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in the myocardium and pericardium.375–379 The true estimate of COVID-19-associated IMPS is variable depending on CMR/ EMB-derived diagnosis ranging from 0.1–4.5/1000 cases380,381 up to 2%–8% of cases in symptomatic patients.382 Symptoms as well as diagnostic work-up are similar to those described for general IMPS (see Sections 4 and 5). The predominant management of symptomatic complicated SARS-CoV-2-related IMPS is antiviral treatment for SARS-CoV-2 virus together with supportive therapy. Several immunosuppressive therapies, such as anti-IL-1 (anakinra and canakinumab) and anti-IL-6 (tocilizumab and sarilumab), have demonstrated promising results in critically ill patients hospitalized for COVID-19.383–385 In less severe cases, the key elements for treatments are those recommended for IMPS. More details can be found in Supplementary data online, Section 5.1.2.

9 Specific types of myocarditis

9.1 Lymphocytic myocarditis

The diagnosis of LM is based on pathological criteria and reflects an inflammatory disease that may be caused by viruses, but also by other infectious agents, including bacteria (such as Borrelia spp.) and protozoa (such as T. cruzi).10 Furthermore, contemporary single-centre and multicentre cohort studies suggest that LM is more commonly non-infectious or immune-mediated/autoimmune.63,73 It is important to note that the aetiopathogenesis and outcome of viral LM varies considerably, based on the different infections. Cytolytic viruses, such as enteroviruses (e.g. coxsackieviruses and echoviruses), destroy cardiomyocytes and induce severe infiltration by macrophages and lymphocytes.386 In contrast to enteroviruses, vasculotropic B19V, which infects cardiac endothelial cells, but not cardiomyocytes, can also induce severe LM, especially in young children.228,387 High viral copy numbers (>500 viral DNA copies/μg of cardiac DNA) were found to be associated with cardiac inflammation and/or systemic infection.228,388 Low B19V DNA copy numbers in cardiac tissue rather reflect virus persistence, and are usually not related to cardiac inflammation. Lymphotropic viruses of the Herpesviridae family [HHV-6, EBV, human cytomegalovirus (CMV)], as well as HCV, influenza viruses, and SARS-CoV-2 may indirectly trigger myocarditis by activating the immune system.389 Regarding the aetiology and pathogenesis of myocarditis, microRNAs (miRNAs) may be promising diagnostic markers, as well as prognostic and therapeutic targets in myocarditis.141,390 However, the precise role of miRNAs in myocarditis remains to be determined.391 In addition to infectious agents, organ-specific autoimmunity to heart autoantigens,66 different systemic immune-mediated diseases, toxic substances, and drugs, including ICIs, are known to induce different forms of acute and chronic LM.66 Immune-mediated myocarditis may occur with exclusive cardiac involvement or in the context of systemic immune-mediated diseases, such as SLE, SSc, and others.349,392 Interestingly, genetic host susceptibilities have also been linked to cardiac dysfunction following myocarditis.91,150

9.1.1 Presentation

Since LM can be induced by various causes, there is no universal, specific clinical presentation. Instead, it must be considered in the context of the different diseases, in line with the stages of myocarditis.

9.1.2 Diagnosis and therapy

The diagnostic pathways were described above and vary depending on the cause. The diagnostic and therapeutic approach has to follow the clinical situation and the stages as described in Section 4 (see Table 12). 9.2 Eosinophilic myocarditis

Eosinophilic myocarditis is a rare form of myocarditis, characterized by eosinophilic infiltration of the myocardium. Underlying disorders that should be evaluated during the work-up of EM include: hypersensitivity and allergic reactions;271 immune-mediated disorders, in particular EGPA; undefined complex HES or its myeloproliferative variant; parasitic infections; and cancer.349 A meta-analysis of single cases or small case series reported a rate of in-hospital death of up to 22%, and a significantly increased occurrence of the hypersensitivity form, up to 36%.271

9.2.1 Presentation

The clinical presentation of EM can be variable, ranging from oligosymptomatic to acute FM, or chronic RCM (Loeffler CMP or endomyocarditis).271 Nevertheless, prior study demonstrates that EM often has a fulminant presentation with abrupt impairment of LVEF, a high risk of malignant arrhythmias, and a high risk of thromboembolic complications, related to the formation of ventricular thrombi.271 Although EM is often accompanied by peripheral eosinophilia, it should be noted that this finding is absent in up to 25% of patients with EM, and may contribute to the underdiagnosis of EM.

9.2.2 Diagnosis

The diagnosis of EM can be established by either the EMB-proven presence of eosinophilic infiltration of the myocardium, or the presence of CMR-proven myocarditis with pathognomonic findings associated with peripheral eosinophilia (Supplementary data online, Figure S3). Furthermore, general clinical signs related to EGPA or HES disorders should be evaluated, such as an increased number of eosinophilic cells, history of asthma and sinusitis, and characteristic skin lesions. Left ventricular function may be preserved, and DCM can occur, but often the phenotype of RCM is present. On echocardiography, a typical finding is Loeffler endocarditis. In the diagnostic work-up, systemic screening for the above-mentioned aetiologies should be carried out systematically.

9.2.3 Therapy

The first-line therapy for EM is the administration of i.v. corticosteroids, but caution should be exercised if EM is caused by an infectious agent. The optimal dose and duration of corticosteroids are unclear, but it is proposed to administer a daily i.v. bolus of corticosteroids followed by dosage tapering in severe forms, while oral steroid administration (see Table 12) can be considered in patients with mild LV dysfunction.39,271 The identification of an EM-associated condition is crucial to administer specific treatments, such as cyclophosphamide or IL-5 inhibitors in EGPA-related EM,34 imatinib in the myeloproliferative variant of platelet-derived growth factor receptor alpha (PDGFRA)-associated HES, or albendazole in Toxocara canis infection. In hypersensitivity/allergic EM, first-line therapy is to withdraw the potential cause of eosinophilia. Since endocavitary thrombi were reported in 12% of EM cases, the use of anticoagulation during the acute phase could be considered for the prevention of endocavitary thrombi.271

9.3 Giant-cell myocarditis

Giant-cell myocarditis is a very rare, but often rapidly progressive disease with a poor prognosis, with an ∼85% rate of death or HT at 3 years.56,82 The incidence of GCM was reported to range from 0.007% to 0.051% in autopsy studies; however, this number might

ESC Guidelines                                                                                                                                                                                          4001

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