A new study by researchers from the Drug Safety Research Unit, Southampton-UK and the School of Pharmacy and Biomedical Sciences, University of Portsmouth-UK warns about the occurrences of myocarditis and pericarditis in men following mRNA-based COVID-19 vaccination.
Though considered rare events, the number of cases being reported worldwide is of a concern.
The study findings found evidence that younger male vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines compared with older vaccinees. Although rare, these events were still of concern.
It was also found that most of these events with mild clinical course followed by full recovery in most cases were more frequent following the second dose.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.09.09.21263342v1
The study team in UK assessed data from around the world to better understand the frequency and risk factors for myocarditis and pericarditis following immunization with messenger RNA (mRNA)-based vaccines designed to protect against the COVID-19 disease.
The warnings of myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the sac surrounding the heart) following mRNA-based COVID-19 vaccination first emerged in Israel in May 2021 and further cases have since been reported in numerous other countries.
Dr Samantha Lane and Dr Saad Shakir from the Drug Safety Research Unit in Southampton and used spontaneous reporting systems from the UK, the United States, and the European Economic Area to estimate the frequency of these events following exposure to the mRNA-based COVID-19 vaccines developed by Pfizer-BioNTech and Moderna.
Although the study findings suggest that both events are rare and that the typical clinical course is mild, with full recovery reached in most cases, the growing number of cases worldwide is adding to concerns.
The study findings also suggested that the events were more common amongst males, occurred more frequently following a second vaccine dose and mostly affected younger vaccinees and the results were consistent across the three data sources used.
Dr Samantha Lane told : “This is an important finding, because as vaccination programs around the world progress, rates of myocarditis and pericarditis are likely to increase. Regulatory authorities should continue to monitor the effect that mRNA vaccination might have on the heart in the populations for which they are responsible.”
Both myocarditis and pericarditis have recently been recognized as rare adverse events following vaccination with the COVID-19 vaccines developed by Pfizer-BioNTech and Moderna.
A medical alert of these events following mRNA-based vaccination was first raised in Israel in May 2021, where 148 cases of myocarditis were reported within 30 days of immunization, usually following a second dose.
This concerning occurrences prompted the Israeli Ministry of Health to issue an investigation into any possible link between these cases of myocarditis and vaccination.
Those study results pointed to a possible link between the second vaccine dose and the onset of myocarditis among young men aged 16 to 30, with a stronger link identified among those aged 16 to 19.
Numerous other such cases emerged and were reported around the world after the medical alert by Israel.
This forced the the product information for both the Pfizer-BioNTech and Moderna vaccines to be updated to include myocarditis and pericarditis as an adverse event of unknown frequency in the UK, Europe, and the US.
Dr Saad Shakir added, “Although most cases appear to have mild severity, further follow-up of cases is ongoing to determine the long-term outcomes of myocarditis and pericarditis following mRNA vaccines. Individual regulatory authorities continue to monitor the events of myocarditis and pericarditis in their own spontaneous reporting systems.”
The COVID-19 and Myocarditis study team used spontaneous reporting outputs from the UK (Yellow Card scheme), the US (Vaccine Adverse Event Reporting System [VAERS]), and the European Economic Area (EudraVigilance) to estimate the frequency of reported cases of myocarditis and pericarditis following immunization with either the Pfizer-BioNTech or Moderna vaccine.
For the study, the data lock points were August 6th, 2021, for VAERS and EudraVigilance, and August 4th, 2021, for the Yellow Card scheme.
It was found from the reporting rates of spontaneous adverse reactions, myocarditis and pericarditis were rare events across all three data sources.
The study findings showed that in the UK, 7.93 cases of myocarditis and 6.73 cases of pericarditis occurred per million recipients of at least one dose of the Pfizer-BioNTech vaccine. For the Moderna product, the corresponding figures were 2.07 and 1.79 cases per million.
However no data were available regarding the age or sex of those reporting the events, or on which vaccine dose either of the events occurred.
For America, 6.47 cases of myocarditis and 3.53 cases of pericarditis were reported per million individuals who had received two doses of the Pfizer-BioNTech vaccine. For the Moderna product, the corresponding figures were 3.65 and 2.69 cases per million.
Importantly of the 968 myocarditis events reported following Pfizer-BioNTech vaccination, 759 (78.4%) occurred in males. Reports of myocarditis were also more frequent in younger age groups, irrespective of gender. Similarly, while pericarditis was more frequently reported among males, this pattern was less pronounced among those older than 40 years.
It was reported that similar trends were observed for the Moderna vaccine.
It was also reported that overall, the majority of both myocarditis and pericarditis events occurred following the second dose of either vaccine.
The study also showed that in the European Economic Area, 4.23 cases of myocarditis and 2.87 cases of pericarditis were reported per million individuals who had received at least one dose of the Pfizer-BioNTech vaccine. For the Moderna product, the corresponding figures were 6.15 cases and 3.84 cases per million.
