key: cord-0909518-o8wssuuq
authors: Ho, Jamie SY; Sia, Ching-Hui; Chan, Mark YY; Lin, Weiqin; Wong, Raymond CC
title: Coronavirus-induced myocarditis: a meta-summary of cases
date: 2020-08-20
journal: Heart Lung
DOI: 10.1016/j.hrtlng.2020.08.013
sha: 2dd694957fe6bef3a8853e5c1f5597a8448626cc
doc_id: 909518
cord_uid: o8wssuuq

BACKGROUND: Myocarditis caused by SARS-CoV-2 infection was proposed to account for a proportion of cardiac injury in patients with COVID-19. However, reports of coronavirus-induced myocarditis were scarce. The aim of this review was to summarise the published cases of myocarditis and describe their presentations, diagnostic processes, clinical characteristics and outcomes. METHODS: A literature search of MEDLINE, EMBASE, Scopus, Web of Science, CENTRAL and OpenGrey on was performed on 3 June 2020. Studies of myocarditis in patients with COVID-19 were included, and those only reporting cardiac injury or heart failure were excluded. Cases were “confirmed” myocarditis if diagnosed on cardiac magnetic resonance imaging (CMR) or histopathology. Those without were grouped as “possible” myocarditis. RESULTS: A total of 31 studies on 51 patients were included; 12 cases were confirmed myocarditis while 39 had possible myocarditis. The median age was 55 and 69% were male. The most common presenting symptoms were fever, shortness of breath, cough and chest pain. Electrocardiogram changes included non-specific ST-segment and T-wave changes and ventricular tachycardia. Most patients had elevated cardiac and inflammatory biomarkers. Left ventricular dysfunction and hypokinesis was common. CMR established the diagnosis in 10 patients, with features of cardiac edema and cardiac injury. Five patients had histopathological examination. Some cases required mechanical ventilation and extracoporeal membrane oxygenation, and 30% of patients recovered but 27% died. CONCLUSIONS: COVID-19 myocarditis was associated with ECG, cardiac biomarker and echocardiographic changes, and the manifestation could be severe leading to mortality. Endomyocardial biopsy was not available in most cases but CMR was valuable.

Myocarditis caused by SARS-CoV-2 infection was proposed to account for a proportion of cardiac injury in patients with COVID-19. However, reports of coronavirus-induced myocarditis were scarce. The aim of this review was to summarise the published cases of myocarditis and describe their presentations, diagnostic processes, clinical characteristics and outcomes.

OpenGrey on was performed on 3 June 2020. Studies of myocarditis in patients with COVID-19 were included, and those only reporting cardiac injury or heart failure were excluded. Cases were "confirmed" myocarditis if diagnosed on cardiac magnetic resonance imaging (CMR) or histopathology. Those without were grouped as "possible" myocarditis.

A total of 31 studies on 51 patients were included; 12 cases were confirmed myocarditis while 39 had possible myocarditis. The median age was 55 and 69% were male. The most common presenting symptoms were fever, shortness of breath, cough and chest pain.

Electrocardiogram changes included non-specific ST-segment and T-wave changes and ventricular tachycardia. Most patients had elevated cardiac and inflammatory biomarkers.

Left ventricular dysfunction and hypokinesis was common. CMR established the diagnosis in 10 patients, with features of cardiac edema and cardiac injury. Five patients had histopathological examination. Some cases required mechanical ventilation and extracoporeal membrane oxygenation, and 30% of patients recovered but 27% died.

CoV-2 infection found that cardiac injury occurred in up to 30% of patients, and was associated with increased disease severity 1 . Myocarditis, an inflammatory disease of the myocardium, has been proposed to account for a proportion of cardiac injury, in addition to systemic inflammation. Myocarditis is classified as acute, chronic or fulminant, the latter being a sudden, severe manifestation associated with acute heart failure, cardiogenic shock and life-threatening arrhythmias. Viral infections such as enteroviruses and adenoviruses are common causes of myocarditis, which can cause a combination of direct cellular injury and T-cell cytotoxic response 2 . However, the evidence for COVID-19 myocarditis has been limited to case reports and case series, which is complicated by a difficulty in establishing a confirmed diagnosis 3 . The aim of this review was to summarise and describe cases of myocarditis caused by COVID-19 in order to increase the understanding of the presentation, clinical characteristics, diagnostic process and outcomes of this relatively rare but possibly severe presentation.

