Pericardial Cases: Myopericarditis Following COVID 19 Vaccination: Worry or Not to Worry?

Podcast Transcript

Announcer:
Welcome to Cleveland Clinic Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart Vascular and Thoracic Institute at Cleveland Clinic.

Alan Klein, MD:
We have another outstanding case by Dr. Harmon, which is actually very, very current. On the way here I was looking at one of the articles, this is hot off the press, an important topic every day in the outpatient, I get a question. "Did I have a complication from the vaccine?" So, Evan?

Evan Harmon, MD:
Thank you. Good morning. So my name is Evan Harmon. I'm a first year cardiology fellow and over the past four weeks, I've had the great honor of working with Dr. Klein in clinic and learning from him. I've really enjoyed my time in the Pericardial Center. As you all know, we find ourselves well over a year into the COVID-19 pandemic, and despite having efficacious vaccines available since December, roughly 50% of the population remains unvaccinated. That hesitancy has been attributed at least in part to concerns over vaccine side effects, among them being myocarditis, particularly in the young.

Evan Harmon, MD:
So I'm going to present two cases of both myocardial and pericardial injury attributed to mRNA COVID-19 vaccination that we saw recently here at the Cleveland Clinic. So starting with the first case, this was an 18 year old man with no significant past medical history who presented to an outside hospital for acute onset of chest pain. He had received the second dose of his Pfizer vaccination in late April and two days later developed profound intermittent pleuritic chest pain while driving, that initially self-resolved, but unfortunately recurred while exercising the following day, prompting his ED presentation.

Evan Harmon, MD:
In the ED, his vitals and exam are unremarkable, but as you can see his high sensitivity troponin, pro-BNP and CRP were all mildly to moderately elevated. I unfortunately don't have access to his presenting EKG, but this was documented as having diffuse ST elevations with PR depression and B1 and PRL elevation in AVR. Because of the patient's symptoms, cardiac biomarkers and the low suspicion for an acute coronary syndrome, he underwent CTPA, which was negative for pulmonary embolism or aortic pathology.

Evan Harmon, MD:
He was admitted for a presumed diagnosis of acute pericarditis, and this was his initial echocardiogram shortly after his admission to the outside hospital. In the interest of time, I've just included the perasternal short and apical four chamber views only to demonstrate what you can see as a mild reduction in his biventricular ejection fraction, and then perhaps a trivial pericardial effusion posteriorly in the parasternal long axis view.

Evan Harmon, MD:
This was read as an ETF of 40% at the outside hospital, and so because of that reduction in EF, there was presumed to be potentially some myocardial involvement as well, and he was started on indomethacin and colchicine for the diagnosis of an acute idiopathic myopericarditis. Because of the patient's reduction in ejection fraction and a low pretest probability of obstructive coronary disease, he subsequently underwent coronary CTA, which is negative for CAD and his colchicine was titrated followed by a cardiac MRI. Here on the left, I've just included a four chamber CNA view just to demonstrate that on this view at least, it looks like the biventricular function is reasonably adequate. There's no obviously diffusion on this particular study, and then you can see in the delayed enhancement mid short axis view, there's no obvious contrast uptake in the myocardium.

Evan Harmon, MD:
Prior to the patient's discharge, he underwent a follow-up limited echocardiogram that also confirmed recovery of his ejection fraction, and he was ultimately discharged home on indomethacin and colchicine for the diagnosis of an acute myopericarditis, presumably due to the COVID-19 vaccine. Was scheduled for follow-up with local cardiology in eight weeks. Instead however, the patient chose to present to the Pericardial Center for a second opinion regarding this diagnosis, and we found that unfortunately, just two weeks after his discharge, he had resumed working out fairly vigorously.

Evan Harmon, MD:
In that context had been still having some ongoing intermittent chest pain following his hospital discharge on dual therapy. You can see his labs obtained in clinic that morning were unremarkable, including his inflammatory markers. He underwent a repeat echocardiogram here at the Clinic, and those images are here on the right, both again in the sort of perasternal long and apical four chamber views compared to those that obtained at the time of his acute illness in May. Really you can see here a more robust ejection fraction, I think both in the RV and LV, and then again, you don't see that sort of trivial effusion that he had on his initial echocardiogram.

