Assessment of Radiation Induced Pneumonitis and Pericarditis in Patients Undergoing Breast Conservative Treatment Using Hypofractionated Simultaneous Integrated Boost Technique.

INTRODUCTION: To determine the proportion of radiationinduced pneumonitis and pericarditis in patients who have received Hypo-fractionated Radiation along with simultaneous integrated boost technique after breast conservative surgery using a prospective observational study from a tertiary hospital. MATERIALS & METHODS: The incidence of radiationinduced pneumonitis and pericarditis was evaluated in all adult patients with biopsy-proven early-stage unilateral breast cancer who underwent breast-conserving surgery followed by hypo-fractionated radiation with a simultaneous integrated boost technique. Baseline assessments including a six-minute walk test, highresolution computed tomography (HRCT), pulmonary function tests (PFTs), electrocardiography (ECG) and echocardiography (ECHO) were performed. At three months post-radiation treatment, patients underwent follow-up assessments with a six-minute walk test, ECG and ECHO. At six months post-radiation treatment, patients underwent further assessments with a six-minute walk test, ECG, ECHO, PFTs, and HRCT of the thorax. Data analysis was performed using SPSS version 19. RESULTS: Our study investigated the incidence of acute radiation-induced pneumonitis and pericarditis in patients treated with hypofractionated VMAT-SIB technique in 20 eligible early breast cancer patients. The study found that the technique is feasible and achieves encouraging dosimetric parameters, including well achieved ipsilateral lung and heart doses. The reduced treatment time of 3-4 weeks compared to the previous 6-7 weeks with sequential boost was also found to be desirable in resource-constrained settings. The incidence of acute radiation pneumonitis and pericarditis was acceptable and comparable to existing data, with 90% of patients experiencing grade 1 radiation pneumonitis according to CTCAE v5.0. Post-treatment pulmonary function tests showed significant changes, particularly in patients who had received neoadjuvant chemotherapy and nodal irradiation. The six-minute walk test and Borg scale also showed a significant positive correlation with pulmonary function tests. There was no significant pericarditis during the follow-up. The study proposes that the hypofractionated radiotherapy using VMAT-SIB is a suitable alternative to conventional fractionation, with acceptable acute toxicities, but longer follow-up is required to assess the impact on late toxicities. CONCLUSION: Our research has shown that hypofractionated adjuvant radiotherapy with SIB is a safe and feasible treatment for patients with early breast cancer. This treatment method doesn't pose any significant short-term risks to the lungs or heart, and the SIB technique provides better coverage, conformity and sparing of organs at risk. Additionally, patients have reported positive cosmetic outcomes with this treatment. However, to make more accurate conclusions, we need to conduct further studies with larger sample sizes and longer follow-up periods to evaluate the potential longterm side effects of this treatment using VMAT in whole breast radiation.

Benefit-risk assessment for the Novavax COVID-19 vaccine (NVX-CoV2373).

A benefit-risk assessment of NVX-CoV2373, a vaccine to prevent COVID-19, was conducted to determine if the benefits of vaccination outweigh the risks of myocarditis/pericarditis. This analysis used data on myocarditis/pericarditis cases observed in the NVX-CoV2373 clinical studies, real-world data of mRNA COVID vaccine effectiveness against predominant SARS-CoV-2 strains in early 2023, and recent COVID-19 burden of disease data from the United States. The benefits of NVX-CoV2373 vaccination were estimated as the number of COVID-19 cases, hospitalizations, and deaths prevented. The risks of myocarditis/pericarditis cases and related hospitalizations and deaths occurring within 7 days of vaccination were also estimated. In our analysis, vaccination with NVX-CoV2373, per 100,000 vaccinated, resulted in an estimated 1805 COVID-19 cases prevented compared with an estimated 5.3 excess myocarditis/pericarditis cases. The number of COVID-19 hospitalizations and deaths prevented were also greater than vaccine-associated myocarditis/pericarditis hospitalizations and deaths. Our analysis indicates a positive benefit-risk balance for NVX-CoV2373.