We performed a search on MEDLINE, Embase, Scopus, Web of Science, CENTRAL and OpenGrey on 3 June 2020. The search terms were "coronavirus" or "COVID" or "SARS" or "MERS" and "myocarditis" or "myopericarditis" or ""heart failure" or "myocardial inflammation" or "myocardium" or "cardiomyopathy" or "myocardial injury" or "cardiac injury". The search was not restricted in time, type or language of publication. The inclusion criteria were clinical studies on (1) laboratory-confirmed COVID-19 infection and (2) reported diagnosis of myocarditis. Additional articles were identified from hand searching of the references of reviews and included articles. Primary research studies including randomised trials, cohort studies, case series and case reports were included, and there were no limitations on publication type. Studies that did not report myocarditis e.g. cardiomyopathy or cardiac injury only and animal studies were excluded. Titles and abstracts were independently screened by two researchers (JSH and CHS) and discrepancies were resolved by discussion. Data from full texts were extracted onto a standardised form, which included the study type, viral infection, patient characteristics, investigations, management and outcomes.

Studies were grouped according to the method of diagnosis and certainty of myocarditis.

Patients with myocarditis diagnosed on histopathological examination or cardiac magnetic resonance imaging (CMR) had "confirmed myocarditis", while patients with reported myocarditis without the above investigations had "possible myocarditis". The quality of the studies were assessed using validated scales such as the modified Pierson, Bradford Hills and Newcastle-Ottawa scale for case series and case reports 4 .

Results were summarised in a results table and meta-summary, and statistical analysis were performed with SPSS (Version 25, Armonk, NY: IBM Corp.). Patients with confirmed cases were compared to possible cases in the meta-summary. Continuous variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR). Categorical variables were presented as frequency and percentage.

The primary search resulted in 764 studies after removal of duplicates from 1196 articles, 31 met the inclusion criteria and were included ( Figure 1 ). There were 24 case reports 5-28 , 5 case series 29-33 and 2 cohort studies 34, 35 , on a total of 51 cases of myocarditis and SARS-CoV-2 infection. The studies were of poor to fair quality due to the high risk of selection bias in case reports and small case series (Supplementary Table 1 ). The demographics and clinical characteristics of the included cases were presented in Table 1 . Overall, the median age was 55 (IQR 34.3-67.8), and 69% were male. Three cases were under 18-years-old, with 2 cases of children under 13 15, 19, 24 . The most common presenting symptoms were fever (62%), shortness of breath (48%), cough (48%), and chest pain (34%). Other reported symptoms include fatigue, nausea and vomiting, diarrhoea, myalgia, weakness and headache. Most patients had no reported cardiovascular co-morbidities, 8 (28%) had hypertension, 2 (7%) had diabetes mellitus, 2 (7%) had hyperlipidaemia.

In the 51 patients, 12 were confirmed cases of myocarditis diagnosed by histopathological evidence or CMR features fulfilling the Lake Louise consensus criteria ( Table 2) 5-7, 9, 13-15, 21-25, 36 . The remaining 39 were possible cases where authors reported a diagnosis of myocarditis, with or without supporting serological, electrocardiogram (ECG) and echocardiographic features. The age of confirmed cases was 39 (28.5-60) years, and 9 (75%) were male. Similarly, the most common presenting symptom was fever (58%), shortness of breath (42%), cough (42%), chest pain (25%), fatigue (25%) and diarrhoea (25%). In terms of comorbidities, 3 patients (25%) had hypertension, 1 had atrial fibrillation, 1 had diabetes mellitus and 1 was overweight. One patient recently recovered from COVID-19 pneumonia 3 weeks prior to presentation with myocarditis. In 10 patients, myocarditis was diagnosed with cardiac magnetic resonance imaging (CMR) based on the Lake Louise Criteria 36 , which included signs of myocardial edema on T2weighted imaging and myocardial injury on T1-weighted imaging with late gadolinium enhancement (LGE) ( Table 2 ). The CMR was performed between day 3 to 18 of the hospital stay. The mean LV ejection fraction (LVEF) measured on CMR was 49% (SD 20%), and one case showed a recovery of LVEF from 35-40% on echocardiogram to 82% on CMR after two weeks. On T1-weighted imaging, 3 patients showed diffuse hypokinesis in the left and/or right ventricles, and one patient had mild hypokinesis at basal and mid LV segments. On T2weighted imaging, 6 patients had diffuse increase in signal uptake suggesting diffuse myocardial edema, one patient had localised edema in the apical region and another in the mid inferoseptal and inferior wall regions. Only one patient reported no edema on initial CMR and 2 patients had resolution of edema within 2 weeks. Imaging with LGE found nonischaemic patterns of enhancement in 8 patients. The inferolateral regions were most commonly affected, and LGE ranged from subepicardial to transmural patterns. In contrast, 3 patients had no LGE and one patient showed normalization of CMR on repeated scan one week after. Three patients had pericardial effusions without tamponade, which was a supporting criterion in the Lake Louise consensus criteria.