Evan Harmon, MD:
He also underwent cardiac MRI here at the Clinic, and I just included this vertical long axis CNA image, just to again, sort of confirm it is a preserved ejection fraction. On his delayed enhancement imaging, similar to the MRI obtained at the outside hospital, again, you see no obvious contrast uptake in the myocardium. So given his improving echocardiogram and essentially normal cardiac MRI and improving inflammatory markers, this patient was felt to have had an acute episode of myopericarditis attributable to his recent mRNA COVID vaccination, his indomethacin was exchanged for ibuprofen in keeping with AHA guidelines. His colchicine was decreased, and he's planning to follow up with us this fall.

Evan Harmon, MD:
The second case is a little bit more complicated, and this was a 22 year old man with a history of myocarditis due to Coxsackievirus in November of 2019, who was presenting to us for a second opinion regarding a recent diagnosis with perimyocarditis. This patient received the first dose of his Pfizer vaccination series in April, and that same day developed headache, chills, nausea and diarrhea, which had been well-described. But more troublesome three days later, developed an acute onset of severe chest pressure with associated diaphoresis, prompting his ED presentation.

Evan Harmon, MD:
Similar to our first cases, vitals and exam are unremarkable, and you can also see that he had elevations to his cardiac and inflammatory biomarkers. Again, I don't have access to this outside hospital EKG, but this was reported as having diffuse ST elevation in quotes, suggestive of pericarditis, and his chest X-ray was negative. Given this patient's history and a concern for recurrent myocarditis, he was transferred to a larger non-Cleveland Clinic facility for ongoing management.

Evan Harmon, MD:
So shortly after his admission, he underwent an echocardiogram that was read as having a mid-range of 45-50% with global hypokinesis of the LV, and because of this concern for recurrent myocarditis, both rheumatology and infectious disease were consulted who recommended a fairly robust lab workup. I've included these just because interestingly though, his SARS-CoV-2 PCR testing for acute infection was negative. His IGG antibody testing against the nucleocapsid protein was positive, suggesting a previous COVID infection, and upon further questioning the patient did recall losing his sense of taste and smell for about three days in the fall of 2020. So he was presumed to have had, he was not tested that time, but was presumed to have had an undiagnosed case of COVID-19.

Evan Harmon, MD:
Also because of his history of Coxsackie myocarditis, he had repeat titers drawn. They were actually found to be four times that were drawn in 2019 at the time of his illness. Ultimately these were felt to be difficult to interpret and not particularly contributory to his acute presentation, but I thought I would include them for completeness sake. You can see he had a robust inflammatory and autoimmune workup, all of which was unrevealing, including Coxsackie PCR.

Evan Harmon, MD:
Shortly after his arrival to the outside hospital in this lab workup, he had an acute recurrence of his chest pain and was transferred to the CICU for closer monitoring, and at that time was started on high dose aspirin and colchicine therapy, with resolution of his chest pain, at which time he also underwent cardiac MRI. Now, fortunately, because of this patient's history of Coxsackie myocarditis, he had a prior MRI for comparison. Here I'm showing actually just the images from his acute illness at current admission, and here in the CNA view, you can see a reasonable biventricular EF and no obvious pericardial effusion in the left image. But on the right, I think you can appreciate a small pericardial effusion here, as well as some degree of mild pericardial thickening.

Evan Harmon, MD:
When you compare his delayed enhancement images to the MRI in January, I think you can appreciate here we're in the basal short axis view, and we can see increased contrast uptake in the inferolateral wall, that is much more robust than was visualized about a year prior. Similarly, in the mid short axis view, I can see mid myocardial uptake throughout the interventricular septum, even extending up into the interior wall in the epicardium, which again was much more profound than was visualized in January of 2020.

Evan Harmon, MD:
So this patient was presumed to have had an episode of acute perimyocarditis, presumably due to his recent COVID-19 vaccination. He underwent a repeat echocardiogram prior to his discharge with recovery of his ejection fraction, and was ultimately discharged on colchicine monotherapy. Ten days after the patient's discharge, he followed up with his local PCP and cardiologist, who found his inflammatory markers to be mildly and persistently elevated, and for that reason, he was started on a prednisone taper as well as coreg.

Evan Harmon, MD:
So by the time we were seeing him for a second opinion in the Pericardial Center roughly a month later, he had completed his prednisone taper and was only on colchicine and carvedilol by that point, with improvement of his symptoms. What he felt was maybe about 90% back to baseline. His inflammatory markers from that clinic visit were running remarkable. I've included his echocardiogram here from the clinic, really just the traditional long and short axis views, just to demonstrate his robust DF and no appreciable pericardial effusion.