Similarly for both mRNA vaccines, 71.56% of the myocarditis events and 53.46% of the pericarditis events were reported to have affected males.
The study team urged that health authorities across the world must continue to monitor the effects on the vaccines on the heart.
Dr Lane further added, “This study adds to existing evidence that younger vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines compared with older vaccinees, and reports are more frequent following the second dose.”
She added, “These rare events with a typically mild disease course occur more frequently among males.”
The study team says that the consistencies in the reporting rates and the trends within the three data sources suggest that the results may be generalizable to other populations.
Dr Lane added, “It is important that regulatory authorities continue to monitor the effects of mRNA vaccines on the heart, particularly as vaccine programs progress to include younger vaccinees in many parts of the world. Myocarditis and pericarditis following mRNA COVID-19 vaccines is an area which requires further research”
It should also be noted that the incidence of developing myocarditis and pericarditis is far much higher for those that contract the SARS-CoV-2 infection compare to the vaccines.
Post-vaccination myocarditis has been reported as early as 1957 after smallpox vaccination . Analysis of the Vaccine Adverse Event Reporting System (VAERS) data between 2011 and 2015, where a total of 357,188 reports were reviewed and found 199 cases of myocarditis and pericarditis.
Only the smallpox vaccine emerged with an expectedly strong correlation with myocarditis and pericarditis . Previous findings should be interpreted with caution regarding limitations affecting the voluntary reporting system and may be underreported.
Conversely, in the current era of heightened surveillance by the CDC’s vaccine safety data (VSD) working group and the Vaccine Related Biological Products Advisory Committee (VRBPAC) on immunization practices after COVID-19, and post-marketing surveillance by the vaccine producing companies in the setting of conditional marketing authorization, the reporting of probable myocarditis and pericarditis cases is significantly higher.
Since April 2021, increased cases of myocarditis and pericarditis have been reported in the United States after mRNA COVID-19 vaccination, particularly in adolescents and young adults [7,8,9,10,11,12].
The American Academy of Pediatrics (AAP) and the American Heart Association (AHA) have endorsed CDC recommendations and reiterated the potential benefits of COVID-19 vaccination, which outweighs rare myocarditis or pericarditis risks and recommend the vaccination for anyone 12 years of age and older [13,14].
Very little published data on the incidence of mRNA vaccine-associated myocarditis and pericarditis exist except those reported in the media. We performed a systematic search of electronic databases (PubMed, Scopus, medRxiv and bioRxV) with a goal to publish the results in the context of expanding the vaccine target population using the terms “mRNA vaccine complications”, “heart inflammation with COVID-19 vaccine”, “impact of COVID-19 vaccine in children and young adults”, “myocarditis after COVID-19 vaccination” and “pericarditis after COVID-19 vaccination”, and “myopericarditis after COVID-19 vaccination”.
We found a total of 29 cases in the literature as of 26 June 2021. This review summarizes 29 published cases of vaccine-induced myocarditis in children and adults, describes a comprehensive management plan and emphasizes that rare instances of myocarditis should not preclude anyone from taking the COVID-19 vaccine.
Incidence of Vaccine Related Myocarditis/Pericarditis
As of 26 June 2021, a total of 322 million doses of vaccine were used, and thus far, 79 children aged 16 or 17 years, and 196 young adults aged 18–24 years have been confirmed by the CDC as having myocarditis/pericarditis following mRNA COVID-19 vaccination after analyzing data in the VAERS .
The adjusted risk ratio for myocarditis and pericarditis events in children and young adults between 16 and 24 years of age has been determined to be 0.94 (95% confidence interval 0.59–1.52) [16,17]. Because of this, the US FDA added a warning about risk of myopericarditis and pericarditis to the fact sheet of mRNA COVID-19 vaccines. Recently, the US military reported 23 patients among 2.8 million doses of mRNA COVID-19 vaccine administered .
While the observed number of myocarditis cases was small, the number was higher than expected among male military members after a second vaccine dose.
In a report from the Israeli Ministry of Health, one in 3000 to one in 6000 men aged 16–24 who received the mRNA COVID vaccine developed myocarditis and pericarditis .
Ninety percent of the cases in Israel appear to be men. Although the background rate of myocarditis in this population is high, the rate following vaccination appeared to be 5–25 times higher than the background rate. The European Medicines Agency has also recently reported that myocarditis and pericarditis can occur in very rare cases following vaccination with COVID-19 vaccines Comirnaty and Spikevax. .
“The Committee is therefore recommending listing myocarditis and pericarditis as new side effects in the product information for these vaccines, together with a warning to raise awareness among healthcare professionals and people taking these vaccines” . The European Medicine Agency’s safety committee (PRAC) has included 145 cases of myocarditis in the European Economic Area (EEA) among people who received Comirnaty and 19 cases following the use of Spikevax. As of 31 May 2021, around 177 million doses of Comirnaty and 20 million doses of Spikevax had been given in the EEA. As of end of May 2021, the incidence of myocarditis is 1 per million for both Comirnaty and Spikevax in the EEA.
