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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 6  |  Issue : 3  |  Page : 239-243

Acute Myocarditis Associated with Coronavirus Disease 2019: Systematic Review and Pooled Analysis of Reported Cases


1 Department of Heart Failure, Pulmonary Hypertension and Transplant, Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina
2 Clinical Cardiology, Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina

Date of Submission05-Sep-2020
Date of Acceptance27-Sep-2020
Date of Web Publication23-Dec-2020

Correspondence Address:
Dr. Lucrecia Maria Burgos
Instituto Cardiovascular de Buenos Aires, Blanco Encalada 1543, CABA. CP1428, Aires, Buenos Aires
Argentina
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcs.jpcs_88_20

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  Abstract 


Context: Coronavirus disease (COVID-19) clinical manifestations are mainly respiratory, although cardiac complications are being reported. However, specific information about the clinical characteristics and in-hospital outcomes of patients with myocarditis associated with COVID-2019 is limited. Aim: The aim is to describe the clinical characteristics and outcomes of patients with acute myocarditis associated with COVID-19. Methods: The study consisted of a systematic review of all available case reports. Systematic searches were conducted using MEDLINE (PubMed interface) LILACS and Scielo to identify studies from December 2019 to 11 July 2020 involving adult patients with acute myocarditis associated with COVID-19. Results: Twenty patients were included. The median age was 49 years (interquartile range [IQR] 32.25–69), and 60% were male. Ten patients presented ST-segment elevation on the ECG. All patients had elevated serum levels of troponin T or I, N-terminal pro-brain natriuretic peptide (median 3436 ng/L, IQR 1315-12054) and C-reactive protein (median 33 mg/L, IQR 18–94). Interleukin-6 was measured in three patients, presenting elevated values as well. Left ventricular ejection fraction (LVEF) was severely impaired in 60% of the patients. Half of the patients received corticosteroids, 43.7% antivirals and 31.3% hydroxychloroquine. Moreover, 15.8% of patients underwent mechanical circulatory support. Most patients (90.9%) recovered heart function with LVEF above 40%. In-hospital mortality rate was 15.8%, the main cause of death being bacterial septic shock (75%). Conclusion: Several cases of coronavirus-related myocarditis have been reported. The clinical presentation was heterogeneous. The vast majority of patients were treated with steroids and antivirals. Most patients recovered cardiac function; however, mortality was relatively high.

Keywords: Cardiogenic shock, coronavirus, COVID-19, heart failure, myocarditis


How to cite this article:
Burgos LM, Ramírez AG, Diez M. Acute Myocarditis Associated with Coronavirus Disease 2019: Systematic Review and Pooled Analysis of Reported Cases. J Pract Cardiovasc Sci 2020;6:239-43

How to cite this URL:
Burgos LM, Ramírez AG, Diez M. Acute Myocarditis Associated with Coronavirus Disease 2019: Systematic Review and Pooled Analysis of Reported Cases. J Pract Cardiovasc Sci [serial online] 2020 [cited 2021 Mar 7];6:239-43. Available from: https://www.j-pcs.org/text.asp?2020/6/3/239/304534




  Introduction Top


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel beta coronavirus that was first described in a cluster of patients presenting with pneumonia-like symptoms in Wuhan, China, in December of 2019,[1] rapidly spreading worldwide and becoming a public health emergency of international concern.

Previous data obtained from influenza virus and preceding coronavirus infections have shown to cause direct myocardial injury, as there are known cases of this virus-related myocarditis.[2],[3],[4]

With the increasing number of confirmed cases and the accumulating clinical data, cardiovascular manifestations induced by this viral infection have generated considerable concern,[1],[5],[6] as some patients with underlying cardiovascular diseases might have an increased risk of death.[1]

However, at present, specific information about the clinical characteristics and in-hospital outcomes of patients with myocarditis associated with coronavirus disease (COVID-19) is limited. We performed an analysis of pooled cases to systemically summarize the clinical characteristics and evolution of patients with COVID-19 associated myocarditis.


