COVID-19 Myocarditis Clinical Presentation, Diagnosis and Management: A Narrative Review

Objective: The purpose of this article is to review the cases of myocarditis in COVID-19 patients and synthesize the current understanding regarding the presentation, diagnosis, and management of myocarditis in the setting of COVID-19 disease. Background: The novel coronavirus disease has shown serious implications for the cardiovascular system, including acute myocardial injury, arrhythmias, venous thromboembolism, and myocarditis. Several cases of myocarditis in COVID-19 patients have been reported since the disease's emergence at the end of 2019. The diagnostic approach and management have been variable. The purpose of this narrative review is to gather the most reliable published material regarding myocarditis in COVID-19 and present it as an overview to simplify the current understanding we have of this disease. Methods: We screened PubMed, Scopus, and Embase. We then selected peer-reviewed and pre-print articles published in English that were related to the involvement of the cardiovascular system in COVID19, with a focus on myocarditis. We included case reports describing myocarditis in COVID-19 patients and summarized their clinical presentation, diagnosis, and management. References of the selected articles were also screened, and some were included when relevant. Discussion: This article is subdivided into sections that discuss the clinical presentation of COVID-19 myocarditis and move on to various diagnostic approaches and management options. Each subsection presents a brief literature review followed by a summary and interpretation of what was found in the reported cases. Conclusion: After noticing the involvement of the cardiovascular system in COVID-19 patients, specifically through myocarditis, we present this narrative review to provide the medical community with a unified Received: 2020.11.12 Accepted: 2020.01.11 Published: 2021.02.15 © Int J Clin Res 2020 ISSN 2675-2611 DOI 10.38179/ijcr.v1i1.27 136 This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ or send a letter to Creative Commons, PO Box 1866, Mountain View, CA 94042, USA. article regarding the current understanding of myocarditis in COVID-19 patients. This article further stresses the necessity of establishing proper treatment guidelines for COVID-19 myocarditis.


Introduction
A novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan City infected clusters in December 2019 and caused an outbreak of SARS-like respiratory illness worldwide with associated human-to-human transmission [1]. The new coronavirus disease 2019 (COVID-19) outbreak was declared a Public Health Emergency of International Concern by the World Health Organization on January 30, 2020 [2] and upgraded to a pandemic on March 11, 2020 [3].
Although COVID-19 mainly manifests with respiratory symptoms, cardiac complications have also been reported in these patients. A study showed that up to 19% of COVID-19 hospitalized patients demonstrated cardiac injury [4]. The mechanism of cardiac disease is thought to be multifactorial, involving (1) the entry of the SARS-CoV-2 virus into cardiomyocytes, which induces direct cardiotoxicity, and (2) the viral driven inflammatory process with cytokine release, which leads to myocarditis, hypercoagulability, vascular inflammation, and plaque instability [5].
While different cardiac manifestations have been reported in COVID-19, such as ACS, arrhythmias, myocardial injury, and thromboembolism, early studies in China reported that 7-20% of patients diagnosed with COVID-19 had viral myocarditis [6]. Viral myocarditis caused by the SARS-CoV-2 has also been documented as a cause of dilated cardiomyopathy, albeit in rare case reports [1,7]. Although many of these early studies did not include echocardiography or Magnetic Resonance Imaging (MRI) data to assert whether the typical myocarditis features were present in these patients, the number of reports of COVID-19 myocarditis published warrants a necessity to review this topic.

Methods
We screened databases including PubMed, Scopus, and Embase and selected peerreviewed articles published in English that were related to the cardiovascular system's involvement in COVID-19, with a focus on myocarditis. To look for case reports of myocarditis in COVID-19 patients, we performed the search on the PubMed database using the combination of the following keywords: COVID-19, myocarditis, and case report and found 44 results. All the articles found up to July 29, 2020, were screened, and we ended up with 27 case reports describing 29 patients with confirmed COVID-19 who were diagnosed with myocarditis. We summarized their clinical presentations, laboratory findings, diagnostic approach, and treatment, regardless of the country from which these cases were reported. We compared the results to the existing literature regarding myocarditis by screening the databases above using combinations of keywords, including myocarditis, clinical manifestations, diagnosis, imaging, cardiac magnetic resonance, and others. References of the selected articles were screened and included when relevant.

