With COVID, Not All Myocarditis Is Created Equal

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.
Second only to George Washington’s use of live smallpox to vaccinate Revolutionary War soldiers in 1777, the COVID vaccines may be the most controversial in US history. This is not to say that they should be controversial; I’m one of those people who look at the data and come down on the side of decent efficacy and minimal safety risk. But we can’t deny the reality here: The public is much more skeptical of COVID vaccines than the flu vaccine or the RSV vaccine, for example. This is true for those who identify as Republicans or Democrats, although the latter group is less vaccine hesitant in general.
Myriad reasons exist for the — in my opinion, unwarranted — COVID vaccine skepticism: mixed messaging about efficacy, poor communication about the underlying mRNA technology, and, of course, this myocarditis thing.
It is now clear that a small percentage of people develop myocarditis, inflammation of the heart muscle, after receiving the Pfizer or Moderna mRNA-based COVID vaccines. Complicating the risk-benefit calculus, the people who are seemingly at the highest risk for vaccine-associated myocarditis are the people at the lowest risk for death from COVID: young men.
So how is a young man to decide whether the vaccine is worth it? Most public health officials cast this as a balance between the risk for myocarditis (which is low) and the risk for COVID complications (which is also low). But one thing seems to keep getting missed, which is that COVID infection can give you myocarditis too.
We are dealing with very small percentages here. Most data suggests an incidence of myocarditis within 7 days of vaccination that ranges from a low of 1 out of 3 million doses in older adults to a high of 1 in 10,000 in males aged 16-17.
As I said, myocarditis happens after COVID infection too. This study found that, for men under age 40, there were 16 excess cases of myocarditis per million individuals after infection compared with 97 after the second dose of the Moderna vaccine. In the overall population, though, there were more cases of myocarditis due to infection than the vaccine. 
Still, these are rates per million people. And it’s not like myocarditis is the only thing COVID can do to you. There’s death, too. But it does complicate the decision-making a bit, particularly for those young, otherwise healthy men. 
There’s one more critical piece of information we need to know, a piece I’m glad to see finally getting answered, based on this study, appearing this week in JAMA. Is post-vaccine myocarditis worse, better, or the same as post-COVID myocarditis?
To answer this question, researchers leveraged the French national health system, which has more or less complete data on every person in that country. I have major epidemiology-envy for these European countries with national health systems, but in America we have Waffle House.
The authors identified every patient in France from December 2020 to June 2022, from ages 12 to 49, who was hospitalized with myocarditis. Out of a country of 68 million people, that was a total of 4635. Remember, myocarditis is very rare. 
If the myocarditis was diagnosed within 7 days of receiving a COVID vaccine, it was classified as post-vaccine myocarditis. If it was diagnosed within 30 days of a COVID infection, it was classified as post-COVID myocarditis. And if neither, it was classified as conventional myocarditis, which formed the majority of all cases. I’ll note that seven individuals were diagnosed with myocarditis both within 7 days after a COVID vaccine and within 30 days of a COVID infection. They were dropped from the analysis.
So, we have three groups here, and as you might expect, they are quite a bit different in terms of baseline characteristics. Those with post-vaccine myocarditis were younger, more likely to be male, and were broadly healthier, with less heart disease, respiratory disease, and diabetes. 
The main question the researchers had is, basically, is all myocarditis created equal? To figure that out, they looked at outcomes that happened after that initial hospitalization for myocarditis — things like rehospitalization for myocarditis, cardiovascular events, heart failure, death, and so on, accounting for the fact that the people with postvaccine myocarditis were healthier to begin with.
Here I’m showing you hazard ratios. This is the relative rate of the given event among people with myocarditis due to either the vaccine or the virus, compared with people with conventional myocarditis who form the reference group.
The pattern is fairly clear. Post-vaccine myocarditis has better outcomes than conventional myocarditis, and post-infection myocarditis has similar outcomes to conventional myocarditis.
This is not to say that post-vaccine myocarditis is benign. There are events here. One individual died, presumably due to complications from post-vaccine myocarditis. Of course, four individuals died in the post-infection myocarditis group. 
These findings held up in some relevant sensitivity analyses, including one where they classified anyone with myocarditis within 30 days of the vaccine as post-vaccine myocarditis as opposed to the conventional 7-day window. 
So, what’s going on here? It’s not entirely clear. Logic would say that because both the vaccine and the virus cause myocarditis, there must be something common to both that is responsible. And the two things common to both are the mRNA code and the spike protein that results from it. Given what we see in this study, with post-infection myocarditis being worse, it lends credence to the hypothesis that the spike protein, perhaps via molecular mimicry, is instigating an inflammatory response against heart muscle cells. It’s just that, with the vaccine, the spike protein dose is self-limited. The COVID virus itself, though, comes with an entire package of proteins to produce more spike protein than what you would get inoculated with. That’s how life finds a way.
But let’s try to answer the fundamental question at the heart of all of these studies: Is the risk of the vaccine worth the benefit? The answer is that myocarditis is not the answer. This outcome is too rare, post-vaccine or post-COVID, to weigh heavily on rational decision-making. It’s like deciding whether to carry a flask of whiskey in your pocket based on its ability to stop bullets. 
To really make an informed decision about vaccination — and vaccination season is right around the corner — you need to understand the aggregate risk and the aggregate benefit. Most data suggest, for most people, that the benefit outweighs the risk by a significant margin. If we imagine ourselves to be average, we would probably choose to get vaccinated.
But humans have a cognitive bias known as dread risk bias, where we consider an outcome to be more likely than it truly is if the outcome itself is particularly horrible. That’s where this myocarditis talk gets us into trouble and impacts vaccine uptake. Myocarditis is scary. And, like shark attacks, we behave as if the outcome is more likely to happen than it really is. 
I’m not saying not to worry about vaccine side effects or COVID effects. In the end, these decisions are personal. But just because they’re personal doesn’t mean they can’t be rational too. 
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilsonand his book, How Medicine Works and When It Doesn’t, is available now. 
 
Any views expressed above are the author’s own and do not necessarily reflect the views of WebMD or Medscape.