Fulminant Myocarditis with SARS-CoV-2 Infection: A Narrative Review from the Case Studies

One of the severe complications of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is myocarditis. However, the characteristics of fulminant myocarditis with SARS-CoV-2 infection are still unclear. We systematically reviewed the previously reported cases of fulminant myocarditis associated with SARS-CoV-2 infection from January 2020 to December 2022, identifying 108 cases. Of those, 67 were male and 41 female. The average age was 34.8 years; 30 patients (27.8%) were ≤20 years old, whereas 10 (9.3%) were ≥60. Major comorbidities included hypertension, obesity, diabetes mellitus, asthma, heart disease, gynecologic disease, hyperlipidemia, and connective tissue disorders. Regarding left ventricular ejection fraction (LVEF) at admission, 93% of the patients with fulminant myocarditis were classified as having heart failure with reduced ejection fraction (LVEF ≤ 40%). Most of the cases were administered catecholamines (97.8%), and mechanical circulatory support (MCS) was required in 67 cases (62.0%). The type of MCS was extracorporeal membrane oxygenation (n = 56, 83.6%), percutaneous ventricular assist device (Impella®) (n = 19, 28.4%), intra-aortic balloon pumping (n = 12, 12.9%), or right ventricular assist device (n = 2, 3.0%); combination of these devices occurred in 20 cases (29.9%). The average duration of MCS was 7.7 ± 3.8 days. Of the 76 surviving patients whose cardiac function was available for follow-up, 65 (85.5%) recovered normally. The overall mortality rate was 22.4%, and the recovery rate was 77.6% (alive: 83 patients, dead: 24 patients; outcome not described: 1 patient).


Background
Te severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (COVID-19) pandemic has been a global public health issue leading to signifcant morbidity and mortality worldwide [1,2].SARS-CoV-2 infection predominately results in an acute respiratory illness; however, sometimes cardiovascular complications arise, such as heart failure, pericardial efusion, and, rarely, myocarditis [3].SARS-CoV-2 infection-related myocarditis has been reported since the beginning of the viral outbreak; fulminant myocarditis is a rare, yet life-threatening, variant with signifcant mortality, and often demands the emergent initiation of mechanical circulatory support (MCS) [3,4].Additionally, balancing infection protection and its treatment is challenging.Fulminant myocarditis due to SARS-CoV-2 infection is very rare and its characteristics still unclear.In this systematic literature review, we aimed to describe all cases of myocarditis associated with SARS-CoV-2 infection reported globally.

Study Design.
We systematically reviewed the literature for reports of fulminant myocarditis associated with SARS-CoV-2 infection.Tis literature review was conducted in concordance with the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [5].Registration of a review protocol was deemed unnecessary, as we used data presented in published literature for this study.

Eligibility and Exclusion
Criteria.Te included publications were full-length manuscripts retrieved with our search that contained data on one or more patients who acutely presented with myocarditis and recent SARS-CoV-2 infection, which was defnitively diagnosed by any tests.Myocarditis was diagnosed by one or more of the following characteristics: clinically suspected myocarditis [6], elevated troponin levels and abnormal electrocardiograms, and impaired cardiac function on echocardiography and fndings consistent with myocarditis on cardiac magnetic resonance (CMR) imaging (including myocardial edema or late gadolinium enhancement) or on endomyocardial biopsy (EMB) [7].Moreover, fulminant myocarditis was defned as myocarditis with the new onset of heart failure with cardiogenic shock requiring ionotropic drugs or MCS, or histologically proven myocarditis with sudden death for which autopsy was available.Publications were frst screened and excluded if they were written in languages other than English without an English interpretation.After the frst screening, publications were excluded if any of the following conditions were met: not a case report or a human report; not a case of SARS-CoV-2 infection-related myocarditis; not a case of related myocarditis (for example, cases of acute coronary syndrome or pericarditis); not a case of fulminant myocarditis, using the defnition provided above.
All articles retrieved from the systematic search were exported to EndNote Reference Manager (Version X9; Clarivate Analytics, Philadelphia, Pennsylvania, USA).All the identifed publications were further screened for the inclusion and exclusion criteria by reading the full-text publications.Te articles were assessed by two assessors (RO and TI) independently; if the two assessors' decision difered, a third assessor (HK) provided the fnal decision for inclusion.Te PRISMA fowchart summarizes the results of our literature search (Figure 1).