Clinical Presentation
Patients with acute myocarditis can be asymptomatic and often present with nonspecific symptoms such as chest pain, dyspnea, and palpitations. Those who develop acute heart failure develop dyspnea, fatigue, and exercise intolerance, often with paroxysmal nocturnal dyspnea and orthopnea [1,[8][9][10]. To note, a viral prodrome with fever, myalgias, and respiratory or gastrointestinal symptoms may be related to myocarditis, though this remains variable [10].
We described patient demographics, including age, sex, ethnicity or nationality, and comorbidities within the supplementary material. As shown in Table 1, we identified the presenting signs and symptoms of the 29 reported cases of COVID-19 myocarditis. We found the clinical presentation to be variable and non-specific. Many patients presented with fever (62.1%), cough (37.9%), and dyspnea (51.7%), which are the typical symptoms in most cases of COVID- 19. Although none of the articles reported patients presenting with paroxysmal nocturnal dyspnea or orthopnea, dyspnea itself was commonly associated with chest pain, with 8 of 29 cases reporting both symptoms combined (27.6%). Both of these are non-specific symptoms of acute myocarditis. Chest pain was reported in 55.2% of cases independently. Many reported cases additionally had fatigue (24.1%), gastrointestinal symptoms such as vomiting and/or diarrhea (24.1%), and myalgias (10.3%), which are non-specific symptoms of viral infections that may be present in viral myocarditis unrelated to COVID-19 as well as in COVID-19 patients without myocarditis. Other less common symptoms such as headaches, dizziness, weight loss, weakness, and odynophagia were reported, each in 1 of the 29 patients. These occurred combined with one or more of the previously discussed symptoms. Three patients reported syncope and/or near syncope episodes, which is considered one of the clinical syndromes associated with with acute myocarditis, as will be discussed later in the classification section. Two reported cases were already diagnosed with COVID-19. They were suspected of having developed acute viral myocarditis after identification of electrocardiography (ECG) changes. One patient developed a hemodynamically unstable newonset ventricular tachycardia and another one developing ST-segment elevation on ECG. A number of these patients were considered as fulminant myocarditis (17.2% of the cases) and developed cardiogenic shock (13.8% of the cases).

Pathogenesis
Myocarditis is an inflammatory cardiomyopathy with several clinical and histological presentations [9]. Acute and chronic myocarditis can involve changes in the number and function of lymphocytes and macrophages as well as antibody-mediated injury [9]. This, in turn, causes a cascade of structural and functional changes in cardiomyocytes and ultimately regional or global contractile impairment, conduction system abnormalities, or chamber stiffening.

Classification
Classification of myocarditis can be either by etiology, histology, immunohistology, or clinicopathological and clinical criteria [9].
Clinical classification seems to be the most practical as many clinical facilities cannot perform endomyocardial biopsy (EMB). The classification is based on increasing diagnostic certainty and includes three categories as per Table 2 [9].
Looking at this classification, we noticed that out of the 29 patients, only one patient had undergone an endomyocardial biopsy, and 1 underwent autopsy and histopathological evaluation after death. Both of these showed positive histological studies confirming a diagnosis of definite myocarditis. Other cases were reported as myocarditis despite commonly falling under probable acute myocarditis.

