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

54-Year-Old Man With Acute Dyspnea on Exertion

Despite great advances in the pathophysiology and etiology of myocarditis, the clinical diagnosis of myocarditis in daily clinical practise remains challenging. Often the diagnosis was not clear because of the heterogeneity of clinical symptoms and the lack of guidelines for adequate diagnostic requirements and consecutive treatment options. The European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases established a working group of experts to improve the diagnosis and management of myocarditis and to provide a common consensus statement as a reference for future registries and controlled trials. The goal was to bridge the gap between clinical- and tissue-based diagnosis by formulating a concept concerning essential diagnostics and treatment of these patients that would be accepted across Europe. Only in this manner is it possible to establish a basis for national and international registries and double-blind randomized treatment trials for the etiologically differentiated treatment of myocarditis, which appear promising due to numerous studies in recent years. In this paper, two members from the expert working group summarize the most important aspects of this position paper on the etiology, diagnosis, management, and treatment of myocarditis, which were published in the July 2013 issue of European Heart Joumal.

BackgroundClinical presentation, diagnosis, and treatment of myocarditis in children can be highly challenging, and results can vary greatly. Research on the precise processes of myocardial injury, including the effects of viral infections and newly identified variables like COVID-19, is still underway. Though treatment approaches, such as immunosuppressive therapy, are still debatable, diagnostic methods such as cardiac MRI and biomarkers show promise in improving diagnostic accuracy. The purpose of this study is to describe the spectrum of pediatric acute myocarditis, assess existing therapy approaches, and develop regional guidelines based on the experience of a tertiary care institution. MethodsChildren diagnosed with acute myocarditis over a six-month period were included in this retrospective and descriptive hospital-based study. Data on demographics, clinical presentations, diagnostic tests, treatments, and results were gathered and examined. Descriptive statistics, non-parametric tests for categorical variables, and Spearman's correlation tests for continuous data were used in the statistical analysis, with a significance level of p < 0.05. ResultsOf the 99 patients included, the mean age was 2.37 years, with males making up the majority (n = 54, 54.55%). Clinical symptoms typically included shortness of breath (n = 998, 99.0%), vomiting (n = 63, 63.6%), and chest pain (n = 6, 6.1%). High levels of troponin I (n = 70, 70.7%), cardiomegaly on a chest X-ray (n = 97, 97.0%), and different degrees of ventricular dysfunction were found in the laboratory and in imaging studies. Methylprednisolone (n = 84, 84.8%) and IV immunoglobulin (n = 54, 54.5%) were the most often used treatment modalities, and there were no appreciable differences in the two treatment groups' outcomes. A weak negative association (Spearman's rho = -0.211, p = 0.036) was found in the correlation study between the administration of methylprednisolone and length of stay (LOS), indicating possible benefits in terms of shortening hospital stays. ConclusionThis research offers a significant understanding of the clinical manifestation, treatment, and complications of acute myocarditis in children. Methylprednisolone administration seems to be linked to a shorter length of stay (LOS), despite disagreements over treatment approaches. To confirm these results and provide guidance for evidence-based management guidelines for pediatric myocarditis in our setup, more studies are necessary.

SARS-COV-2 INDUCED MYOCARDITIS

Diagnosis and treatment of viral myocarditis.

Myocarditis is an inflammatory disease of the cardiac muscle caused by myocardial infiltration of immunocompetent cells following any kind of cardiac injury. Myocarditis is a challenging diagnosis due to the heterogeneity of clinical presentations. It can be caused by infections, drugs, toxic substances, and autoimmune diseases. Chronic inflammatory events may survive successful clearance of initial cardiotoxic agents, be triggered or amplified by autoimmunological processes, or develop in the context of systemic diseases. Progression of myocarditis to its sequela, dilated cardiomyopathy, has been documented in 25 % of cases and is pathogenically linked to chronic inflammation and viral persistence. Therapeutic decisions must be based on the results of endomyocardial biopsy studies while taking account of the individual patient's clinical course. Moreover, specific immunosuppressive and antiviral treatment can help only if a treatable cause is present (e. g., a viral infection, or inflammatory process), and only if the myocardium still has regenerative potential. Once irreversible myocardial injury has occurred then the development or progression of heart failure in the long term can no longer be prevented. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management of aetiology-driven treatment in inflammatory heart muscle disease.