  Methods Top


We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement in conducting and reporting this systematic review.

Search methods for identification of studies

This study was a systematic review of case reports. Systematic searches were conducted using MEDLINE (PubMed interface), LILACS and Scielo to identify studies from December 2019 to July 11, 2020. Reference lists of the relevant articles were reviewed to identify additional studies. Articles in Spanish, English, and Portuguese were included. Medical Subject Heading, and keywords “myocarditis” OR “myocardial” AND “coronavirus” OR “COVID19” “COVID-19” OR “2019-nCoV” OR “SARS-CoV-2 were used.

Selection of studies for inclusion

To enter this analysis, case reports had to fulfill all these inclusion criteria: (1) provide data on patients with new-onset (days up to 3 months) myocarditis associated with COVID-19; (2) use of either endomyocardial biopsy (EMB) or clinical criteria (elevated myocardial injury biomarkers, electrocardiographic (ECG) findings suggestive of cardiac injury, abnormal cardiac function on echocardiogram or cardiac magnetic resonance (CMR)) for the diagnosis of acute myocarditis;[7],[8] (3) include patients aged 18 years or older; (4) report patients' characteristics, such as clinical presentation, biochemical markers, ECG findings, and echocardiographic features, treatment used and in-hospital outcomes; and (5) be a prospective or retrospective observational investigation.

The exclusion criteria were as follows: (1) Articles studying non-human samples; (2) reviews, (3) duplicate articles for the same investigation.

Titles and abstracts were independently screened by two reviewers (LMB and AGR) to identify potentially relevant articles. Discrepancies in judgment were resolved after discussion (MD). Full-text articles were included in our analysis if they fulfilled the inclusion criteria.

Data extraction and synthesis

Data extraction was performed independently by two reviewers (LMB and AGR), and it included first author, number of patients, study period, characteristics of the study population, diagnostic tests, treatment, and clinical outcomes. Because most of the published literature were case reports and individual information could be achieved from the original studies, a pooled analysis using was made.

Statistical analysis

Continuous variables were expressed as mean and standard deviation or median and interquartile range (IQR), according to the observed distribution. Kolmogorov–Smirnov or Shapiro–Wilk test according to the sample size were used to determine distribution. Categorical variables were expressed as numbers and percentages. SPSS Statistics, Version 23.0 (IBM Corporation, Armonk, NY, USA) was used for statistical analysis.


  Results Top


Search results

Four hundred and fifty-nine studies were identified through literature search, among which 399 were excluded after an initial review of titles and abstracts. The remaining publications were reviewed in full-text and assessed against inclusion criteria. Finally, twenty were selected for systematic review and meta-analysis.[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28]

Patients characteristics and diagnostic test

A total of 20 patients were included. The median age was 49 years (IQR 32.25-69), and 60% were male. Ten patients presented ST-segment elevation on the ECG. All patients had elevated serum levels of troponin T or I, N-terminal pro-brain natriuretic peptide (median 3436 ng/L, IQR 1315-12054) and C-reactive protein (CRP) (median 33 mg/L, IQR 18-94). Interleukin-6 (IL) was measured in three patients, finding elevated values [Table 1].
Table 1: Basal characteristics of included patients

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The left ventricular ejection fraction (LVEF) was impaired in 78.9% of patients and severely decreased (<40%) in 60% of them. EMB or CMR was performed in 13 patients (65%). Coronary artery disease, with coronary angiogram or coronary tomography, was excluded in ten patients [Table 2]. Moreover, this evaluation was performed in 60% of patients with ST-segment elevation.
Table 2: Diagnostic procedures

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Treatment and clinical outcomes

From the available data of 19 patients, 15.8% underwent mechanical circulatory support. Regarding reported medical treatment: 50% received corticosteroids and 43.7% antivirals, 25% immunoglobulin, 31.3% hydroxychloroquine, and 12.5% Interferon. The treatment each patient received is summarized in [Table 3].
Table 3: Treatment and evolution

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Most patients recovered heart function (ten out of eleven), with LVEF >40%. Data on mortality were available in 19 patients, presenting a rate of 15.8%. The main cause of death was bacterial septic shock (75%).