Diagnostic Testing a) ECG Findings
Most patients with myocarditis have non-specific changes on ECG, including sinus tachycardia, ST-wave and T-wave abnormalities like STsegment elevation or depression, pathologic Q waves, and occasionally atrioventricular or bundle branch block [9,10]. A widened QRS and Q waves are associated with poor prognosis in acute myocarditis [9]. Pericarditis often manifests with PR depression and diffuse STsegment elevation [9]. The sensitivity of ECG for myocarditis is low (47%) [9].
The ECGs of the reported cases of COVID-19 myocarditis showed a variety of changes (Table  3). Of the 29 cases reported, 6 did not include the ECG findings of the patient, and 1 case was reported as having a normal ECG. Several patients showed ST-segment elevation; however, some were diffuse [11,19,35] while others were localized to specific leads. Due to the ST-segment elevation in some cases, Table 2: Classification of Myocarditis suspicion of myocardial ischemia was raised, and many patients underwent a conventional coronary angiography or a coronary computed tomography angiography to rule out coronary stenosis. In all cases, there was no coronary narrowing [14,16,19,33] except for one case which had mild luminal irregularities [29]. Other patients' ECGs showed non-specific ischemic changes such as T-wave inversions [11,26]. Tachyarrhythmias, mainly sinus tachycardia, was noted [17,18,25,28,30,34], as well as ventricular tachycardia and atrial fibrillation [2,19].

b) Laboratory Blood Tests
Serum biomarkers are elevated in a minority of patients with acute myocarditis. Troponin I has a high specificity (89%) but a low sensitivity (34%) in the diagnosis of myocarditis [10]. Increased troponin I is more common than high levels of creatine kinase myocardial band CKMB [10]. Other serum markers of inflammation that are non-specific, such as C-reactive protein, erythrocyte sedimentation rate, and leucocyte count, can be elevated in patients with suspected myocarditis but these markers are of limited value due to their low specificity [9].
Three of the cases did not report any laboratory blood test results [20,22,27]. In the rest of the cases, the most reported laboratory blood tests included different combinations of troponin T, Troponin I, N-terminal pro b-type natriuretic peptide (NT-proBNP), and C-Reactive Protein (CRP), all of which, when done, were consistently elevated. Some cases also reported CK-MB levels as high [11,14,23,30,35]. One case reported an elevated serum myoglobin level [17]. Serum creatine kinase, also known as creatine phosphokinase, was reported as high in two cases [10,32]. In addition, inflammatory markers like erythrocyte sedimentation rate (ESR), procalcitonin, lactate, and ferritin were reported as high in some cases, and at times they were reported as unremarkable. D-dimers, when reported were found to be elevated [13,21,26,30,31,33,36]. Interleukin 6 (IL-6) was reported as elevated in two cases [31,34]. Complete blood count and electrolytes were not consistently reported and were not included in Table 4.

Echocardiography
Acute myocarditis does not have any specific features. The most important role of transthoracic echocardiogram (TTE) on the assessment of acute myocarditis is to rule out primary valvular disease, congenital disease, or pericardial constriction [9]. Hence, imaging is used to rule out other causes of heart failure [10]. Many reported cases of myocarditis in COVID-19 patients had normal findings on echocardiography [15,26,36]. One patient had no changes compared to his previous echocardiography results; he was already known to have left ventricular hypertrophy due to his chronic hypertension and there were no findings otherwise [16]. Of the 29 cases summarized in this narrative review, 9 cases did not report echocardiography results or reported not having performed an echocardiography due to COVID-19 restrictions [13, 19, 20, 22-24, 27, 29, 36]. These cases will be excluded when calculating percentages and the total number of cases will be considered as 20.
Any new regional or global wall motion abnormality that is not correlated with a coronary distribution has confirmatory and prognostic value in acute myocarditis [9]. Many cases relied on this finding to confirm the diagnosis of acute myocarditis with 15% reporting diffuse hypokinesia or dyskinesia [11,17,18], and 10% reporting regional hypokinesis on echocardiography [32,34]. In fulminant myocarditis, there is a possibility of wall thickening and increased ventricular sphericity [9]. Such findings were not reported in the selected case reports. Left ventricular dysfunction may be found, and 55% of cases were reported to have a left systolic dysfunction [8,11,12,14,17,18,28,30,31,34,35]. However, the strongest predictor of death or need for cardiac transplantation was a loss of right ventricular function [9,10].
In the 29 cases reported, only 2 were found to have right ventricular dysfunction [29,30]. Both cases were in cardiogenic shock and on inotropic and vasoactive support. The first case underwent pericardiocentesis yielding around 300 mL of serous fluid, but with worsening status, she was escalated to veno-arterial extracorporeal membrane oxygenation (VA-ECMO). She later recovered and was discharged successfully [29]. The second case also had to undergo pericardiocentesis which yielded 600 mL of serosanguinous fluid.
She was also on vasopressor and inotropic support and cardiothoracic surgeons were consulted to initiate ECMO therapy, however, it was not started due to multi-organ failure, and the patient died on day 4 of hospitalization despite maximal supportive care [30] (Table 5).
While chest X-Rays performed on COVID 19 patients with myocarditis did not elicit a diagnostic pattern, transthoracic echocardiography revealed a drop in the ejection fraction ranging from mild all the way to severe in patients with no prior history of heart failure. In the cases we reviewed, the lowest ejection fraction reported was 20% [35].