Evan Harmon, MD:
Then on repeat cardiac MRI here at the Clinic, comparing back to the time of his acute illness, you can see that in the inferior lateral wall, there is much less delayed contrast uptake compared to that study in April. Similarly, when you look in the mid short axis view, there is much less contrast uptake in the mid myocardial wall and the anterior wall and epicardium, that was viewed in that previous study. So with this patient's normal echocardiogram and approving cardiac MRI and inflammatory biomarkers, this patient was felt to have had a resolving episode of acute perimyocarditis due to his mRNA COVID vaccination. His colchicine was decreased from twice daily to once daily. He was counseled on exercise reduction and weight loss, and he too will follow up with us this fall.

Evan Harmon, MD:
So just how common is this? Before I talk a little bit about that, I just wanted to give just a brief timeline, and I'll try to be quick with this, just to kind of give an idea of how we ended up here today. So as you all know, the mRNA Pfizer and Moderna vaccines were approved for emergency use in December of 2020, and it was just two months later that the first presumed case of vaccine-related myocarditis was reported. This was actually first reported in the lay press, this particular headline actually came from the Jerusalem Post. Over the month of March and April multiple governing bodies, including the CDC, WHO and the Israeli Ministry of Health would continue to monitor ongoing cases of presumed vaccine related pericarditis and myocarditis.

Evan Harmon, MD:
In parallel to that though was a randomized study by Pfizer, looking at the vaccination in 12 to 15 year old adolescents and given a reassuring safety profile, the FDA extended the emergency use authorization to patients as low as 12 years of age, which at the time, and given the ongoing reports of myocarditis and pericarditis, was met with both praise and some controversy. Less than a month later, the Israeli Ministry of Health released their own statement regarding cases they had observed in Israel, following Pfizer vaccination in myocarditis and pericarditis, and overall felt that these cases were quite rare and mostly self-limiting.

Evan Harmon, MD:
Meanwhile, in the United States, however, there continued to be ongoing reports in both the pediatric and adult literature of COVID vaccine related myocarditis and pericarditis, which ultimately culminated in the CDC releasing a formal statement this month. In the CDC data, they found that of the 296 million doses of mRNA COVID vaccine given since December, 52 million of those have been given to patients 12 to 29 years old. Despite all of those vaccine doses, there had only been 1,226 reports of pericarditis and myocarditis since that time. You can see they found that the vast majority of these cases occurred after the second dose of the mRNA vaccine with a male predominance in mostly patients under 30.

Evan Harmon, MD:
Looking closer at data from the vaccine safety data link and confirmed cases of myocarditis and pericarditis following vaccination, the CDC found that the case rate was only 12.6 cases per million second doses of mRNA vaccine given. So obviously quite low and reassuring. But why did this happen? And I think the short answer right now is that we don't know, but there have been some mechanisms proposed. I think the most popular of those proposed mechanisms is this is likely a dysregulated autoimmune and inflammatory response in genetically susceptible hosts.

Evan Harmon, MD:
So if you remember, the mRNA vaccine works by packaging, mRNA encoded for the key SARS-CoV-2 spike protein into lipid nano particles or LNPs. These are injected intramuscularly and taken up by antigen presenting cells like dendritic cells, which then translate the mRNA into that spike protein and stimulate T-lymphocytes. The real key of mRNA vaccination of course, is its ability to stimulate not only CD-4 lymphocytes, but also cytotoxic CD-8 T-cells.

Evan Harmon, MD:
So in this way, the mRNA vaccines are able to generate a robust immune response, utilizing both the antibody mediated and cytotoxic and cell-mediated immune pathways. Unfortunately the mRNA itself can act as an immunogenic trigger in some individuals, and it's felt that some patients may be particularly susceptible to this phenomenon, essentially resulting in a profound inflammatory response and cytokine release that can be damaging to the myocardium and pericardium. Also, keep in mind, the mRNA is frequently genetically modified to preserve its integrity, given its inherent instability, and sometimes those mRNA modifications themselves can stimulate an immunogenic response in some patients.

Evan Harmon, MD:
Another mechanism that's been proposed is maybe an eosinophilic hypersensitivity reaction to the vaccine. This is based primarily on the idea that the lipid nano particles themselves have multiple components to maintain their integrity and stability. One of those being polyethylene glycol, which has been implicated as a potential trigger of anaphylactic reactions to the vaccine in other patients. Other authors have noted that patients who seem to suffer this complication frequently seem to be "primed," either by an initial dose of the vaccine or by a prior COVID-19 infection. So that has given some rise to the idea of a hypersensitivity reaction. Then finally we know that other vaccines, most notably the live smallpox vaccine, have caused eosinophilic myocarditis in the past as well.

