Adding to the growing list of the multisystem effects of coronavirus disease 2019 (COVID-19) infection, a significant number of cases of post-COVID-19 myocarditis have been reported. According to a 2020 review, approximately 5%-25% of patients hospitalized with COVID-19 have hqad evidence of myocardial injury.1

This may pose an especially high risk to competitive athletes, in whom myocarditis is a top cause of sudden death. In light of this development, the Big Ten Conference now requires comprehensive cardiac testing for student athletes before they can return to play after COVID-19 infection.2

In a study published online in May 2021 in JAMA Cardiology, Daniels et al investigated rates of COVID-19 myocarditis among 1,597 athletes from 13 of the 14 Big Ten universities. They observed an overall prevalence of 2.3%, with 9 cases of clinical myocarditis and 28 cases of subclinical myocarditis, categorized based on the presence of cardiac symptoms and findings on cardiac magnetic resonance imaging (CMR).2


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The use of CMR led to a 7.4-fold increase in the detection of myocarditis cases; only 0.31% of cases would have been detected without CMR. “The role of CMR in routine screening for athletes safe return to play should be explored further,” the authors concluded.2

The US Centers for Disease Control and Prevention (CDC) recently reported myocarditis cases (along with some cases of pericarditis) that occurred after receipt of the mRNA COVID-19 vaccines by Pfizer-BioNTech and Moderna. These cases have been primarily observed in male adolescents and young adults and tend to occur following the second vaccine dose.3

Given the relative rarity of such cases in the context of hundreds of millions of administered vaccines in the United States to date, the CDC continues to recommend vaccination for individuals aged 12 years and older. “The known and potential benefits of COVID-19 vaccination outweigh the known and potential risks, including the possible risk of myocarditis or pericarditis,” as stated in the CDC report.3 “Also, most patients with myocarditis and pericarditis who received care responded well to treatment and rest and quickly felt better.”

We interviewed Neha P. Raukar, MD, MS, CAQSM, physician in the department of emergency medicine at Mayo Clinic in Rochester, Minnesota, Leslie T. Cooper, MD, cardiologist and chair of the department of cardiovascular medicine at Mayo Clinic in Jacksonville, Florida, and founder of the Myocarditis Foundation, and Saurabh Rajpal, MBBS, MD, cardiologist and assistant professor in the division of cardiovascular medicine at The Ohio State University College of Medicine to dive deeper into this topic.

Drs Raukar and Cooper conducted a systematic review on the topic that was published in March 2021 in Sports Health, and Dr Rajpal co-authored the JAMA Cardiology study mentioned above.4,2

What does the evidence suggest thus far about the incidence and outcomes of myocarditis in athletes after COVID-19 infection? 

Dr Raukar and Dr Cooper: What we are learning about myocarditis as the COVID-19 pandemic unfolds has been in evolution. Early studies in collegiate athletes who tested positive for COVID-19 reported that 15% had CMR findings consistent with myocarditis.5 This finding was even more concerning given that all of these athletes had either an asymptomatic or mildly symptomatic course of infection, other tests such as ECG and troponin levels were normal, and the athletes were either asymptomatic or mildly symptomatic from their myocarditis. The clinical significance of this was unknown, as the same study found that 30.8% of athletes had exhibited late gadolinium enhancement (LGE) without T2 elevation, suggestive of prior myocardial injury.    

In the COVID-19 Myocardial Pathology Evaluation in AthleTEs with Cardiac Magnetic Resonance (COMPETE CMR) study, only 3% of competitive athletes were found to have myocarditis on CMR.6 None of these athletes had experienced symptoms of COVID-19.

In a larger study where all athletes who tested positive for COVID-19 underwent cardiac testing, 1.4% were identified as having myocarditis with the similar theme of poor sensitivity/specificity of ECG, troponin, and echocardiographic testing.7

Dr Rajpal: We have learned that about 2-3% athletes can get myocarditis post-COVID-19. We also know that in an overwhelming majority, these cases are mild and resolve after a few weeks of rest, and adverse events have been rare, especially in the short term. We still do not know the long-term consequences of myocarditis in this population. However, there have been more rare severe cases.