Evaluation of potential adverse events following COVID-19 mRNA vaccination among adults aged 65 years and older: Two self-controlled studies in the U.S.

BACKGROUND: Our near-real-time safety monitoring of 16 adverse events (AEs) following COVID-19 mRNA vaccination identified potential elevation in risk for six AEs following primary series and monovalent booster dose administration. The crude association with AEs does not imply causality. Accordingly, we conducted robust evaluation of potential associations. METHODS: We conducted two self-controlled case series studies of COVID-19 mRNA vaccines (BNT162b2 and mRNA-1273) in U.S. Medicare beneficiaries aged ≥ 65 years. Adjusted incidence rate ratio (IRRs) and 95 % confidence intervals (CIs) were estimated following primary series doses for acute myocardial infarction (AMI), pulmonary embolism (PE), immune thrombocytopenia (ITP), disseminated intravascular coagulation (DIC); and following monovalent booster doses for AMI, PE, ITP, Bell's Palsy (BP) and Myocarditis/Pericarditis (Myo/Peri). RESULTS: The primary series study included 3,360,981 individuals who received 6,388,542 primary series doses; the booster study included 6,156,100 individuals with one monovalent booster dose. The AMI IRR following BNT162b2 primary series and booster was 1.04 (95 % CI: 0.91 to 1.18) and 1.06 (95 % CI: 1.003 to 1.12), respectively; for mRNA-1273 primary series and booster, 1.01 (95 % CI: 0.82 to 1.26) and 1.05 (95 % CI: 0.998 to 1.11), respectively. The hospital inpatient PE IRR following BNT162b2 primary series and booster was 1.19 (95 % CI: 1.03 to 1.38) and 0.86 (95 % CI: 0.78 to 0.95), respectively; for mRNA-1273 primary series and booster, 1.15 (95 % CI: 0.94 to 1.41) and 0.87 (95 % CI: 0.79 to 0.96), respectively. The studies' results do not support that exposure to COVID-19 mRNA vaccines elevate the risk of ITP, DIC, Myo/Peri, and BP. CONCLUSION: We did not find an increased risk for AMI, ITP, DIC, BP, and Myo/Peri and there was not consistent evidence for PE after exposure to COVID-19 mRNA primary series or monovalent booster vaccines. These results support the favorable safety profile of COVID-19 mRNA vaccines administered in the U.S. elderly population.

Comparative assessment of myocarditis and pericarditis reporting rates related to mRNA COVID-19 vaccines in Europe and the United States.

OBJECTIVES: The novel mRNA vaccines proved to be safe and effective in averting severe COVID-19. Vaccine-related complications recorded by pharmacovigilance systems, such as 'EudraVigilance' in Europe and 'VAERS' in the United States (US), rarely include myocarditis and pericarditis. Given the novelty of the platform and the increasing global-scale vaccine production needs, we assessed their reporting rates comparatively across continents. METHODS: Data of myocarditis and pericarditis cases post COVID-19 vaccination reported from week 52/2020 (December 21 to 27, 2020) to week 40/2021 (October 4 to 10, 2021) were collected for mRNA vaccines from EudraVigilance and VAERS. The corresponding administered vaccine doses were used as denominators to estimate reporting rates for comparison purposes. Cross-tabulation analysis was employed to compare the reporting rates of mRNA vaccines-associated myocarditis and pericarditis between EudraVigilance and VAERS. RESULTS: Low reporting rates of myocarditis (7.64/million vaccine doses) and pericarditis (5.32/million) were found, with higher rates of both disorders in EudraVigilance compared to VAERS; these differences were more pronounced post-mRNA-1273 (5-6-fold, p=0.000 for myocarditis and p<0.001 for pericarditis) than post-BNT162b2 vaccination (1.5-2-fold, p<0.001 for both conditions). Most myocarditis cases occurred in males <30 years. Pericarditis affected predominantly males <40 and both sexes >40 years. The extremely rare fatalities related to myocarditis (0.102/million) or pericarditis (0.017/million) were also higher in EudraVigilance versus VAERS. CONCLUSIONS: Understanding the underlying causes of the observed differences could provide guidance for the enhanced quality of mRNA vaccines that would also foster vaccine acceptance.

