Dr Helen Dixon MbChB, anaesthetic trainee at East Lancashire Hospitals NHS Trust, reviews the presentation, diagnosis and management of myocarditis in COVID-19 .
On the 31st December 2019, Wuhan Municipal Health Commission reported a cluster of unusual Pneumonias in Hubei Province. By the 7th January 2020 they had identified the causative organism as a novel Coronavirus [1, 2]. Since then more than 9 million people worldwide have been infected with what we now know as ‘SARS-CoV-2’referred to as COVID-19. With death rates fast exceeding 500,000 globally, mortality has far surpassed that of the biologically similar MERS and SARS viruses .
While many features of SARS-CoV-2 are generic to other respiratory viruses, there are ever growing concerns over patients developing a clinical picture similar to that of myocarditis [2-6].
This article reviews the presentation, diagnosis and management of myocarditis, comparing this to current SARS CoV-2 research and its potential for causing myocarditis.
What is myocarditis?
Myocarditis is inflammation of cardiac myocytes. In Western Europe and Northern America the most common causative agent is a virus . Myocarditis can present in many ways from mild chest pain to ventricular arrhythmias and cardiogenic shock . ECG analysis demonstrates a wide range of non-specific changes with low sensitivity including sinus tachycardia, ventricular conduction delays, ST segment elevation or depression and ventricular arrhythmias .
The pathogenesis of myocarditis has been linked to the overexpression of T helper 1 cells (Th1) with Tumour Necrosis Factor (TNF) alpha and Interleukin 1 (IL-1) beta commonly found within cardiac myocytes during the acute stage . Studies have shown that approximately 30 per cent of people with acute myocarditis will go on to develop dilated cardiomyopathy , with animal studies suggesting that genetic susceptibility, and the male sex hormone testosterone, further predisposes to this clinical progression .
How is it Diagnosed?
A combination of clinical suspicion, serial biomarkers, ECG changes otherwise proven not to be caused by an ischaemic event, Echocardiography and more specialist diagnostic tests are required to adequately diagnose myocarditis.
Whilst troponins may not always be raised in myocarditis, serial troponins showing a plateau more than 24 hours after an initial rise can be suggestive of ongoing inflammation – again, other more time sensitive diagnoses must always be investigated in the presence of raised cardiac markers .
B-type natriuretic peptide (BNP) and N Terminal Pro-BNP levels are raised in the presence of ventricular hypertrophy or dilatation and can signify progression to dilated cardiomyopathy in patients with myocarditis.
Echocardiography is non-specific in patients with myocarditis and is, rather, a useful tool to exclude valvular pathologies or other explanations for the clinical presentation. Acute myocarditis may demonstrate biventricular wall thickening with progression to impaired Right Ventricular function having an associated high mortality rate in patients with previously biopsy proven myocarditis.
The gold standard for diagnosis is the endomyocardial biopsy (EMB). The Dallas Criteria states that the presence of inflammatory infiltrate with or without myocyte necrosis (that is not otherwise characteristic of an ischaemic event) is required to diagnose myocarditis [7,9]. The Dallas Criteria has been criticised however for its inability to include the presence of the viral genome, within cardiac myocytes, as a potential diagnostic feature in symptomatic individuals . Further sensitivity has also been found in the detection of focal or diffuse mononuclear infiltrate (CD3 stained T Lymphoctes or CD68 stained macrophages) . While being the gold standard, EMB may mean referring patients to more specialist centres who have the capabilities to perform such an investigation.
A less invasive investigative tool is Cardiac MRI (CMR) imaging. This can be used to assess myocyte inflammation and differentiate from ischaemic causes. The Lake Louise Criteria requires the presence of two or more of: oedema (on T2 weighted imaging), necrosis and fibrosis (on late gadolinium enhancement) . A 2017 meta analysis of CMR and EMB revealed however that there are limitations in the ability of CMR to diagnose myocarditis when compared to the gold standard EMB .
What evidence do we have for myocarditis occurring in COVID-19 patients?
It is apparent that a cohort of coronavirus patients are experiencing a range of arrhythmias from sinus tachycardia, T wave inversion, ST depression and elevation in association with raised troponins but with no other explanatory cause found [2,5]. Further evidence of Duke’s Criteria on CMR has also been reported .
Research into rises in inflammatory markers in COVID patients has demonstrated increased levels of IL-1 beta, Interferon gamma (IFN-gamma), Interferon-gamma Inducible Protein 10 (IP-10) and Monocyte Chemoattractant Protein 1 (MCP-1) leading to increased Th1 response which is evidenced to have a role in the development of myocarditis. Further to this, increased levels of Granulocyte Colony Stimulating Factor, IL-2,7&10 as well as TNF-alpha have been found in patients requiring intensive care compared to those who did not . Significantly raised levels of IL-6 have also been found to be associated with fulminant myocarditis in SARS Cov-2 patients . These form the basis for the well recognised ‘Cytokine Storm’ inflammatory response associated with disease severity.
In March 2020, a retrospective cohort study performed in China by Zhou et al. demonstrated significant links between mortality and cardiac complications. More than 50 per cent of patients that died experienced ‘Acute Cardiac Injury’ or ‘Heart Failure’. Raised troponins were found in 24 patients, 23 of whom went on to die within the study time frame .