Diagnosis and Management
The common clinical presentation of COVID-19 vaccine-associated myopericarditis includes chest pain, fever, palpitation, shortness of breath, fatigue, nausea, vomiting, abdominal pain or unusual symptoms such as forceful or thumping heart beats. Common signs of myopericarditis include tachypnea, tachycardia, murmur, gallop, diminished pulses, hypotension, hepatomegaly, edema and signs of low cardiac output .
The laboratory tests commonly used include testing to detect any viral causes of myocarditis, serum concentrations of an inflammatory marker (C-reactive protein, erythrocyte sedimentation rate) and cardiac biomarker (troponin, brain type natriuretic peptide), electrocardiogram, echocardiogram, CMR and serologic testing for SARS-CoV-2 antibodies.
Historically, the diagnosis of myocarditis is confirmed by histologic criteria, including acute myocyte injury with inflammatory cells’ infiltration, especially lymphocytes . A paradigm shift in the diagnosis of myocarditis has occurred .
According to an AHA statement, four strata of diagnosis of myocarditis in children are recommended: biopsy proven, clinically suspected, confirmed by CMR and possible myocarditis. The shift in diagnosis acknowledges advancements in CMR and improvement in identifying a constellation of clinical signs and symptoms supportive of myocarditis.
In most cases, COVID-19 vaccine-associated myocarditis is transient and self-limited; it is not justifiable to obtain an endomyocardial biopsy. Furthermore, the clinical impact of myocarditis varies widely due to the range of etiologies and the unpredictable physiologic responses depending upon the host’s response to the inciting agent.
Elevated cardiac troponin may indicate acute cardiac injury, but not specific to the diagnosis of myocarditis, as many myocarditis patients are asymptomatic and are subclinical. Furthermore, features of myocarditis and pericarditis may overlap and commonly present as myopericarditis.
Because of variable clinical manifestations of myocarditis, it is essential to follow the CDC definition of acute myocarditis (Figure 1) and acute pericarditis (Figure 2). Cardiac magnetic resonance imaging with tissue characterization using T1 and T2 mapping is a useful non-invasive modality for diagnosing myocarditis .
Localized or generalized myocardial edema on T2 recovery images without evidence of late gadolinium enhancement (LGE) and no other clinical features can be the only CMR evidence of myocardial inflammation in mRNA COVID vaccine associated myocarditis in early stages.
The AHA recommended “everyone to keep in touch with their primary care professional and seek care immediately if they have any of these symptoms in the weeks after receiving the COVID-19 vaccine: chest pain including sudden, sharp, stabbing pains; difficulty breathing/shortness of breath; abnormal heartbeat; severe headache; blurry vision; fainting or loss of consciousness; weakness or sensory changes; confusion or trouble speaking; seizures; unexplained abdominal pain; or new leg pain or swelling” .
Acute myopericarditis associated with COVID-19 vaccine can be associated with arrhythmia. Anticipatory care includes judicious triaging of the disposition of patients seen in ambulatory or emergency setting for work-up or management of probable myopericarditis patients. Whenever possible, serology and PCR for common viral causes of myocarditis such as parvovirus B19, herpesvirus type-6, adenovirus, enterovirus, Epstein–Barr and cytomegalovirus should be obtained to rule out common causes of viral myocarditis.
The treatment considerations for COVID-19 vaccine-associated myopericarditis include anti-inflammatory medications and guideline-directed medical therapy if left ventricular function is reduced . No data for any specific treatment for vaccine-associated myocarditis are available. Steroids are used for their potent anti-inflammatory action in cases where the patient has continued symptoms and troponin leak even after NSAIDs.
However, steroids and IVIG are also immunomodulatory and immunosuppressive agents and could reduce the specific immune response against SARS-CoV-2 triggered by the vaccine. Thus, the duration of steroids administration should be limited to the resolution of the symptoms or ventricular arrhythmias or the recovery of the LV function.
Among 29 cases with a known outcome, all were discharged to their homes within 1 week, and all made full clinical recoveries. However, the long-term impact of myocardial inflammation following COVID-19 mRNA vaccine as detected on CMR, remains unknown and needs to be systematically evaluated. Further studies are required to elucidate the pathophysiology that underlies this complication to seek mitigation strategies and to delineate optimal therapy.
It is prudent to maintain regular follow-up of patients with COVID-19 vaccine-associated myocarditis patients especially those with documented inflammation on CMR. Pending publication of long-term outcome data after SARS-CoV-2 vaccine-related myocarditis, we suggest adherence to the current consensus recommendation to abstain from competitive sports for 3 to 6 months with re-evaluation before sports participation [32,33].
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305058/