Benefit-risk assessment of COVID-19 vaccine, mRNA (Comirnaty) for age 16-29 years.

Since authorization of the Pfizer-BioNTech COVID-19 Vaccine, mRNA (Comirnaty), real-world evidence has indicated the vaccines are effective in preventing COVID-19 cases and related hospitalizations and deaths. However, increased cases of myocarditis/pericarditis have been reported in the United States associated with vaccination, particularly in adolescents and young adults. FDA conducted a benefit-risk assessment to determine whether the benefits of vaccination outweigh the risks among various age (16-17, 18-24, 25-29) and sex (M/F) subgroups being considered for approved use of the vaccine. We conducted a simulation study with sensitivity analysis of the benefits and risks of the vaccine across possible pandemic scenarios. The model results show benefits outweigh the risks for all scenarios including the high-risk subgroup, males 16-17 years old. Our worst-case scenario used sex and age subgroup-specific incidences for COVID-19 cases (47-98 per million per day) and hospitalizations (1-4 per million per day) which are the US COVID-19 incidences as of July 10, 2021, vaccine efficacy of 70% against COVID-19 cases and 80% against hospitalization, and unlikely, pessimistic, non-zero vaccine-attributable myocarditis death rate. For males 16-17 years old, the model predicts prevented COVID cases, hospitalizations, ICUs, and deaths of 13577, 127, 41, and 1, respectively; while the predicted ranges for excess myocarditis/pericarditis cases, hospitalizations, and deaths attributable to the vaccine are [98-196], [98-196], and 0, respectively, for the worst-case scenario. Considering the different clinical implications of hospitalization due to COVID-19 infection versus vaccine-attributable myocarditis/pericarditis cases, we determine the benefits still outweigh the risks even for this high-risk subgroup. Our results demonstrate that the benefits of the vaccine outweigh its risks for all age and sex subgroups we analyze in this study. Uncertainties exist in this assessment as both benefits and risks of vaccination may change with the continuing evolution of the pandemic.

Incidence, Clinical Presentation, and Management of Myocarditis following mRNA-Based Covid-19 Vaccines: A Brief Report.

BACKGROUND: Recent surveillance studies following nationwide mass vaccination are investigating rare complications such as myocarditis, pericarditis, and thromboembolic events related to mRNA-based Covid-19 vaccines. SUMMARY: In the current report, we present an overview of the incidence, clinical presentation and management of post-mRNA vaccine myocarditis, and pericarditis in view of the currently available data. Our main focus is directed toward myocarditis. KEY MESSAGES: Myocarditis following mRNA-based Covid-19 vaccines is rare, more frequently affects younger men <30 years and is usually of mild severity with spontaneous recovery. The overall benefit of mRNA vaccines in terms of protecting from severe Covid-19 infection and associated cardiovascular complications outweighs the risk of postvaccination myocarditis. Currently, there are no dedicated guidelines for patients with postvaccination myocarditis or pericarditis in terms of the frequency of follow-up including clinical assessment, repeated echocardiography, and cardiac resonance imaging. However, follow-up studies in terms of long-term consequences are underway.

Incidence, clinical presentation, management, and outcome of acute pericarditis and myopericarditis.