Data Extraction
Process.Te included publications were analyzed for the authors' names, publication year, and patient-related data, namely, demographics, comorbidities, history of vaccination, clinical presentation, fndings on echocardiography, arrhythmia, CMR data, biopsy fndings, treatments, and outcomes.
Myocarditis with concurrent pneumonia occurred in 43 cases (45%), of which 20 were in 2020 and 2021, and only 3 after 2021.
Regarding arrhythmia, lethal arrhythmias, namely, ventricular tachycardia and ventricular fbrillation, occurred in 11 and 5 patients, respectively.Cardiac arrest, presented as pulseless electrical activity or asystole, occurred in 6 and 6 cases, respectively.Identifed cardiac conduction defects included right bundle branch block (n � 5) and complete atrioventricular block (n � 4).
Finally, the overall mortality rate was 22.4%, and the recovery rate was 77.6% (alive: 83 patients, dead: 24 patients; outcome not described: 1 patient).One patient underwent a heart transplant.

Discussion
In this systematic review, we summarized the features of fulminant myocarditis with SARS-CoV-2 infection, including patients' demographics, comorbidities, history of vaccination, symptoms, clinical characteristics, treatments, and outcomes.To our knowledge, this is the frst comprehensive review analyzing all cases of fulminant myocarditis related to SARS-CoV-2 infection.

4.1.
Patients' Clinical Characteristics.Te incidence of acute myocarditis in the general population is estimated to be approximately 10-22 per 100,000 people [98,99].Te estimation of the mean prevalence of SARS-CoV-2 infectionrelated acute myocarditis was reportedly between 0.0012 and 0.0057 among hospitalized patients with SARS-CoV-2 infection [3].Although the incidence of fulminant myocarditis is less well-defned, the condition is considered quite rare.Our systematic review revealed that only 108 cases of fulminant myocarditis with SARS-CoV-2 infection were reported between 2020 and 2022.
Te mean age of the 108 patients with myocarditis with SARS-CoV-2 infection was 35 years, and 62% of them were male.Myocarditis has been reported to occur more frequently in males, with a male to female ratio around 1.5 : 1-1.7 : 1; therefore, the current review was consistent with previous reports [100,101].Surprisingly, the case of a 3day-old newborn with myocarditis was reported; if mothers                    Canadian Journal of Infectious Diseases and Medical Microbiology do not possess antibodies against COVID-19, newborns can be infected with the virus [38].Conversely, the incidence was not so high among the elderly.Myocarditis typically occurs between 3 and 9 days after the onset of COVID-19 symptoms.Te time course of the occurrence of myocarditis was similar to other viral infections, such as infuenza [102].