The acquired immune response to COVID-19 lends itself to the development of a pro-inflammatory state which is adequate to have the potential of causing myocarditis. The high prevalence of elevated troponins and cardiac injury in those dying from the virus leads to the hypothesis of a causal relationship.
Do we need to know more?
A post mortem performed on 9 African American Patients in New Orleans following death from SARS Cov-2 looked at both lung and cardiac pathologies. They found that cardiomegaly and right ventricular dilatation was common to all patients in association with diffuse pulmonary haemorrhage, parenchymal oedema and peripheral parenchymal thrombi. Myocardial histology revealed a common pattern of scattered myocyte necrosis. Lymphocytes were found adjacent to some of these areas of necrosis but not surrounding them altogether . This pattern was thought not to be typical of viral myocarditis but potentially representing early stages. Although unable to detect the SARS Cov-2 virus, they were unable to rule out the presence of direct viral invasion with the methods used. A further case study demonstrating EMB performed on an inpatient showed absence of the viral genome .
Whilst patients can develop clinical features suggestive of myocardial and haemodynamic compromise the evidence to confirm a diagnosis of myocarditis is often lacking or incomplete .
What we know about myocarditis and the diagnostic challenges associated with it poses further difficulties in SARS Cov-2 patients.
Whilst EMB is still thought of as the gold standard, this is a complex challenge for clinicians in centres without access to this specialist diagnostic procedure, coupled with patients often too unwell to be transferred elsewhere.
Cardiac MR is also not necessarily readily accessible and often excludes the more unwell patients due to lack of MR compatible monitoring systems in smaller hospitals.
Cardiac biomarkers are relatively inexpensive and easy to access. Whilst Troponins may be normal in patients with myocarditis , current evidence suggests that there is value in performing serial samples where there is clinical suspicion [6,8]. It is also evident that raised troponins do also contribute to an indication of disease severity .
BNP may be raised in conjunction with other conditions such as renal failure . However, the finding that 30 per cent of patients with Myocarditis may progress to developing Dilated Cardiomyopathy  suggests the relevance of baseline and periodic serial measurements in patients where suspicion is high.
With any test in medicine it is always pertinent to consider how it will affect your management. To date there is still relative uncertainty about medications suitable and effective in SARS Cov-2. Recent outcomes from the ‘RECOVERY trial’ have revealed a mortality benefit in patients requiring oxygen who received dexamethasone . Immunosuppressive therapy, often in the form of steroids, has also been found to have beneficial effect in patients with myocarditis . It will be of great interest in future to see whether widespread treatment has an effect on also reducing the cardiac complications seen in these patients.
While the inflammatory response seen in many patients has the pathological possibility to go on to cause myocyte inflammation and necrosis, there is much more work to be done in terms of histological analysis and genome detection in patients with suspected SARS Cov-2 induced myocarditis before we are able to pinpoint a causal relationship with certainty.
- World Health Organisation Online, https://www.who.int/emergencies/diseases/novel-coronavirus-2019 Accessed 28th June 2020
- UpToDate, ‘Coronavirus disease 2019 (COVID-19): Myocardial injury’ https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-myocardial-injury?topicRef=4935&source=see_link Accessed 28th June 2020 Topic 127537 Version 17.0
- Zhou.F et al. Clinical Course and Risk Factors for Mortality of adult inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study, Lancet 2020; 395: 1054-62
- Huang.C et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506
- Doyen.D Myocarditis in a patient with COVID-19: a cause of raised troponins and ECG changes, Lancet 2020; 395: 1516
- Chen, C., Zhou, Y. & Wang, D.W. SARS-CoV-2: a potential novel etiology of fulminant myocarditis. Herz 45, 230–232 (2020). https://doi.org/10.1007/s00059-020-04909-z
- Elamm, Chantal et al. “Republished: pathogenesis and diagnosis of myocarditis.” Postgraduate medical journal vol. 88,1043 (2012): 539-44. doi:10.1136/postgradmedj-2012-301686rep
- Alida L. P. Caforio et al Current state of knowledge of aetiology, diagnosis, management and therapy of myocarditis: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases, European Heart Jounral (2013) 34, 2636-2648 doi:10.1093/eurheartj/eht210
- Baughman KL. Diagnosis of myocarditis: death of Dallas criteria. Circulation. 2006;113(4):593-595. doi:10.1161/CIRCULATIONAHA.105.589663
- Wei S, Fu J, Chen L, Yu S. Performance of Cardiac Magnetic Resonance Imaging for Diagnosis of Myocarditis Compared with Endomyocardial Biopsy: A Meta-Analysis. Med Sci Monit. 2017;23:3687-3696. Published 2017 Jul 29. doi:10.12659/msm.902155
- Fox, Sharon E et al. “Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.” The Lancet. Respiratory medicine, S2213-2600(20)30243-5. 27 May. 2020, doi:10.1016/S2213-2600(20)30243-5
- Sala.S et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. CARDIOVASCULAR FLASHLIGHT doi:10.1093/eurheartj/ehaa286 Online publish-ahead-of-print 8 April 2020
- University of Oxford – RECOVERY, Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of covid-19, https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19