AIMS: Little is known about the epidemiology, clinical presentation, management, and outcome of acute pericarditis and myopericarditis. METHODS AND RESULTS: The final diagnoses of acute pericarditis, myopericarditis, and non-ST-segment elevation myocardial infarction (NSTEMI) of patients presenting to seven emergency departments in Switzerland with acute chest pain were centrally adjudicated by two independent cardiologists using all information including serial measurements of high-sensitivity cardiac troponin T. The overall incidence of pericarditis and myopericarditis was estimated relative to the established incidence of NSTEMI. Current management and long-term outcome of both conditions were also assessed. Among 2533 chest pain patients, the incidence of pericarditis, myopericarditis, and NSTEMI were 1.9% (n = 48), 1.1% (n = 29), and 21.6% (n = 548), respectively. Accordingly, the estimated incidence of pericarditis and myopericarditis in Switzerland was 10.1 [95% confidence interval (95% CI) 9.3-10.9] and 6.1 (95% CI 5.6-6.7) cases per 100 000 population per year, respectively, vs. 115.0 (95% CI 112.3-117.6) cases per 100 000 population per year for NSTEMI. Pericarditis (85% male, median age 46 years) and myopericarditis (62% male, median age 56 years) had male predominance, and commonly (50% and 97%, respectively) resulted in hospitalization. No patient with pericarditis or myopericarditis died or had life-threatening arrhythmias within 30 days [incidence 0% (95% CI 0.0-4.8%)]. Compared with NSTEMI, the 2-year all-cause mortality adjusted hazard ratio of pericarditis and myopericarditis was 0.40 (95% CI 0.05-2.96), being 0.59 (95% CI 0.40-0.88) for non-cardiac causes of chest pain. CONCLUSION: Pericarditis and myopericarditis are substantially less common than NSTEMI and have an excellent short- and long-term outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov, number NCT00470587, https://clinicaltrials.gov/ct2/show/NCT00470587.

Disease and Economic Burden Associated with Recurrent Pericarditis in a Privately Insured United States Population.

INTRODUCTION: Approximately 30% of patients with a first acute pericarditis episode experience a recurrence ≤ 18 months; ~ 15% experience multiple recurrences. This study assessed the recurrence and economic burden among patients with multiple recurrences. METHODS: Adults with idiopathic pericarditis were identified in the OptumHealth Care Solutions, Inc., database (2007-2017). Recurrent pericarditis (RP) was defined as ≥ 2 episodes of care separated by > 28 days; multiple recurrences were defined as ≥ 2 recurrences. RESULTS: Among 944 patients with RP, 375 (39.7%) experienced multiple recurrences and were propensity score-matched 1:1 to 375 patients without recurrence. Among patients with multiple recurrences, median disease duration (time from first episode to end of last recurrence, confirmed by a 1.5-year recurrence-free period) was 2.84 years. The multiple recurrences cohort had higher rates of hospitalizations per-patient-per-month (PPPM) than the no recurrence cohort (rate ratio [95% confidence interval (CI)] = 2.22 [1.35-3.65]). Mean total healthcare costs were significantly higher in the multiple recurrences versus no recurrence cohort ($2728 vs. $1568 PPPM, cost ratio [95% CI] = 1.74 [1.29-2.32]), mainly driven by higher hospitalization costs in the multiple recurrences cohort (mean: $1180 vs. $420 PPPM, cost ratio [95% CI] = 2.81 [1.80-4.66]). Mean work loss costs were higher in the multiple recurrences versus no recurrence cohort ($696 vs. $169 PPPM, cost ratio [95% CI] = 4.12 [1.64-9.61]). In patients with multiple recurrences, mean cost of the first episode was $19,189; subsequent recurrences ranged from $2089 to $7366 (second recurrence = $6222). CONCLUSION: In conclusion, among patients with multiple pericarditis recurrences, disease symptoms persisted several years, and healthcare and work loss costs were further compounded in this subset of patients.

Myocarditis and Pericarditis After COVID-19 mRNA Vaccination: Practical Considerations for Care Providers.

The mRNA vaccines against COVID-19 infection have been effective in reducing the number of symptomatic cases worldwide. With widespread uptake, case series of vaccine-related myocarditis/pericarditis have been reported, particularly in adolescents and young adults. Men tend to be affected with greater frequency, and symptom onset is usually within 1 week after vaccination. Clinical course appears to be mild in most cases. On the basis of the available evidence, we highlight a clinical framework to guide providers on how to assess, investigate, diagnose, and report suspected and confirmed cases. In any patient with highly suggestive symptoms temporally related to COVID-19 mRNA vaccination, standardized workup includes serum troponin measurement and polymerase chain reaction testing for COVID-19 infection, routine additional lab work, and a 12-lead electrocardiogram. Echocardiography is recommended as the imaging modality of choice for patients with unexplained troponin elevation and/or pathologic electrocardiogram changes. Cardiovascular specialist consultation and hospitalization should be considered on the basis of the results of standard investigations. Treatment is largely supportive, and myocarditis/pericarditis that is diagnosed according to defined clinical criteria should be reported to public health authorities in every jurisdiction. Finally, we recommend COVID-19 vaccination in all individuals in accordance with the Health Canada and National Advisory Committee on Immunization guidelines. In patients with suspected myocarditis/pericarditis after the first dose of an mRNA vaccine, deferral of a second dose is recommended until additional reports become available.