Pathophysiology and Comorbidities.
Te possible pathophysiology of COVID-19 myocarditis is thought to involve the direct invasion of cardiac myocytes by the SARS-CoV-2 virus, and indirect cardiac injury due to increased release of cytokines and infammatory pathways [103,104].Te densities of CD68+ macrophages and CD3+ lymphocytes have been reported to be relatively high in myocarditis, from the results of EMB; additionally, myocardial macrophage and lymphocyte densities displayed a positive correlation with the symptom duration of myocarditis [105].Tus, cytokines and infammatory pathways are likely to play key roles in myocarditis' pathogenesis.Previous reviews described that patients with cardiovascular comorbidities, such as hypertension, diabetes, obesity, hyperlipidemia, and ischemic heart disease were at a higher risk of developing COVID-19 myocarditis [104].Te results of our analysis revealed that hypertension, obesity, and diabetes mellitus were the most common comorbidities among patients with SARS-CoV-2 infectionrelated "fulminant" myocarditis.Te association between hypertension and infammation is well-known; infammatory responses increase the disease's severity and patients' complications [106].Obesity is associated with adipose tissues, chronic low-grade infammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of proinfammatory cytokines.Increased epicardial and pericardial thickness can be observed on echocardiography of patients with myocarditis and has been attributed to an increased amount of epicardial adipose tissue (EAT), a highly infammatory reservoir with dense macrophage infltration and increased levels of proinfammatory cytokines, such as interleukin 6 (IL-6) [107].EATcould fuel COVID-19-induced cardiac injury and myocarditis [108].Te EAT volume, as well as the volume of visceral adipose tissue, is increased in obese patients; therefore, obesity is also one of the major risk factors for myocarditis [109].

Vaccination and Variant of the Virus.
Regarding vaccination, myocarditis following vaccination has been reported, with an incidence of myocarditis/pericarditis of 4.5 Canadian Journal of Infectious Diseases and Medical Microbiology per 100,000 vaccinations across all doses [110].Our review revealed that most cases of fulminant myocarditis caused by COVID-19 did not receive vaccination; however, vaccination's number was limited, with the accumulation of more fndings being expected in the future.Te incidence of concurrent myocarditis and pneumonia has decreased over time, probably because of the change of viral variant and the widespread use of vaccines.Te severity of COVID-19 is milder with the Omicron variant, compared with Alpha and Delta variants, identifed by whole genome sequencing.In addition, Omicron has difculty replicating in the lungs compared to the Delta variant, which may explain the reduced respiratory impairment with the Omicron [111,112].