Histopathological evidence was found in two patients, one from endomyocardial biopsy (EMB) and the other from autopsy after sudden death. In a patient with hypokinesis and diffuse myocardial oedema at basal and mid left ventricular segments on CMR, EMB showed diffuse T-lymphocytic inflammatory infiltrates. There was huge interstitial oedema and limited foci of necrosis, fulfilling the Dallas criteria 37 . However, SARS-CoV-2 genome was not identified within the myocardium, suggesting a diagnosis of acute virus-negative lymphocytic myocarditis. The second case was a previously healthy 17-year-old African American male who died on arrival to hospital after complaining of severe headaches, dizziness, nausea and vomiting for two days. Pathological examination of the heart found diffuse inflammatory infiltrates composed of lymphocytes, macrophages and prominent eosinophils, mainly in the interstitium and associated with multiple foci of myocyte necrosis.

This was identified in both ventricles, and eosinophilic myocarditis was diagnosed.

Of the 12 patients with confirmed myocarditis, 3 were treated with hydroxychloroquine, 3 had steroids (methylprednisolone, hydrocortisone or oral prednisolone), 2 had azithromycin, 2 had lopinavir/ritonavir, 1 had colchicine, 1 had tocilizumab, 1 had oseltamivir and 1 had intravenous immunoglobulins. Heart failure was treated with diuretics, angiotensin converting enzyme inhibitors (ACEi) and beta-blockers. Although patients had complications such as heart failure, respiratory failure and multi-organ dysfunction, recovery of cardiac function occurred in 3 COVID-19 patients after severe disease requiring ICU admission. Six patients recovered or were discharged, one showed improvement and 2 patients died.

Cardiac injury identified from an increase in cardiac biomarkers such as cardiac troponins has been shown to be associated with more severe disease in COVID-19 and was predictive of ICU admission and mortality 38 

Pericardial Diseases 43 recommended that heart failure and arrhythmias caused by myocarditis should be optimally managed, including use of diuretics, ACE inhibitors, beta-adrenergic blockade, anti-arrhythmics, temporary pacing and extracoporeal membrane oxygenation.

Immunomodulatory therapy using anti-viral medications and intravenous immunoglobulins has been suggested but evidence of benefit is limited. Immunosuppression using steroids, azathioprine and ciclosporin is often attempted but guidelines recommend that they should be started only after ruling active infections by polymerase chain reaction. Although steroid therapy was initially thought to impair clearance of the SARS-CoV-2 virus 44 , the recent RECOVERY trial demonstrated that dexamethasone reduced mortality in patients receiving invasive mechanical ventilation and other oxygen therapy, but not in those without respiratory support 45 . The role of steroids in myocarditis caused by COVID-19 is therefore unclear and needs to be investigated further.

Recent studies identified a Kawasaki-like multisystem inflammatory syndrome in children, despite children previously thought to mainly present with mild respiratory symptoms unlike adults 46, 47 . The prospective observational study found that 76% of the 21 children and adolescents with features of Kawasaki disease had myocarditis diagnosed on cardiac troponins, ECG and echocardiogram. All the patients in the case series, as well as two case reports included in this study, recovered 19, 24 , suggesting that prognosis is good.

The studies included in this meta-summary were mostly case reports and case series, which were low on the hierarchy of evidence and the cases may not be representative or generalizable. The reporting of data in case reports were also incomplete, therefore risk of information bias is high. The diagnostic uncertainty of included cases was a major limitation, and there may be mimics such as stress and septic cardiomyopathy, although this was reduced by only including cases with confirmed myocarditis using pathological or CMR evidence at the expense of increased selection bias. EMB was not available in most cases but CMR was valuable to confirm myocarditis in coronavirus infections.