We also know that a high-quality comprehensive CMR-based strategy will give the highest yield to detect myocarditis. We know that there is wide variability in reporting of myocarditis, which is related to both performance of quality CMR based on guidelines, variable implementation of recommended criteria, and expertise of CMR interpretation. This is especially difficult in athletes, as changes of athletic remodeling as they pertain to modern CMR interpretation are not well-established.

What are recommendations for clinicians regarding screening and treating these patients to clear them for return to sports?

Dr Raukar and Dr Cooper: Recommendations for return to sport after COVID-19 infection vary. In efforts to reduce mortality among athletes who have myocarditis, a cautious approach to return to play is advised. The American Heart Association recommends 3 to 6 months of withdrawal from activity and then testing with a resting echocardiogram, Holter monitoring for 24 hours, and exercise electrocardiography and returning to play if these are normal.4 The role of CMR, and specifically resolution of myocarditis-related late gadolinium enhancement, in clearance to play has not yet been determined.

Dr Rajpal: Each institution must develop its own protocols based on available resources and expertise. Our study clearly shows that a large number of cases will be missed based on a symptoms-based strategy. At our institution we are still using CMR in competitive athletes recovering from COVID-19 prior to return to play. We believe this is the safest strategy for our patients.

Some people argue that lack of symptoms might mean the inflammation is not clinically relevant and might never become a problem for that athlete. While that is possible, I would like to say that we do not yet fully know the clinical relevance – we are in uncharted territory. Never before in our lifetimes has a virus affected this many people or athletes.

However, historically, when you see autopsy studies of athletes who had sudden cardiac death, you will find that a large percentage of athletes, especially younger athletes, had myocarditis. Also, another large percentage of athletes that died had scarring in heart tissue which is thought to be from prior myocarditis. We should continue to follow up on these findings and use the latest tools and resources at our disposal to keep athletes safe.

What should be the focus of future research on this topic?

Dr Raukar and Dr Cooper: Based on the available studies and the poor diagnostic yield of standard cardiac testing, and taking into consideration the cost and level of expertise required for interpretation of CMR and the stresses this places on healthcare resources, the utility of universal CMR screening prior to return to play after COVID-19 infection is low. Furthermore, demonstration of injury on CMR may not correlate to a clinically significant condition, especially when the clinical pretest probability of myocarditis is low. 

 

In the near future, a microRNA, designated has-miR-Chr8:96, may distinguish myocarditis from ischemic forms of chest pain.8 At this time, investigation of the relevance of findings on CMR as well as the appropriate workup for those with suspected post-COVID-19 myocarditis needs to be better understood.

Dr Rajpal: Clinical as well as imaging follow up of athletes to determine the long-term consequences of viral infection as well as athletic participation need to be a focus of research. Duration of persistence or resolution of myocardial inflammation post-infection also needs to be studied. Better criteria to diagnose myocarditis on CMR and how best to differentiate these changes from athletic remodeling also need to be studied. Other imaging modalities like PET imaging or blood biomarkers could be investigated as well.

Regarding the potential link between COVID-19 vaccines and myocarditis in young adults, what are the implications for clinicians?

Dr Raukar and Dr Cooper: In the post-vaccine era, and in the wake of the FDA issuing a warning about vaccine-induced myocarditis, this rare finding deserves notice.9 There have been more than a dozen publications, both in the US and internationally, that show a rate of myocarditis typically within 4 days of the second dose of the mRNA vaccine.

As of Friday, June 25, 2021, in the US, there have been 323 people who meet the definition of myocarditis. Of these, 309 were hospitalized, some in the ICU for close cardiac monitoring, and 295 had been discharged at the time the data was reported. There has been a preponderance of male patients.10

In the US military experience with COVID-19 vaccination, the observed rate of myocarditis in males following the second dose was 19/100,000 compared to an expected rate of 0-8/100,000, and all patients recovered quickly.11

As we await long-term data about post-vaccine myocarditis, it is important to maintain vigilance about exercise intolerance and the development of symptoms such as chest pain and shortness of breath.  