Cardiac Magnetic Resonance
Cardiac MRI is being increasingly used as a routine and non-invasive imaging tool for the diagnosis of suspected acute myocarditis and as a means to localize sites for EMB [9,10]. In the 29 reported cases of myocarditis in patients diagnosed with COVID-19, 14 did not report or perform a cardiac MRI [14, 17, 19, 21, 22, 25-30, 34, 35].
Among patients with nonischemic dilated cardiomyopathy (DCM) and myocarditis, the correct diagnosis was obtained through cardiac MRI alone in 80% of cases [9]. A combination of T2 weighted MRI and post-gadolinium early and late T1 weighted MRI provided the highest sensitivity (67%) and specificity (91 %) for diagnosis [9]. In the reported cases of COVID-19 myocarditis, the combination of increased signal intensity on T2WI along with late gadolinium enhancement often confirmed the diagnosis of several cases by fulfilling the Lake Louise criteria [11,23,24]. In other cases, the findings on cardiac magnetic resonance did not completely meet the criteria and so the patient was considered to have an atypical myocarditis [20].
The Lake Louise criteria are based on regional or global myocardial signal intensity increase in T2 weighted images, increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle, and late gadolinium enhancement.

d) Histopathology: Endomyocardial Biopsy (EMB)
The gold standard for the diagnosis of myocarditis is histological or immumohistological evidence of an inflammatory cell infiltrate with or without myocyte damage [9]. Endomyocardial Biopsy (EMB) should be used in a risk vs. benefit approach when there is more prognostic and therapeutic information gained from the biopsy [9]. The American Heart Association/American College of Cardiology/ European Society of Cardiology (AHA/ACC/ESC) joint scientific statement class 1 recommendations include performing EMB in patients with heart failure with: "(1) Normal or dilated dimensions of the LV, symptoms for a maximum of 2 weeks duration, and hemodynamic compromise (2) A dilated ventricle, symptoms lasting from 2 weeks to 3 months, new onset of ventricular arrhythmias, Mobitz type 2 second-or third-degree block, or a failure to respond to care withing 1-2 weeks" [9] In other clinical scenarios, the use of endomyocardial biopsy remains debatable [10]. However, those with an indication for an EMB should be sent to a medical center with biopsy capability and expertise [10]. To confirm the diagnosis of myocarditis in the reported cases of COVID-19, only one case underwent an endomyocardial biopsy [8]. The medical team refrained from performing a biopsy in the rest of the cases due to several reasons, of which they mentioned: no evidence of heart failure or arrythmias, hemodynamic instability along with significant coagulopathy, rapid and favorable improvement, and establishment of a diagnosis based on the Cardiac Magnetic Resonance (CMR) findings and clinical context. In the case that underwent an EMB, the pathology demonstrated a diffuse infiltrate of Tlymphocytes (with a CD3+ > 7/mm 2 ) and described a huge area of interstitial edema as well as limited foci of necrosis. There was no replacement fibrosis which suggested the acute nature of the inflammatory process. No SARS-CoV-2 genome was detected in the myocardium. No microvascular abnormalities or contraction band necrosis were reported [8].
Another case also had a histopathologic confirmation of the diagnosis, however it was not through an EMB, rather on autopsy, as the patient reported in the case was found pulseless and resuscitation was unsuccessful [27]. Macroscopically, the heart weighed 500g (reference for age 262-295 g), was soft, rubbery, mottled, and there were 80 mL of pericardial fluid. Microscopically, diffuse inflammatory infiltrates were described, with lymphocytes, macrophages, and prominent eosinophils. These were mainly in the interstitium. Multiple foci of myocyte necrosis were found in the RV and LV. There was no evidence of perivascular infiltrates, vascular thrombi, vascular inflammation, or endothelial prominence. No fibrinoid necrosis or granulomatous component was visualized. Only minimal interstitial fibrosis was seen. Although this case was reported as a case of eosinophilic myocarditis in a patient with COVID-19, the authors concluded that this eosinophilic myocarditis is not necessarily specific to the COVID-19 infection, and could instead be idiopathic or resulting from a cardiac decompensation contributed by the SARS-CoV-2.