Evan Harmon, MD:
I would say that I think overall, this is felt to be a less likely mechanism, primarily because one, many of these patients who have presented following COVID-19 vaccination have not had a profound peripheral eosinophilia. They also, to my knowledge, there's been no case reports demonstrating endomyocardial biopsy evidence of eosinophils infiltrating the myocardium. Then also many cases of eosinophilic myocarditis are typically quite profound and have severe outcomes, and the majority of these cases have been quite mild. But certainly it's an ongoing area of investigation.

Evan Harmon, MD:
So how do these patients present when you look at the cohort of confirmed cases reviewed by the CDC? The median age was 19 years with a male predominance. Most patients present within a week of symptoms and very many presented within two to three days of their vaccination. Of those confirmed cases, almost all the patients were hospitalized, but to date there's been no reported deaths in that confirmed cohort of patients. I've included here, just the CDC definitions of probable and definitive confirmed acute myocarditis, as well as acute pericarditis and myocarditis. I've included this mainly just to reiterate that a key feature obviously, of this diagnosis, is that we still need to be thinking about other causes of myopericarditis in these patients, before attributing their symptoms purely to the mRNA vaccines.

Evan Harmon, MD:
So what diagnostic workup should we perform? Obviously history is incredibly important in teasing out potential alternative etiologies, troponin and pro-BNP are helpful, and as a reminder, in the case of at least myocarditis, troponin does not correlate with heart failure and arrhythmia development, but does correlate with ECMO requirement and mortality, and so can be helpful in these patients.

Evan Harmon, MD:
Inflammatory markers can be supportive of the diagnosis and certainly the EKG is helpful with ST elevations and PR depressions in the case of pericarditis, and more nonspecific ST changes T wave inversions and arrhythmia in myocarditis. All these patients probably should have at least a baseline simple auto-immune workup, including ANA and rheumatoid factor. But certainly you should have a low threshold of involving our rheumatology colleagues in these sort of undifferentiated cases. Obviously COVID testing, both PCR and antibody testing, can be helpful. Then to that end, the utility of a very robust workup like we saw in our second patient is unclear.

Evan Harmon, MD:
I think that probably that most helpful are typically peripheral based PCR tests that are targeted based on the patient's specific risk factors. Obviously the diagnostic standard being endomyocardial biopsy with viral culture and PCR, but that, in the age of multi modality cardiac imaging is becoming, I think, less and less pursued. To that end, I've just included some of the common findings you may see in both echocardiogram and cardiac MRI in these cases. I'll just note for echocardiogram specifically, that in the cases of myocarditis at least, biventricular dysfunction is a particularly poor prognostic sign. Fortunately, many of the cases related to the COVID-19 vaccine present with a preserved ejection fraction, which is reassuring.

Evan Harmon, MD:
Then with regard to cardiac MRI, certainly there's hyperemia, edema, necrosis, and scar that remains late criteria, they can be helpful. But really I think CMR in many of these cases is utilized as a second line imaging modality to either support or verify a diagnosis as suspected that is not clearly confirmed by history, labs and imaging. In terms of management the backbone is really still NSAIDS and colchicine and corticosteroids in patients who are either NSAIDS intolerant or their symptoms prove refractory to dual therapy.

Evan Harmon, MD:
We should be counseling these patients obviously on alcohol avoidance and exercise restriction for at least the three months following their diagnosis, and appropriate heart failure and arrhythmia management obviously is important in patients in which those complications arise. Though, I will say in the available case reports of COVID vaccine related myocarditis and pericarditis, these seem to be very rare.

Evan Harmon, MD:
Finally, there have been case reports utilizing both IV steroids and IVIG, but I would say to this point, a data supporting their use is limited. Finally, just to end here, I did want to just provide an overall risk-benefit analysis provided by the CDC. So using the CDC's data, when they look at the benefits of COVID vaccination, particularly benefits conferred by a second dose of an mRNA vaccine, when you look at COVID cases, prevented hospitalizations, prevented ICU admissions and deaths, prevented. Weigh that against the risk of myocarditis developing within seven days of the second dose of an RNA vaccine, that data can be broken down here by sex and age.