Clinical Presentation.
Te most reported symptoms were fever, dyspnea, shortness of breath, chest pain, and cough.Tese are typical manifestations in myocarditis as well as in COVID infections; accordingly, reaching an appropriate diagnosis can be challenging [113].
Regarding LVEF at admission, more than 90% of the patients with fulminant myocarditis were classifed as having heart failure with reduced ejection fraction (LVEF ≤ 40%).Notably, regardless of the severity of the acute myocardial injury, the cardiac function of most patients returned to normal if they survived; our review showed that 85.5% of the patients recovered to a normal cardiac function.In previous reports of acute cardiac injury in patients with SARS-CoV-2 infection, 89% of the patients presented a LVEF of approximately 67%, while 26% developed myocarditis-like scars [114].Te long-term efect of such cardiac injury data is still unknown, and waiting for the follow-up data is warranted.
Te overall incidence of arrhythmia in patients with COVID-19 was reported as 16.8%, of which approximately 8.2% constituted atrial arrhythmias (atrial fbrillation or atrial futter), 10.8% conduction disorders, 8.6% ventricular tachycardia (ventricular tachycardia, tachycardia/ventricular futter/ventricular fbrillation), and 12% unclassifed arrhythmias [115].Our review revealed that lethal arrhythmias or cardiac arrest occurred in a total of 26 cases with fulminant myocarditis (24.1%), a rate higher than previously reported.Tese arrhythmias often required MCS, and 62% of the patients in our review received MCS.4.5.Diagnosis.CMR and EMB are essential myocarditis diagnostic tests.However, due to the risk of infection, such were sometimes not performed in patients with COVID-19.Additionally, CMR is usually performed after myocarditis stabilization, in a subacute phase.According to the revised Lake Louise Criteria of 2018, CMR-based diagnosis of myocarditis is based on at least one T1-based criterion (increased myocardial T1 relaxation times, extracellular volume fraction, or late gadolinium enhancement) with the presence of at least one T2-based criterion (increased myocardial T2 relaxation times, visible myocardial edema, or increased T2 signal intensity ratio).
Additionally, supportive criteria include the presence of pericardial efusion in cine CMR images or high signal intensity of the pericardium in late gadolinium enhancement images, T1-mapping or T2-mapping, and systolic left ventricular wall motion abnormality in cine CMR images [7].Diagnosis of myocarditis using the Lake Louise Criteria has a 91% specifcity and 67% sensitivity.CMR can be used as a primary diagnostic technique for screening COVID-19-associated myocarditis in the absence of contraindications [116].
EMB remains the gold standard invasive technique in diagnosing myocarditis, and, especially for fulminant myocarditis with a fatal outcome, autopsy is also an useful diagnostic tool [117].Te sequence of myocardial damage after SARS-CoV-2 infection obtained from autopsy reviews varied.Raman et al. reported that only four patients (5%) presented suspected cardiac injury in an early autopsy series of 80 consecutive SARS-CoV-2 positive cases; two patients had comorbidities and died of sudden cardiac death, one presented acute myocardial infarction, and another showed right ventricular lymphocytic infltrates.Tese results suggested that extensive myocardial injury as a major cause of death may be infrequent [118].Basso et al. investigated cardiac tissue from the autopsies of 21 consecutive patients with COVID-19 assessed by cardiovascular pathologists.Myocarditis (characterized as lymphocytic infltration as well as myocyte necrosis) was seen in 14% of the cases, infltration of interstitial macrophage in 86%, and pericarditis as well as right-sided ventricular damage in 19% [119].Halushka and Vander Heide reviewed 22 publications that described the autopsy outcomes of 277 afected individuals.Lymphocytic myocarditis was mentioned in 7.2% of cases, however, only 1.4% met the strict histopathological criteria for myocarditis, implying that proper myocarditis was uncommon; such cases comprised autopsies from patients with COVID-19 without a defnitive myocarditis diagnosis before death [120].Our review showed that difuse lymphocytic infammatory infltrates with edema was the most common fnding, and a few cases were associated with eosinophilic infltrations in patients with confrmed myocarditis with SARS-CoV-2 infection.
In addition, it is difcult for clinicians to diferentiate myocarditis with pneumonia from myocarditis with acute pulmonary edema.Te distinction between myocarditis with COVID-19 pneumonia and myocarditis with acute pulmonary edema is primarily based on imaging fndings and laboratory markers.Both conditions often present with similar symptoms such as fever, cough, and dyspnea.However, patients with myocarditis and pneumonia often have imaging studies that show localized pulmonary infltrates or consolidation.Te hallmark of COVID-19 pneumonia is the presence of ground-glass opacities, typically with a peripheral and subpleural distribution.In addition, the involvement of multiple lobes, particularly the lower lobes, has been reported in most cases of COVID-19 pneumonia [121].In contrast, myocarditis with acute pulmonary edema typically presents with bilateral alveolar infltrates indicating fuid overload [121].Elevated  [122,123].Hospitalization is recommended for patients with confrmed myocarditis that is either mild or moderate in severity, ideally at an advanced heart failure center.Patients with fulminant myocarditis should be managed at centers with an expertise in advanced heart failure, MCS, and other advanced therapies [122].
European consensus suggested that escalation to MCS should be carefully weighed against the development of coagulopathy associated with COVID-19 and the need for specifc treatments for acute lung injury, such as prone position; when MCS is required, ECMO should be the preferred temporary technique, because of its oxygenation capabilities [123].
Regarding the specifc treatment of COVID-19-associated myocarditis, no compelling evidence exists to support the use of immunomodulatory therapy, including corticosteroids and IVIG [123].However, some authors indicate a possible beneft of high-dose steroids and IVIG, as the condition can be considered an immune-mediated myocarditis.Corticosteroids are indicated when respiratory involvement is present and have been administered to patients who showed favorable clinical outcomes [124,125].For those with pericardial involvement, nonsteroidal anti-infammatory drugs may be used to help alleviate chest pain and infammation.Regarding IVIG in myocarditis not associated with COVID-19, a metaanalysis reported improved survival and ventricular function with its administration with corticosteroids, especially in acute fulminant myocarditis [126].Other immunomodulatory therapies, such as tocilizumab and anakinra, are currently being studied for SARS-CoV-2associated myocarditis [122,127].Regarding antiviral treatment, none demonstrated efcacy at reducing COVID-19 mortality [128].In this review, remdesivir was employed in 14 cases, and four of them culminated in death.Lopinavir/ritonavir were used in 4 cases, all of which survived.As for MCS, a large retrospective review that analyzed 147 patients with a diagnosis of acute myocarditis treated with ECMO from 1995 to 2011 showed that survival to hospital discharge was 61%, confrming ECMO as a useful therapy in adults with myocarditis with cardiogenic shock and highlighting its high in-hospital mortality [129].Inadequate aortic valve opening or lack of left ventricular support could occasionally occur with single ECMO therapy; therefore, those cases may require dual cardiac assist devices to ensure adequate ventricular unloading, such as ECMO with Impella ® or with IABP.4.7.Prognosis and Outcomes.Rathore et al. reported that approximately 38% of the patients with SARS-CoV-2 infection-related myocarditis required vasopressor support; out of 28 patients, 82% survived, whereas 18% died [117].Furthermore, Urban et al. reported that death was the outcome in 11 out of 63 cases (17%) [130].Our review showed that the overall mortality rate was 22.4%, and the recovery rate was 77.6%, which were worse outcomes than the previously reported, because of our focus on fulminant myocarditis.However, reported cases are usually severe and complicated, which may constitute a bias for reporting a higher mortality.
4.8.Limitations.Tis systematic review had several limitations.First, our study is retrospective and descriptive in nature.In some cases, the myocarditis diagnosis was based on clinical expertise.CRM image acquisition was not standardized and relied on local protocols.A possibility of publication bias also exists, in which fatal forms of SARS-CoV-2 infection-associated myocarditis may not have been reported or identifed due to its challenging diagnosis.Additionally, only published data including inpatient cases were included in the study.Clinical evaluations such as subjective symptoms reporting and many of the objective values may vary.Lastly, the clinical workup was heterogeneous.