Dr Rajpal: While the CDC data suggest a potential link between mRNA COVID-19 vaccination and myocarditis, these cases appear to be rare. Based on the data, the risk is about 12.6 per million second doses administered. The highest risk group appears to be young adolescent males, in whom the risk is about 70 per million second doses administered.12 This risk is likely lower than the risk of myocarditis or other cardiac complications seen after COVID-19 infection. 

The CDC estimated that every million second doses given to boys ages 12 to 17 might cause a maximum of 70 myocarditis cases but would prevent 5,700 infections, 215 hospitalizations, and 2 deaths. In males aged 18-24 years, each million doses were projected to prevent 12,000 cases, 530 hospital admissions, 127 ICU admissions, and 3 deaths.12

Similarly, in males aged 24-29 years, a million vaccine doses were estimated to prevent 15,000 cases, 936 hospitalizations, 215 ICU admissions and 13 deaths. So even in these high-risk groups, the benefits of vaccination outweigh risks. If you consider females and males over the age of 29 years, the benefits outweigh risks by far.12

Although rare, we now know that myocarditis is a possible complication. One should be aware of symptoms, especially in high-risk group patients (young males), which include chest pain, palpitations, and shortness of breath. Based on published reports, most post-vaccine myocarditis cases have been mild and self-limiting, requiring only supportive treatment. Rest for 3-6 months is recommended. The long-term consequences of post-vaccine myocarditis are not known yet and are currently being studied.

References

  1. White-Dzuro G, Gibson LE, Zazzeron L, et al. Multisystem effects of COVID-19: a concise review for practitioners. Postgrad Med. 2021;133(1):20-27. doi:10.1080/00325481.2020.1823094
  2. Daniels CJ, Rajpal S, Greenshields JT, et al; Big Ten COVID-19 Cardiac Registry Investigators. Prevalence of clinical and subclinical myocarditis in competitive athletes with recent SARS-CoV-2 infection: Results from the Big Ten COVID-19 Cardiac Registry. JAMA Cardiol. Published online May 27, 2021. doi:10.1001/jamacardio.2021.2065
  3. Centers for Disease Control and Prevention. Myocarditis and pericarditis following mRNA COVID-19 vaccination. Last updated June 23, 2021. Accessed online June 30, 2021.
  4. Raukar NP, Cooper LT. Implications of SARS-CoV-2-Associated myocarditis in the medical evaluation of athletes. Sports Health. 2021;13(2):145-148. doi:10.1177/1941738120974747
  5. Rajpal S, Tong MS, Borchers J, Zareba KM, Obarski TP, Simonetti OP, Daniels CJ. Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection. JAMA Cardiol. 2021;6(1):116-118. doi:10.1001/jamacardio.2020.4916
  6. Clark DE, Parikh A, Dendy JM, et al. COVID-19 myocardial pathology evaluation in athletes with cardiac magnetic resonance (COMPETE CMR). Circulation. 2021;143(6):609-612. doi:10.1161/CIRCULATIONAHA.120.052573
  7. Starekova J, Bluemke DA, Bradham WS, et al. Evaluation for myocarditis in competitive student athletes recovering from coronavirus disease 2019 with cardiac magnetic resonance imaging. Published online January 14, 2021. JAMA Cardiol. doi:10.1001/jamacardio.2020.7444
  8. Blanco-Domínguez R, Sánchez-Díaz R, de la Fuente H, et al. A novel circulating microRNA for the detection of acute myocarditis. N Engl J Med. 2021;384(21):2014-2027. doi:10.1056/NEJMoa2003608
  9. US Food and Drug Administration. Coronavirus (COVID-19) update: June 25, 2021. Accessed online June 30, 2021.
  10. Jenko M. Health officials, AAP urge COVID-19 vaccination despite rare myocarditis cases. Published online June 23, 2021.  AAP News. Accessed online June 30, 2021.
  11. Montgomery J, Ryan M, Engler R, et al. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. Published online June 29, 2021. JAMA Cardiol. doi:10.1001/jamacardio.2021.2833
  12. Saey TH. The benefits of COVID-19 mRNA vaccines outweigh the risk of rare heart inflammation. Published online June 23, 2021. Science News. Accessed online June 30, 2021.