v. Management
The management of myocarditis generally depends on the clinical scenario. For possible subclinical acute myocarditis, treatment is not known. If the ventricular function is preserved, patients are reassessed after 1 to 2 weeks for heart failure symptoms or arrhythmias [10]. However, those with an impaired left ventricular ejection fraction (less than 40%), Angiotensinconverting-enzyme inhibitors (ACEi) or Angiotensin Receptor Blocker (ARB) and possibly a β adrenergic blocker is to be given as per the AHA/ACC, Heart Failure Society of America (HFSA), and ESC guidelines for the management of stage B heart failure [10]. In the case of probable acute myocarditis, patients have a good response to standard heart failure treatment as well as avoidance of heavy activity for up to 6 months post infection or until ventricular recovery has been proven [10]. The use of immunosuppressive drugs is not recommended. In addition, there is not enough evidence to recommend use of IV immunoglobulin [10]. In the case of chronic dilated cardiomyopathy, immunosuppression with Azathioprine and prednisone showed improvement in ventricular function and quality of life. The use of antiviral therapy still requires further investigation [10]. As for mechanical circulatory support or extracorporeal membrane oxygenation, these can be used until transplantation or recovery from cardiogenic shock [10]. Survival after transplantation is the same as that of transplantation for other cardiac etiologies [10]. For myopericarditis resembling an acute coronary syndrome, administration of colchicine for around 3 months can help alleviate chest pain related to pericarditis [10]. nonsteroidal anti-inflammatory drug like indomethacin should be kept for patients with normal ventricular function [10]. In the case of syncope from ventricular arrhythmias or heart block, routine management of ventricular arrhythmias due to myocarditis is recommended with hospital admission and ECG monitoring [10]. The use of implantable cardiac defibrillator has the same indications as in non-ischemic DCM but may in some cases be used earlier in giant cell myocarditis [10].
The evidence for the management of myocarditis in COVID-19 is scarce. The mainstay treatment of severe COVID-19 patients with cardiac involvement remains supportive care. General principles in the management include the avoidance of overaggressive hydration, and prevention of hypotension while targeting Mean Arterial Pressure MAP of 60-65 mmHg. Dobutamine can be considered in the setting of worsening hypotension with cardiac dysfunction, as well as epinephrine in refractory hypotension [37].
ECMO should be considered for patients with the greatest chance of recovery as well as those with refractory hypoxemia and respiratory acidosis despite advanced ventilation. Patients in cardiogenic shock can benefit from VA ECMO. However, more studies on needed on the topic to better delineate the role of ECMO in COVID-19 patients with myocarditis [37].
As for the evidence on anti-inflammatory and anti-viral therapies, a wide range of strategies has been used including but not limited to IVIG, tocilizumab, anakinra, and remdesivir/ritonavir. The data on the effect of the above drugs on cardiac outcome are mainly from case reports and more research is still needed to guide recommendations [37]. Data from our reports showed different management plans for the treated patients. Out of all the reports included in this study, 19 cases reported the management of the patients. Antiviral therapy was initiated in 7 out of 19 cases, with lopinavir/ritonavir use mostly reported. Antibiotics were initiated in 6 cases. IVIG were used in 6 cases. In addition to that, 6 cases reported the use of Hydroxychloroquine, whereas 5 cases out of the 19 reported the use of colchicine. Steroids, mainly Intravenous methylprednisolone, was initiated in 9 cases. Tocilizumab, the drug that blocks the effect of interleukin 6 was administered in 2 cases.
Vasopressors and inotropes were however used in 9 cases. 6 case reports placed their respective patients on ECMO (Table 7).

