Myocarditis and COVID-19 Vaccines: New Review Tackles Knowns, Unknowns

Myocarditis is a rare complication of COVID-19 vaccination, but it’s minor and fleeting in the majority of cases and the potential risk of vaccines is far outweighed by their benefits in both males and females over age 12, authors of a new review conclude.

Within weeks of the first reports of myocarditis following COVID-19 vaccination, the Advisory Committee on Immunization Practices (ACIP) to the US Centers for Disease Control and Prevention (CDC) determined that there is a “likely association” between mRNA vaccines and myocarditis. For their paper published in Circulation today, Biykem Bozkurt, MD, PhD (Baylor College of Medicine, DeBakey VA Medical Center, Houston TX), and colleagues summarize the evidence to date (including the CDC’s own numbers), explore the potential underlying mechanisms, address questions of diagnosis and management, and—critically—try to quantify the myocarditis risk from vaccinations against the cardiac and other risks associated with COVID-19 infection itself.

The aim of the paper, Bozkurt told TCTMD, was “to provide a comprehensive review of all the information to date, including a potential conceptualization of mechanisms, guidance to clinicians and scientists, and a call for action for . . . appropriate studies. We also wanted to put the risk versus benefit ratio in the right perspective, demonstrating that the benefit is much higher than the potential risk.”

The Circulation paper summarizes the Vaccine Adverse Event Reporting System (VAERS) and Vaccine Safety Datalink (VSD) data released during a June 23 ACIP public meeting, as reported by TCTMD last month; the data has since been published in Morbidity and Mortality Weekly Report. It then goes on to sum the vaccine-linked myocarditis cases reported in the medical literature, by the US Department of Defense, and by the Israeli Ministry of Health series, which was one of the first to raise concerns about this association back in April. A table handily summarizes all of the case series and reports to date.

But COVID-19 itself also has been linked to cardiac damage, Bozkurt et al point out. And while direct virus invasion has largely been ruled out in favor of inflammatory effects and other secondary effects as the causative factor, it remains possible that COVID-19 may “incite a form of myocarditis that is different from the typical lymphocytic myocarditis associated with other viral myocarditis presentations,” they conclude.

Deep Dive Into Mechanisms

A large portion of the paper is what Bozkurt called a “deep dive” into the possible mechanisms by which vaccines might produce a myocarditis reaction and why younger males are most at risk, more often following a second dose.

The three most plausible explanations, explored in depth, are molecular mimicry between the spike protein and a self-antigen; a triggering of a preexisting immune dysregulation in certain people who have a genetic predisposition; or auto-antibody formation, “meaning you develop antibodies to your own antigens,” she said, which again suggests an underlying or preexisting dysregulation. A fourth possibility, but one that Bozkurt dismissed as “unlikely,” is an innate response to messenger RNA.

I think we're talking about kind of a one-time exposure with the vaccine versus probably ongoing issues with the virus that we are just starting to understand. Donald Lloyd-Jones

Future studies should evaluate each of these potential mechanisms to better understand why myocarditis is cropping up, the authors urge. But while more work needs to be done to elucidate the link, the takeaway for physicians and patients should be that the benefit-risk ratio “shows a favorable balance” for vaccines for all age and sex groups, they write.

Summarizing for TCTMD, Bozkurt put the risk of myocarditis—almost all of which were mild, self-limiting cases—in the range of 12 to 14 per million vaccinations. By contrast, the potential risk of serious complications with COVID-19 infection, including hospitalizations and death, ranges from 0.1 to 1 per 100,000 for people aged 12-29 years. Risk of myocarditis appears to be highest among males in the age 16 to 18 range, she noted, but this age group also falls in the category identified by the CDC as facing a risk of hospitalization for COVID-19 infection of 183 per million, a risk of ICU admission of 38 per million, and a risk of dying of 1 per million.

The risk of either outcome is very small, she noted, but the risk of myocarditis following vaccination is “even smaller” than for COVID-19 complications following infection. “COVID-19 is a deadly disease and we do see this even in the young populations,” she said. “Beyond that, [it] can result in hospitalizations and also myocardial injury. This tries to put that in that right perspective.”

In the section of the paper dedicated to patient management, Bozkurt and colleagues write that clinicians should be aware of the myocarditis and pericarditis risk in young patients, especially males, presenting with chest pain within the few days following vaccination. An ECG and cardiac troponin should be the first tests, while tests for C-reactive protein and erythrocyte sedimentation rate “can be helpful,” they say. Cardiac consult along with echocardiography or MRI are needed for suspected cases, and if there are ECG changes, abnormalities on imaging, arrhythmias, or hemodynamic instability that develop, then hospitalization and close follow-up will likely be required.

Bozkurt stressed more than once to TCTMD that the vast majority of myocarditis cases were mild. While nonsteroidal anti-inflammatory drugs, steroids, and colchicine were all used in some of the reported cases, very few patients required intravenous immunoglobulin or other agents and no randomized trial data exists to support the best strategy.

“Though the clinical course appears mild with likely resolution of symptoms and signs, it is reasonable to restrict or defer strenuous physical activity and competitive sports until after complete resolution of symptoms, signs, hemodynamic, rhythm, diagnostic and biomarker abnormalities,” the authors advise.

The CDC has said that if a person develops myocarditis or pericarditis following a first dose of an mRNA vaccine, a second dose can be considered if the case is mild and resolves. To TCTMD, Bozkurt said that whether or not a patient should actually go ahead and get that second dose, and on what schedule, should depend on their particular circumstances.

“The decision will need to be made accordingly to the age, presentation, the amount of involvement, the extent and severity of the myocarditis, how it was diagnosed, and how long that took, along with what the prevalence of [certain] variants are in the community and the individuals ability to self-seclude or isolate,” she explained.

Apples to Oranges?

Commenting on the paper for TCTMD, Donald Lloyd-Jones, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), called it an important “evidence synthesis of what's out there. . . . It does a nice job of presenting quite starkly, for me, the absolute risk comparison of myocarditis from the vaccine versus serious complications from the virus.”

At some level, though, this is like “comparing apples to oranges,” he noted, since the long-term effects of COVID-19 are unknown.

“It appears that the exposure from a second vaccine dose and the occurrence of myocarditis, from everything we have today, indicates that is a self-limited, generally mild [reaction] with, as far as we can tell, no longer-term consequences,” Jones said. “But I think we are still learning about the long-term consequences of actual viral infection, which is associated with much higher rates of complications not only in terms of myocarditis in the heart, but also for the lungs, for the kidneys, and for other major organs, not least of which the brain. So I think we're talking about kind of a one-time exposure with the vaccine versus probably ongoing issues with the virus that we are just starting to understand.”

That said, “anyone diagnosed with myocarditis as a result of either the vaccine or the virus must be followed over the long-term . . . to make sure that there a full recovery of heart’s pumping function. . . . We'd certainly strongly recommend that anyone who's had severe COVID or myocarditis after the vaccine should have an ongoing relationship with a cardiologist appropriate to their age group.”