In this meta-summary of cases of myocarditis associated with COVID-19, we identified 12 cases with myocarditis diagnosed on CMR or histopathology and 39 cases with reported myocarditis based on cardiac biomarkers, ECG and/or echocardiogram. Patients with myocarditis often showed typical symptoms of fever, cough, shortness of breath and chest pain. In general, myocarditis is a rare presentation, but fulminant myocarditis can lead to severe disease and mortality in patients with COVID-19. Future studies should focus on 13 reliable diagnosis of myocarditis in an outbreak scenario, and characterising these patients in larger, prospective studies. NT-pro-BNP -N-terminal pro B-type natriuretic peptide; RV -right ventricular; WCCwhite cell count

Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (covid-19)

Molecular biology and pathogenesis of viral myocarditis

Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (covid-19) pandemic

Methodological quality and synthesis of case series and case reports

A recovered case of covid-19 myocarditis and ards treated with corticosteroids, tocilizumab, and experimental at-001. JACC Case Rep

Acute myocarditis presenting as a reverse tako-tsubo syndrome in a patient with sars-cov-2 respiratory infection

An 'asymptomatic' driver with covid-19: Atypical suspected myocarditis by sars-cov-2

Cardiac injury, arrhythmia, and sudden death in a covid-19 patient. HeartRhythm Case Rep

Cardiac involvement in a patient with coronavirus disease 2019 (covid-19)

Clinical and biochemical indexes from 2019-ncov infected patients linked to viral loads and lung injury

Clinical feature changes of a covid-19 patient from mild to critical condition and cardiopulmonary pathological results

Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin

Covid-19-related myocarditis in a 21-year-old female patient

Diffuse myocardial inflammation in covid-19 associated myocarditis detected by multiparametric cardiac magnetic resonance imaging

Fatal eosinophilic myocarditis in a healthy 17-year-old male with severe acute respiratory syndrome coronavirus 2 (sars-cov-2c)

First case of covid-19 complicated with fulminant myocarditis: A case report and insights. Infection

Life-threatening cardiac tamponade complicating myo-pericarditis in covid-19

Multisystem inflammatory syndrome with features of atypical kawasaki disease during covid-19 pandemic

Myocardial localization of coronavirus in covid-19 cardiogenic shock

Myocarditis detected after covid-19 recovery

Myocarditis in a patient with covid-19: A cause of raised troponin and ecg changes

Myocarditis revealing covid-19 infection in a young patient

Pediatric life-threatening coronavirus disease 2019 with myocarditis

Terra incognita: Clinically suspected myocarditis in a sars-cov-2 positive patient

The variety of cardiovascular presentations of covid-19

Transient st segment elevation in two patients with covid-19 and a normal transthoracic echocardiogram

Use of tocilizumab for covid-19-induced cytokine release syndrome: A cautionary case report

Covid-19 (sars-cov-2) and the heart -an ominous association. Cardiovasc Revasc

Covid-19 in solid organ transplant recipients: A single-center case series from spain

Pulmonary and systemic involvement of covid-19 assessed by ultrasound-guided minimally invasive autopsy

The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (covid-19): Report of 3 autopsies from houston, texas, and review of autopsy findings from other united states cities

Invasive strategy for covid patients presenting with acute coronary syndrome: The first multicenter italian experience

Clinical predictors of mortality due to covid-19 based on an analysis of data of 150 patients from wuhan, china

Suspected myocardial injury in patients with covid-19: Evidence from front-line clinical observation in wuhan, china

Cardiovascular magnetic resonance in myocarditis: A jacc white paper

Diagnosis of myocarditis

Cardiac injury is associated with mortality and critically ill pneumonia in covid-19: A metaanalysis

Effect of coronavirus infection on the human heart: A scoping review

Fulminant myocarditis: Characteristics, treatment, and outcomes

Echocardiographic findings in fulminant and acute myocarditis

Cardiac magnetic resonance assessment of myocarditis

Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position statement of the european society of cardiology working group on myocardial and pericardial diseases

The effect of corticosteroid treatment on patients with coronavirus infection: A systematic review and meta-analysis

Effect of dexamethasone in hospitalized patients with covid-19: Preliminary report. medRxiv

Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in paris, france: Prospective observational study

Kawasaki-like disease: Emerging complication during the covid-19 pandemic