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This article was originally published by Science 2.0
COVID-19 has thrown North American professional baseball a curveball. An outbreak among players for the Miami Marlins, that has spread to the Philadelphia Phillies and St. Louis Cardinals, brings into question the infection control protocols touted by Major League Baseball.1,2 But perhaps more concerning is the report that Boston Red Sox pitcher Eduardo Rodríguez developed myocarditis as a result of COVID-19.3 Will myocarditis from COVID-19 be a strike out pitch for professional baseball?
The Starter: Myocarditis
Myocarditis is an inflammatory injury virus.4 Damage to the heart can be directly caused by a virus entering and killing heart muscle cells, or indirectly by the immune system that is activated to fight the infection
The Hit and Run of Myocarditis
The fact that SARS-CoV2 impacts the heart is not surprising. ACE2, a protein that the virus uses to enter cells, is found in high amounts in the muscle cells of the heart. While there is evidence the virus can infect cardiac muscle, whether SARS-CoV2 causes direct injury to the heart is not known.5
A key component of the immune reaction to SARS-CoV2 infection is an increase in molecules called cytokines. Cytokines are released throughout the body in response to infection and help coordinate the immune response. In COVID-19 patients, the immune response can be hyperactive, and the cytokine release is excessive. Dangerously high levels of inflammatory molecules are called a “cytokine storm”
Riders on the Storm
A cytokine storm causes damage throughout the body, which explains the systemic effects of COVID-19. In the heart, these molecules damage muscle and can cause heart failure. Evidence for cytokine storms in COVID-19 patients, coupled with their known role in driving cell death, implicates indirect damage of heart muscle through a cytokine storm as an important mechanism for SARS-CoV2 myocarditis.
Interestingly, most cytokine storms appear late in the timeline of COVID-19. The delay means damage to the heart may not start until after a patient is cleared of SARS-CoV2 and discharged from hospital. For most patients who develop myocarditis related to COVID-19, symptoms do not appear until several weeks after being symptom free and testing negative for SARS-CoV2.5 In the case of Eduardo Rodríguez, the Red Sox pitcher tested positive for COVID-19 in March, but the signs of myocarditis were not detected until July, almost a week after he was cleared to return to play.6
The Elusive Strikeout Pitch for COVID-19
Treatment of myocarditis includes therapies that kill the virus. But, given the lack of proven therapies to eliminate SARS-CoV2, treatment for myocarditis in COVID-19 patients is largely limited to supportive care to help maintain heart function. Common treatments to support the heart include diuretics, inhibitors of the angiotensin system, beta-blockers, and blood thinners.7
Broad suppression of the immune system to limit hyperactivation has not proven effective in non-COVID-19 cases, and there is no evidence to support its use with COVID-19 patients.5 Drugs like Tocilizumab, Sarilumab, and Siltuximab interfere with the cytokines that cause cardiac damage and are the subject of on-going clinical trials. However, their effectiveness has not been proven.5
What’s The Count?
The incidence of myocarditis is 1.5 million cases worldwide each year.7 Myocarditis is more common in males than females and tends to afflict healthy, young adults (< 35 years old).8,9
While viral infections are known to cause heart damage, studies suggest that SARS-CoV2 may have a higher prevalence of injury than many other viruses.5 Heart biopsies are the definitive diagnostic tool for myocarditis. However, complications with COVID-19 including instability of the patient and the infection risk to healthcare workers have limited the use of biopsies. Instead, a diagnosis of myocarditis in COVID-19 patients is often done by imaging the heart to show dysfunction and blood tests to rule out other conditions. The inability to accurately test for myocarditis has led some studies to suggest that myocarditis is underdiagnosed in COVID-19 patients.10
Myocarditis, The Utility Player
Myocarditis manifests over a range of severity from full recovery, to heart failure, to sudden death. Myocarditis is associated with irregular heart rhythms called arrhythmias, which can be fatal.5 Despite potentially severe complications approximately half of cases resolve within 2-4 weeks.11
Although most patients with myocarditis fully recover, a significant number experience long-term consequences. Myocarditis accounts for approximately 10% of sudden deaths in young adults.12 Up to 25% of patients experience a continual decline in heart function that results in death or requires a heart transplant.11 In fact, myocarditis is the most common reason for heart transplantation, accounting for almost half of heart transplants.4
The Minor Leagues
Current data suggest that babies and children are more likely to experience mild forms of COVID-19.13 Despite an apparently uneventful recovery from COVID-19, fighting off SARS-CoV2 may not be the end of the health challenge for kids.