Limitations
This narrative review covers a breadth of literature regarding myocarditis in patients with COVID-19. It is however limited by its methodology as a narrative literature review which entails subjectivity in the way articles are selected and conclusions are drawn. However, within the limitations of the selection criteria and analysis conducted by the authors, we believe it brings valuable knowledge and insight regarding the clinical presentation, diagnosis and management of myocarditis in COVID-19. Further studies and systematic reviews are essential to reach conclusive evidence and establish policies regarding COVID-19 myocarditis.

Conclusions
After reviewing 29 reported cases of COVID-19 myocarditis we conclude that its clinical presentation is variable with a predominance of fever, cough, dyspnea, and chest pain. Although the clinical classification requires an endomyocardial biopsy to confirm definite myocarditis, only one patient had undergone the histopathological evaluation as part of the diagnostic approach. The rest of the cases mostly relied on the Lake Louise Criteria. Therefore, cardiac magnetic resonance had an important role in the diagnosis of myocarditis. Other diagnostic modalities were also helpful in establishing a diagnosis. Electrocardiography was the most consistently reported modality and commonly showed ST-segment elevation which resulted in a suspicion of myocardial ischemia. Thus, conventional coronary angiography, or a coronary computed tomography angiography were often used to rule out coronary stenosis. On the other hand, serum biomarkers, when reported were found to be elevated, but this may be a bias in reporting. Echocardiography was also helpful, commonly showing wall motion abnormalities. As for the management, it was not consistent. Besides supportive management and the use of COVID-19 targeted antivirals, antibiotics, and anti-inflammatory treatments, several cases reported the use of IVIG and colchicine. This narrative review highlights our current understanding of myocarditis in COVID-19 patients and stresses on the necessity of establishing proper treatment guidelines for a better management of COVID-19 myocarditis.
reported the use of Hydroxychloroquine, whereas 5 cases out of the 19 reported the use of colchicine. Steroids, mainly Intravenous methylprednisolone, was initiated in 9 cases. Tocilizumab, the drug that blocks the effect of interleukin 6 was administered in 2 cases. Vasopressors and inotropes were however used in 9 cases. 6 case reports placed their respective patients on ECMO (Table 7 )

Limitations
The following narrative review covers a breadth of literature regarding myocarditis in patients with COVID-19. It is however limited by its methodology as a narrative literature review which entails subjectivity in the way articles are selected and conclusions are drawn. However, within the limitations of the selection criteria and analysis conducted by the authors, we believe it brings valuable knowledge and insight regarding the clinical presentation, diagnosis and management of myocarditis in COVID-19. Further studies and systematic reviews are essential to reach conclusive evidence and establish policies regarding COVID-19 myocarditis.

Conclusions
After reviewing 29 reported cases of COVID-19 myocarditis we conclude that its' clinical presentation is variable with a predominance of fever, cough, dyspnea, and chest pain. Although the clinical classification requires an endomyocardial biopsy to confirm definite myocarditis, only one patient had undergone the histopathological evaluation as part of the diagnostic approach. The rest of the cases mostly relied on the Lake Louise Criteria. Therefore, cardiac magnetic resonance had an important role in the diagnosis of myocarditis. Other