Evan Harmon, MD:
I just wanted to draw your attention here to this particularly high risk cohort of young adult males, and even in this really high risk cohort, you can see that the number of cases, hospitalizations, ICU admissions and deaths prevented by full COVID-19 vaccination seems to far outweigh the risk of expected myocarditis. So just to summarize myocarditis following mRNA COVID-19 vaccination seems to be a very rare, mild, and mostly self-limiting phenomenon. It does tend to occur in young male patients following the second dose of the vaccine. The diagnosis can be challenging and obviously requires a fairly comprehensive assessment.

Evan Harmon, MD:
The treatment is oftentimes supportive with NSAIDS and colchicine therapy in many of these patients, even those who are hospitalized typically have very short lengths of stay on those therapies. Obviously future work is to focus, not only on continuing to monitor these cases going forward for long-term side effects, but I think also continuing to tease out the actual mechanism of its occurrence, with aims at potentially preventing this complication in the future. That's all I had. Thank you.

Allan Klein, MD:
Great Evan. That was a fabulous, very timely and very current. I had a case yesterday, a possible case. Though it actually was a woman. Doesn't fit the spectrum, but had the vaccine. It was in London, England, and had a bad case of myopericarditis and actually was on anakinra so this is interesting. But let's ask the panel, let me start with doctor Dr. Tang, who's an expert in heart failure. Should you get the second shot? In other words, they've had this reaction, what are the risks and benefits and anything about mechanism?

Wilson Tang, MD:
Yeah. Great question. No clear answer, but I think nature did help us here, because the majority of cases actually are after the second dose. In fact, I think in the Israeli data it's only 10 per million, I think, or seven per million in the first does. So there are some patients that do have also a nonspecific symptom that mimic myocarditis, usually do present to us. But in general, most people's recommendation right now is to let the entire symptom resolve, and have a shared decision making regarding the risk and have some closer monitoring.

Wilson Tang, MD:
So I think currently we still recommend having the second dose. Now that's maybe a little different with the allergic reaction, which I don't think you mentioned. There are some people who have severe allergic reaction, tryptase goes sky high, really. Less of the anaphylactic, but a lot of swelling, and I think there's even some recent data from a multicenter evaluation, I think, when we presented this week, that many of them after some resolution, is safe to get the second dose too. So short answer is yes, we still, particularly with the complete resolution. Now the challenge is if somebody truly gets cardiac dysfunction, that is a very different story and we do have to manage them aggressively.

Allan Klein, MD:
Also I know in some countries they mix and match the vaccine. So if somebody got one shot and got the myocarditis, should they get the Astrazeneca or the vaccine, which doesn't have the mRNA?

Wilson Tang, MD:
That is actually also not very clear. I do not know exactly the data that was done, mainly in Europe regarding the mixed vaccines. I do know that they do elicit different kind of elements of immune responses we know that in, say, the immunocompromised patients getting booster shots. So I think in general, vaccine associated myocarditis, as Evan mentioned, there are literally two components. The component about the preservatives, may be of interest when you actually counsel patients.

Wilson Tang, MD:
That's why when we get our vaccine, we will ask about whether we have previous allergies. Also we try to space out the vaccines, as you remember, we cannot have vaccines within one month of another vaccine. So those are just precautions, but in general, I do think that we don't know enough to comment on that. That being said, it is very rare. There's literally a paper yesterday in pre-print, using electrotonic medical record consortiums, and found out that COVID myocarditis itself, which is another enigma, is at least six times higher than the actual vaccine related.

Wilson Tang, MD:
I think we have to kind of really understand the denominator and numerator. The second thing is it is much more risky in the young male population, whereas the female and other cohorts, elderly patients, more of the related to more autoimmune mechanisms.

Allan Klein, MD:
Great, let me ask Drs. Jellis and Kwon now, just what you said, Wilson, the COVID-19 and MRIs, in athletes, is it over called/under called, how do you make that diagnosis? I know we have a little series that when we repeat the MRI here, we don't find much. So it was it over called in the community, Christine and Debbie?

Christine Jellis, MD, PhD:
Oh, I think it's a difficult question. I'm not sure if Debbie's got any great adds, probably much better than me. I think sometimes the beauty is in the eye of the beholder, and sometimes we interpret studies differently in different places. But I think we have to be careful about the decisions that we make and the reports that we generate, particularly with MRI and particularly ... Sorry, that's my pager going off,; because these are young people, they're college kids who are on athletic scholarships, they've got potential careers and livelihoods ahead of them.