Shortly after COVID-19 was declared a global pandemic, physicians in several countries reported cases of a syndrome that was similar to Kawasaki disease.14
Kawasaki disease is an inflammatory illness that impacts blood vessels. The primary population affected by Kawasaki disease is children under 5 years old, and only about 3% of children with Kawasaki disease develop a myocarditis-like inflammation of the heart.15 The paediatric cases linked to COVID-19 differed from Kawasaki disease in that they consisted of children whose average age was older than 5 years, and a stunning 44-70% of patients developed myocarditis.
Children who developed a Kawasaki-like condition either tested positive for SARS-CoV2 infection, had antibodies against the virus indicating previous exposure, or had been exposed to COVID-19 positive patients. The development of myocarditis correlated with severity of COVID-19 illness, as 86% of severe cases had cardiac inflammation, compared to only 11% in non-severe cases.
Although the mechanisms for this paediatric myocarditis are not known, it typically does not develop until 2-4 weeks after SARS-Cov2 infection or exposure. This means heart damage is likely related to a delayed cytokine storm rather than the virus itself. The delay in symptom development should not be taken as a sign of a benign, slowly progressing condition as many of these children were admitted to hospital for heart failure.16
Bringing It Home
Cardiovascular disease is a risk factor for COVID-19.17 People with pre-existing conditions like high blood pressure or coronary artery disease are more likely to experience severe illness or die. At the same time, SARS-CoV2 infection damages the cardiovascular system and can cause heart disease in an otherwise healthy individual.
Myocarditis is a classic example in which young, healthy individuals are infected with SARS-CoV2 and recover, seemingly without incident. Weeks after being cleared, cardiac dysfunction begins to appear, and the downward spiral of heart failure starts. Without a treatment to kill the virus, there is no ability to stop cardiac injuries associated with COVID-19, and outcomes are dependent on the ability of the body to defend itself.
Children are described as being largely immune to COVID-19. While it is true that the mortality rate among children and young adults is lower than average, it does not mean that the paediatric population is free of consequences from COVID-19. Disturbing trends in myocarditis and acute heart failure have been reported in several studies at medical centres throughout the world. These cases appear 2-4 weeks after the patient has been cleared of virus and even in patients who were asymptomatic.
Defeating COVID-19 requires limiting infections. The simplest approach is to follow public health guidelines like physical distancing and face coverings to limit the spread of SARS-CoV2. The alternative is managing patients with COVID-19 with unproven or palliative therapies, and continuing to treat them post-infection to control any side-effects. And that is a tricky double play.
- 1. https://www.cbssports.com/mlb/news/marlins-covid-19-outbreak-another-player-tests-positive-friday-20-total-reported-cases-among-team/
- 2. https://www.sportsnet.ca/baseball/mlb/reports-cardinals-brewers-postponed-positive-covid-19-tests/
- 3. https://www.cbssports.com/mlb/news/red-sox-pitcher-eduardo-rodriguez-confirms-hes-dealing-with-heart-issue-stemming-from-covid-19-infection/
- 4. Kindermann I et al. J Am Coll Cardiol. 59. 779-792. 2012.
- 5. Hendren NS et al. Circ. 141: 1903-1914. 2020.
- 6. https://www.nbcsports.com/washington/orioles/red-sox-sp-eduardo-rodriguez-diagnosed-heart-issue-after-covid-19-bout
- 7. Kang M and An J. J Viral Myocarditis. June 24, 2020.
- 8. Fung G et al. Circ Res. 118. 496-514. 2016.
- 9. https://www.myocarditisfoundation.org/about-myocarditis
- 10. Pirzada A et al. Can J Cardiol. 2. 278-285. 2020.
- 11. Lazaros G et al. Expert Rev Cardiovasc Ther. 15. 25-24. 2017.
- 12. Fabre A and Sheppard MN. Heart. 92. 316-20. 2006.
- 13. https://www.hopkinsmedicine.org/health/conditions-and-diseases/coronavirus/coronavirus-in-babies-and-children
- 14. Tissieres P and Teboul JL. Ann Intensive Care. 10. 98. 2020.
- 15. Pouletty M et al. Ann Rheum Dis. 1-8. 2020.
- 16. Belhadjer Z et al. Circ. May 17, 2020.
- 17. https://www.science20.com/w_glen_pyle/getting_to_the_heart_of_the_coronavirus_pandemic-246762