US Database Study of Clinical Burden and Unmet Need in Recurrent Pericarditis.

Background Patients with recurrent pericarditis (RP) may develop complications, multiple recurrences, or inadequate treatment response. This study aimed to characterize disease burden and unmet needs in RP. Methods and Results This retrospective US database analysis included newly diagnosed patients with RP with ≥24 months of continuous history following their first pericarditis episode. RP was defined as ≥2 pericarditis episodes ≥28 days apart. Some patients had ≥2 recurrences, while others had a single recurrence with a serious complication, ie, constrictive pericarditis, cardiac tamponade, or a large pericardial effusion with pericardiocentesis/pericardial window. Among these patients with multiple recurrences and/or complications, some had features relating to treatment history, including long-term corticosteroid use (corticosteroids started within 30 days of flare, continuing ≥90 consecutive days) or inadequate treatment response (pericarditis recurring despite corticosteroids and/or colchicine, or other drugs [excluding NSAIDs] within 30 days of flare, or prior pericardiectomy). Patients (N=2096) had hypertension (60%), cardiomegaly (9%), congestive heart failure (17%), atrial fibrillation (16%), autoimmune diseases (18%), diabetes mellitus (21%), renal disease (20%), anxiety (21%), and depression (14%). Complications included pericardial effusion (50%), cardiac tamponade (9%), and constrictive pericarditis (4%). Pharmacotherapy included colchicine (51%), NSAIDs (40%), and corticosteroids (30%), often in combination. This study estimates 37 000 US patients with RP; incidence was 6.0/100 000/year (95% CI, 5.6‒6.3), and prevalence was 11.2/100 000 (95% CI, 10.6‒11.7). Conclusions Patients with RP may have multiple recurrences and/or complications, often because of inadequate treatment response and persistent underlying disease. Corticosteroid use is frequent despite known side-effect risks, potentially exacerbated by prevalent comorbidities. Substantial clinical burden and lack of effective treatments underscore the high unmet need.

Clinical and economic outcomes associated with hospitalizations for acute idiopathic pericarditis in the United States.

BACKGROUND: Outcomes-based data regarding the management of hospitalized U.S. patients with acute idiopathic pericarditis (AIP) are lacking. OBJECTIVES: This study sought to elucidate the clinical and economic outcomes associated with the inpatient care of AIP. METHODS: Cohort study of adults with AIP; multivariable analyses of clinical and economic outcomes (inpatient mortality, surgical or medical complications, length of stay, and medical charges). RESULTS: Surgical or medical complications, pericardiocentesis, and pericardiotomy were each independently associated with a significantly higher odds of inpatient mortality (p<0.05). Pericardiocentesis, pericardiotomy, and pericardiectomy were also independently associated with significantly higher odds for complications (p<0.001) and, overall, surgical or medical complications were associated with longer lengths of stay and higher charges (p < 0.001). A higher odds of inpatient mortality was associated with micropolitan or rural patient residence, Medicaid payor, and African American race (p<0.05). CONCLUSIONS: U.S. inpatient cases of AIP are associated with significant use of healthcare resources, disparities, morbidity, and mortality.

Burden of Recurrent Pericarditis on Health-Related Quality of Life.