Conclusions
In conclusion, we reviewed previously reported cases of fulminant myocarditis with SARS-CoV-2 infection.We summarized an international experience with this severe condition that was accumulated for the last three years, since the start of this pandemic.We demonstrated that SARS-CoV-2 infection-associated fulminant myocarditis required MCS in 62% of the cases and resulted in death of one out of fve patients, therefore demonstrating its high mortality.Conversely, most of the surviving patients recovered to normal systolic functions.Terefore, rapid bridging therapy including immunomodulatory therapies and/or MCS, if appropriate, may play an important role for improving outcomes in patients with fulminant myocarditis with SARS-CoV-2 infection.

Abbreviations
Infectious Diseases and Medical Microbiology Infectious Diseases and Medical Microbiology Infectious Diseases and Medical Microbiology Infectious Diseases and Medical Microbiology Infectious Diseases and Medical Microbiology

Table 1 :
Literature review of cases with fulminant myocarditis with SARS-CoV-2 infection.
Canadian Journal of Infectious Diseases and Medical Microbiology

Table 2 :
Demographics and clinical data of studied patients.All descriptive parameters are obtained from the original papers.
[113]adian Journal of Infectious Diseases and Medical Microbiology biomarkers of heart failure such as brain natriuretic peptide (BNP) or N-terminal pro-BNP also suggest myocarditis with pulmonary edema[113].Ultimately, the distinction is made by a combination of symptoms, specifc imaging features, and the presence of biomarkers to guide the appropriate management of each condition.
CoV-2: Acute respiratory syndrome coronavirus 2.Canadian Journal of Infectious Diseases and Medical Microbiology