METAPNEUMOVIRUS PNEUMONIA UNMASKING COXSACKIE MYOCARDITIS

ACUTE HEART FAILURE SECONDARY TO FULMINANT MYOCARDITIS IN SETTING OF INFLUENZA A VIRUS: A CASE REPORT

Determining the etiology of cardiac dysfunction in patients with heart failure influences management and prognosis.1 Myocarditis, diagnosed by the current histopathological Dallas criteria, accounts for &10% of patients with new-onset cardiac dysfunction submitted to endomyocardial biopsy.1,2 Despite complete evaluation including history, physical examination, blood work, echocardiography, coronary angiography, and endomyocardial biopsy, &50% of patients with dilated cardiomyopathy have no etiology identified.1 Recent data suggest that patients in the “idiopathic” category may be suffering from myocardial inflammation due to persistent viral replication or autoimmune activation after a viral infection. These studies raise the question of whether the current histopathological criteria for myocardial inflammation (the Dallas criteria) are sensitive enough to identify the population with viral or autoimmune-related heart compromise. The Dallas criteria were proposed in 1986 and provided a histopathological categorization by which the diagnosis of myocarditis could be established. Dallas criteria myocarditis requires an inflammatory infiltrate and associated myocyte necrosis or damage not characteristic of an ischemic event. Borderline myocarditis requires a less intense inflammatory infiltrate and no light microscopic evidence of myocyte destruction.3 These criteria have been used exclusively by American investigators over the last 2 decades. Sampling error, variation in expert interpretation, variance with other markers of viral infection and immune activation in the heart, and variance with treatment outcomes all suggest that the Dallas criteria are no longer adequate. Chow et al and Hauck et al4,5 demonstrated by biopsying postmortem hearts of patients who had died with myocarditis that, from a single endomyocardial biopsy, histological myocarditis could be demonstrated in only 25% of samples. With >5 biopsies, Dallas criteria myocarditis could be diagnosed in approximately two thirds of subjects. A recent MRI study used focal imaging abnormalities to guide heart biopsy investigation of possible myocarditis. The authors showed that the earliest myocardial …

Association between anti-cardiac autoantibodies in acute myocarditis and downstream clinical outcomes

Myocarditis is clinically and pathologically defined as “inflammation of the myocardium.” Despite its rather clear-cut definition, the classification, diagnosis, and treatment of myocarditis continue to prompt considerable debate. The more routine use of endomyocardial biopsy has helped to better define the natural history of human myocarditis and to clarify clinicopathological correlations. Clinical presentations of the disease range from nonspecific systemic symptoms (fever, myalgias, palpitations, or exertional dyspnea) to fulminant hemodynamic collapse and sudden death. The extreme diversity of clinical manifestations has made the true incidence of myocarditis difficult to determine. Recent prospective postmortem data have implicated myocarditis in sudden cardiac death of young adults at rates of 8.6% to 12%.1,2 Furthermore, it has been identified as a cause of dilated cardiomyopathy in 9% of cases in a large prospective series.3 Recent molecular techniques have facilitated new insights into inflammatory autoimmune processes that affect the myocardium and ultimately result in acute or chronic dilated cardiomyopathy. Despite the well-established morbidity and mortality associated with myocarditis,4–7 clinical practice guidelines with regard to its evaluation and treatment are lacking.8 The wide variety of etiologies implicated in myocarditis and its heterogeneous clinical presentations5,7,9 have impeded patient identification and consensus on the most appropriate diagnostic criteria. The Dallas pathological criteria, published in 1986, served as the first attempt to develop standardized diagnostic guidelines for the histopathological classification of myocarditis.10 Active myocarditis is characterized by an inflammatory cellular infiltrate with evidence of myocyte necrosis (Figure 1), whereas borderline myocarditis demonstrates an inflammatory cellular infiltrate without evidence of myocyte injury (Figure 2). The inflammatory infiltrate should be further described as lymphocytic, eosinophilic, or granulomatous (Figure 3). The amount of inflammation may be mild, moderate, or severe, and its distribution may be focal, confluent, or diffuse, respectively. A retrospective study of 112 consecutive …

The influence of different viral infections in patients with myocarditis is unknown. Myocarditis is an inflammatory disease of heart muscle that is commonly caused by viruses. The impact of different viral infections in patients with myocarditis is unknown. We conducted a retrospective cohort study using data between 2016-2020 in the National Inpatient Sample in the USA to evaluate admissions with myocarditis and concomitant viral infection. The outcomes of in-hospital mortality, length of stay (LoS), and cost, among patients hospitalized for myocarditis was evaluated. A total of 27,050 hospital admissions for myocarditis were included and 6750 (25.0%) had a co-diagnosis of viral infection. Patients with myocarditis and viral infection had significantly higher mortality compared to those without viral infection (23.6% vs. 4.4%, p 0.001). Viral infection was associated with increased in-hospital mortality (odds ratio (OR) 2.03, 95% CI 1.51 to 2.73, p 0.001), greater median LoS (7 vs. 3 days, p 0.001) and median hospitalization cost ($21,445 vs. $11,596, p 0.001), compared to patients without viral infection. The rate of death was greatest for patients with a diagnosis of coronavirus disease 2019 (COVID-19), viral pneumonia and herpes zoster, respiratory syncytial virus, chronic hepatitis, and influenza which was 36.0%, 34.3%, 27.3%, 21.4%, 20.0%, and 14.5%, respectively. In conclusion, the diagnosis of viral infection is present in one in four patients hospitalized with myocarditis and is correlated with greater mortality, LoS, and in-hospital cost.