Christine Jellis, MD, PhD:
So whatever we do, we really want to make sure that we get it right. I think that's the beauty of working in a place like this, where we're very thoughtful in how we analyze these images. It often, as we've mentioned before, very much a team approach discussing it with our sports cardiologists, our Imaging staff, and really making sure that we get it right, and we craft those reports so that they're clinically relevant as well as having all the radiology information. But I think it's a really difficult area. I'll hand over to Debbie, see what she says.

Deborah Kwon, MD:
Yeah, it's a very intriguing topic. We're getting a lot more referrals for patients with COVID, especially with the long haulers, and a lot of patients who continue to have persistent symptoms. I'd say probably again, echoing what Christine said, it's kind of subjective in the sense that you can have T1 and T2 elevation, but that doesn't necessarily definitively mean they have myocarditis. Because you can have, especially in a more acute situation, you have hyperemia, does hyperemia mean direct myocardial infection of the virus? That's really what's uncertain at this point. But I think the last case that you showed where there's significant delayed hyper enhancement no one would argue that that's myocarditis, that's pretty clear cut.

Deborah Kwon, MD:
That was actually a very striking case to me, because that was a significant amount of late gadolinium. Most of the patients that we're seeing that come in with questionable myocarditis, it's very subtle T1, T2 changes, and maybe a subtle LGE, but that person has a significant amount. So the question is, I'd say the amount of patients that we see like that are probably in the single digits in terms of percentage. But the question is what are the long-term implications. This person has normal ejection fraction, but when you did the follow-up MRI, he still had persistent LGE.

Deborah Kwon, MD:
There's literature on non-COVID myocarditis, but just any other kind of viral myocarditis, showing the people who have persistent LG have increased risk for adverse events. So these patients still have to be followed. Their LV function is normal, but what's going to happen to them long-term? They're going to have to follow up with cardiology and have to repeat imaging down the line. I think we still don't really know what this means in terms of long-term implications.

Christine Jellis, MD, PhD:
Alan, can I ask a question? I think we're seeing the issue of vaccine hesitancy and now we're seeing increasing numbers again, and I'm certainly getting MyChart messages from patients who've got a history of pericarditis, who are concerned and have put off having their vaccination, worrying because they're hearing all these things in the media. So it's certainly reassuring to let them know that these are rare cases, and that they're at risk for myopericarditis from the virus itself.

Christine Jellis, MD, PhD:
But I just bring it up because I think we're going to continue to get these types of questions, and while we have the panel here to see how people are approaching this, because a lot of these patients are young men in their twenties who've had a history of pericarditis and they have a legitimate reason to ask that question, I think.

Allan Klein, MD:
I'd say that's very true. A lot of MyChart messages get asked about this. I think if you've had pericarditis, I still think the getting the vaccine, the benefit outweighs the risk of the myocarditis. The other question is some people are on all these antiinflammatories, including anakirna and rilonocept and what's the effect of the vaccine with all these antiinflammatories, is it less effective? We don't really know.

Allan Klein, MD:
Should these be getting boosters as well in the future? So there's a lot of unknown in this field, but it's a very dynamic field, everything is ... With exercise, some of these are division one athletes, some of them are professional players, and Debbie, if they have that sort of scarring in the heart, edema in the heart, what do you tell them in terms of their professional career? Big stakes, big money, and these are young people. So it's a tough thing.

Wilson Tang, MD:
I think it's similar for myocarditis, too. I think Shah Amdani at our pediatric cardiology group have been very interested in this question and actually has observed that several people with history of myocarditis seem to have uneventful course after getting their vaccine. So I think it's again, just what I said before, the risk and benefits and the overall protection does outweigh, and many of these cases are treatable and manageable.

Wilson Tang, MD:
I think back to what Debbie was saying, the second case has a history of Coxsackie myocarditis. So there's been kind of the multi hit hypothesis, not only genetic and also prior immune dysfunction that is kind of manifested with this type of a reaction, both for the vaccine and for viral infections.

Allan Klein, MD:
Evan, you have the last word, you did the research on this area, it's a very intriguing literature review and what's going, and I'm sure there's an article every day, and the journals. Any comments about this field now, on the vaccine.

Evan Harmon, MD:
No. I think everything that's important has been said, I just think it's a very complex question, and I think it really just speaks to the dynamic nature of not only the SARS-CoV-2 virus itself, but also find a way to use this vaccine and be transparent with patients. But also reassuring that it does still seem, I think in my opinion, that vaccination overall does seem to outweigh a risk. Obviously I understand there's more complex and unique cases that maybe need more thought and intention.

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