The extent to which recurrences of pericarditis episodes impact patients' health-related quality of life (HRQOL) remains poorly understood. This study aimed to evaluate HRQOL and work productivity in patients with recurrent pericarditis (RP). Adult patients from a centralized recruitment database for the rilonacept Phase 2/3 clinical trials were invited to participate in a survey. Inclusion criteria were confirmed RP diagnosis and ≥1 recurrence within the previous 12 months. The 11-Point Pain Numeric Rating Scale, Patient Global Impression of Pericarditis Severity, Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health v1.2, PROMIS Short Form Sleep Disturbance 8b, Work Productivity and Activity Impairment v2.0, and customized questions about fear and economic impact were used. In total, 83 patients (55% female, average age = 49.3 years) completed the survey. The median time since pericarditis diagnosis was 3.0 years at the time of survey completion; 49% experienced ≥3 recurrences in the previous 12 months. Forty percent had an emergency room visit, and 25% were hospitalized for their most recent recurrence. Sixty-six percent of participants rated the symptoms of their last recurrence as severe. The mean value for worst pericarditis pain (0 to 10 scale) during the most recent recurrence was 6.1. The average T-scores for PROMIS physical and mental health were 37.6 and 42.8, respectively, compared with 50 in the general population. Participants reported 50% of overall work impairment and 62% of activity impairment due to RP. In conclusion, patients with RP experienced a high number of recurrences with severe symptoms that substantially reduced their HRQOL and work productivity.

The Role of 18FDG PET/CT in the Assessment of Endocarditis, Myocarditis and Pericarditis.

Endocarditis, myocarditis and pericarditis are a heterogeneous group of phenotypic syndromes where the culprit area of inflammation is the heart. Inflammation may be determined by an infective agent, toxins, drugs or an activated immune system. Clinical manifestations can be subtle and diagnosis remains a challenge for cardiologists, requiring high level of suspicion and advanced multimodal cardiac imaging to avoid life-threatening consequences. The purpose of this review is to report the recent advances of PET/CT imaging with 18FDG in helping the management of patients affected by inflammatory heart disease. Two independent reviewers searched in PubMed articles published before or in June 2019 and final decisions on the inclusion of references were done in consensus with a third reviewer. At the end of the selection process 23/206 articles on "cardiac inflammation"; 26/235 articles on "endocarditis", "prosthetic heart valve", "pacemaker", "implantable cardiac device"; 7/103 articles on "myocarditis"; 13/330 articles on sarcoidosis" and 2/19 articles on "pericarditis" were included. Compared with the conventional methods, molecular imaging has the advantage to non-invasively and directly trace the inflammatory process, and to identify earlier the presence and the extent of intra-cardiac and extra-cardiac involvement, to enable quantification of disease activity, guide therapeutic interventions, and monitor treatment success.

Cancer Treatment-Associated Pericardial Disease: Epidemiology, Clinical Presentation, Diagnosis, and Management.

PURPOSE OF REVIEW: Cancer therapeutics have seen tremendous growth in the last decade and have been effective in the treatment of several cancer types. However, with advanced therapies like kinase inhibitors and immunotherapies, there have been unintended consequences of cardiotoxicities. While traditional chemotherapy and radiation-induced cardiotoxicity have been well studied, further research is needed to understand the adverse effects of newer regimens. RECENT FINDINGS: Both immune-mediated and non-immune-medicated cytotoxicity have been noted with targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. In this manuscript, we describe the pericardial syndromes associated with cancer therapies and propose management strategies. Pericardial effusion and pericarditis are common presentations in cancer patients and often difficult to diagnose. Concomitant myocarditis may also present with pericardial toxicity, especially with immunotherapies. In addition to proper history and physical, additional testing such as cardiovascular imaging and tissue histology need to be obtained as appropriate. Holding the offending oncology drug, and institution of anti-inflammatory medications, and immunosuppressants such as steroids are indicated. A high index of suspicion, use of standardized definitions, and comprehensive evaluation are needed for early identification, appropriate treatment, and better outcomes for patients with cancer treatment-associated pericardial disease. Further research is needed to understand the pathophysiology and to evaluate how the management of pericardial conditions in these patients differ from traditional management and also evaluate new therapies.