  Discussion Top


In this study, based on a systematic review of case reports, we summarize the basal characteristics, diagnostic tests, treatment received, and clinical outcomes of patients with myocarditis associated with COVID-19.

Myocarditis usually demonstrates heterogeneous clinical presentations, ranging from a paucisymptomatic disease to cardiogenic shock requiring mechanical ventricular assistance.[29] The main clinical findings include changes in the electrocardiogram and cardiac biomarkers, higher plasma concentrations of IL-6 and CRP, and impaired cardiac function.

The pathophysiological mechanisms underlying myocardial injury caused by COVID-19 are not clearly understood. The proposed mechanisms of myocardial injury are direct viral damage to the cardiomyocytes, consequent systemic inflammation, myocardial interstitial fibrosis, interferon-mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization and hypoxia.[30]

“Point-of-care” focused ultrasound and critical care echocardiography are probably the preferred imaging modalities for patients with COVID-19. They are effective options to screen for cardiovascular and pulmonary complications of COVID-19 infection.[31],[32] In this review, left ventricular dysfunction was evident in most patients with myocarditis associated with COVID-19.

The presence of acute myocarditis could not be confirmed with CMR o BEM in all patients, and in only half of patients, the acute coronary syndrome was excluded. Even though most patients recovered left ventricular function, they presented high mortality, mainly those who required mechanical circulatory assistance with added bacterial infectious complications.

It is important to note that the chosen therapeutic scheme was different in all cases; however, corticosteroids, antiviral, and immunomodulatory therapy were the most frequently used. Ideally, treatment of COVID-19 associated myocarditis should be decided within a multidisciplinary team that includes infectious disease consultation to guide therapy selection. Several experimental therapies attempting to limit SARS-CoV-2 replication or the immune response have been proposed, with multiple clinical trials currently underway. At present, there are no therapies with rigorous, clinically supported efficacy for COVID-19.[33] Immunosuppression has been proposed as a treatment option; however, prior experiences with broad immunosuppression for acute myocarditis historically have not been favorable. In the Myocarditis Treatment Trial, no significant difference was seen in LVEF or survival between patients treated with cyclosporine/prednisone, those treated with azathioprine/prednisone, and those receiving placebo among patients with myocarditis in the pre-COVID era.[34]

Although EMB is considered the gold standard to confirm the histological diagnosis of myocarditis,[35] most centers rarely perform it during the pandemic, because of complications and lack of proper setting. CMR is currently the most comprehensive and accurate diagnostic tool, targeting several features of myocarditis: inflammatory hyperemia and edema, necrosis/scar, and contractile dysfunction.[36] However, CMR is not available in most centers, also taking into account the scarce resources, risk of infection and contamination, availability, and clinical status of the patient. This led us to use clinical evaluation as diagnostic criteria, with the limitations that this entails.

It is important to mention that due to the nature of the case reports, the results presented are subject to investigator and selection bias. The first reported cases are probably published initially and later the atypical or severe cases or cases with unusual findings.

Understanding the effects of COVID-19 on the cardiovascular system is essential for providing comprehensive medical care for cardiac patients. Further research is urgently needed; due to the low prevalence of this association, it will require multicenter studies. It would be encouraging to publish data specifically describing the presentation, treatment, and evolution of patients with acute myocarditis and COVID-19. This would aid in clinical management and to understand the pathogenic effect and causal relationship between myocarditis and SARS-CoV-2.


  Conclusion Top


Several cases of coronavirus-related myocarditis have been reported. The clinical presentation was heterogeneous. The vast majority of patients were treated with steroids and antivirals. Most patients presented recovery of cardiac function; however, mortality was relatively high. Further research is urgently needed, due to the low prevalence of disease, it will probably require multicenter studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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