2023. All autopsy studies that include COVID-19 vaccine-induced myocarditis as a possible cause of death were included, without imposing any additional restrictions. Causality in each case was determined by three independent reviewers with cardiac pathology experience and expertise. Results: We initially identified 1,691 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 2 cases, myocarditis was characterized as a consequence from multisystem inflammatory syndrome (MIS). The mean and median number of days from last COVID-19 vaccination until death was 6.2 and 3 days, respectively. Most of the deaths occurred within a week from the last injection. We established that all 28 deaths were causally linked to COVID-19 vaccination by independent adjudication. Conclusions: 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 there is a high likelihood of a causal link between COVID-19 vaccines and death from suspected myocarditis in cases where sudden, unexpected death has occurred in a vaccinated person. Urgent investigation is required for the purpose of risk stratification and mitigation in order to reduce the population occurrence of fatal COVID-19 vaccine-induced myocarditis.