ImportanceAcute myocarditis, defined as a sudden inflammatory injury to the myocardium, affects approximately 4 to 14 people per 100 000 each year globally and is associated with a mortality rate of approximately 1% to 7%.ObservationsThe most common causes of myocarditis are viruses, such as influenza and coronavirus; systemic autoimmune disorders, such as systemic lupus erythematosus; drugs, such as immune checkpoint inhibitors; and vaccines, including smallpox and mRNA COVID-19 vaccines. Approximately 82% to 95% of adult patients with acute myocarditis present with chest pain, while 19% to 49% present with dyspnea, and 5% to 7% with syncope. The diagnosis of myocarditis can be suggested by presenting symptoms, elevated biomarkers such as troponins, electrocardiographic changes of ST segments, and echocardiographic wall motion abnormalities or wall thickening. Cardiac magnetic resonance imaging or endomyocardial biopsy are required for definitive diagnosis. Treatment depends on acuity, severity, clinical presentation, and etiology. Approximately 75% of patients admitted with myocarditis have an uncomplicated course, with a mortality rate of approximately 0%. In contrast, acute myocarditis that is complicated by acute heart failure or ventricular arrhythmias is associated with a 12% rate of either in-hospital mortality or need for heart transplant. Approximately 2% to 9% of patients have hemodynamic instability, characterized by inability to maintain adequate end-organ perfusion, and require inotropic agents, or mechanical circulatory devices, such as extracorporeal life support, to facilitate functional recovery. These patients have an approximately 28% rate of mortality or heart transplant at 60 days. Immunosuppression (eg, corticosteroids) is appropriate for patients who have myocarditis characterized by eosinophilic or giant cell myocardial infiltrations or due to systemic autoimmune disorders. However, the specific immune cells that should be targeted to improve outcomes in patients with myocarditis remain unclear.Conclusions and RelevanceAcute myocarditis affects approximately 4 to 14 per 100 000 people per year. First-line therapy depends on acuity, severity, clinical presentation, and etiology and includes supportive care. While corticosteroids are often used for specific forms of myocarditis (eg, eosinophilic or giant cell infiltrations), this practice is based on anecdotal evidence, and randomized clinical trials of optimal therapeutic interventions for acute myocarditis are needed.

By including immunohistochemical parameters the WHF Task Force for the Definition of Acute and Chronic Myocarditis expanded the light microscopical Dallas criteria of myocarditis. The rapid development of new molecular biological techniques such as polymerase chain reaction (PCR) and in-situ hybridization has improved our understanding of the underlying etiological and pathophysiological mechanisms in inflammatory heart disease. Treatment of dilated cardiomyopathy with inflammation is still controversial, however. The American Myocarditis Treatment Trial could not demonstrate a significant difference in the improvement of ejection fraction between patients with active myocarditis in the cyclosporine/prednisolone treated group when compared to placebo. In the European Study of Epidemiology and Treatment of Inflammatory Heart Disease (ESETCID) patients with acute or chronic myocarditis are treated specifically according to the etiology of the disease. Patients are screened not only for infiltrating cells, but also for the presence of persisting viral genome (enterovirus, cytomegalovirus and adenovirus). By investigating endomyocardial biopsies of 3,055 patients ongoing inflammatory processes in the heart could be found in 17.2%. Only 182 showed a reduced ejection fraction below 45% fulfilling the entrance criteria for the ESETCID trial. These data imply that in symptomatic patients inflammatory heart muscle disease has to be considered regardless of left ventricular function and that endomyocardial biopsy can be an important tool for diagnosis. Virus could be detected in 11.8% (enterovirus 2.2%, cytomegalovirus 5.4%, adenovirus 4.2%). These first epidemiological results of this prospective randomized study demonstrate that viral persistence may contribute to the pathogenesis of inflammatory heart muscle disease, and that in chronic myocarditis viral persistence occurs in a smaller percentage of patients compared to previously published studies which were performed on highly selected patients.

Myocarditis is an inflammatory disease of the heart muscle, most often caused by viral infections. Its diagnosis can be difficult due to the heterogeneity of presentations that often mimic other common cardiological conditions, such as acute coronary syndrome (ACS) and heart failure. Although most cases are benign and self-limiting, it can also take on a more malignant course complicated by life-threatening arrhythmias, cardiogenic shock, and sudden cardiac death (SCD). A certain proportion of patients progress to develop dilated cardiomyopathies (DCMO). The developed world has experienced a shift in viral pathogens detected in patients with acute myocarditis over the past 20 years, and Parvovirus B19 (PVB19) and human herpesvirus-6 (HHV6) are currently the most commonly identified viruses in the myocardium of patients with viral myocarditis. The clinical relevance and pathological roles of these viruses however remain questioned. This focused review aims to use 2 cases of PVB19 myocarditis managed by our unit to explore issues related to the clinical presentation, diagnosis, treatment and prognosis of PVB19 myocarditis along with controversies surrounding the pathogenic role and clinical relevance of PVB19 in myocarditis.