**1. Introduction**

As of October 2022, the COVID-19 pandemic has been responsible for over 1 million deaths in the United States and over 6.5 million deaths globally [1, 2]. Its clinical manifestations range from asymptomatic to a mild, self-limited infection, to severe multi-organ failure and/or death. Due to the wide spectrum of illness and organ involvement as well as the diversity of cardiovascular manifestations and methods for its diagnosis, myocarditis can pose a particular challenge to clinicians.

Myocarditis is an inflammatory disease of the myocardium that can weaken the efficiency of the heart to pump blood or interfere with its conduction system. Most commonly, it occurs as a result from viral infection or autoimmune activation, toxins, drugs, or vaccine exposure. The diagnosis ranges widely and can be made based on history and various clinical aspects or via biopsy, which relies on an established criteria including histologic and immunohistochemical evidence. In 1986, the proposed

Dallas criteria established histopathological classifications to aid in the diagnosis of myocarditis requiring evidence of an inflammatory infiltrate with or without associated myocyte necrosis/fibrosis unrelated to ischemia [3]. Endomyocardial biopsy has remained the gold standard for diagnosis, despite recent advances in imaging technologies. However, postmortem analysis has revealed many limitations, stemming from challenges in specimens and sampling errors, in addition to variation in expert interpretation [4]. Furthermore, numerous studies have shown that a virus may be present in the myocardium in a replicative or non-replicative form in the absence of inflammation sufficient to meet the Dallas criteria [5, 6].

More commonly in clinical practice, a patient's clinical symptoms, laboratory tests and imaging studies—including the use of cardiac magnetic resonance imaging (CMR)—is not only sufficient to establish a diagnosis but represents a non-invasive alternative to biopsy. CMR can detect early myocardial tissue response such as edema, hyperemia, and necrosis, as well as late consequences such as myocardial fibrosis and provide enhanced information that can be utilized in prognostication and clinical decision making [7].

### **2. Etiology/pathogenesis**

The global incidence of myocarditis in 2017 was 3,071,000 cases, a 59.6% increase from 1990 according to data from the Global Burden of Disease Study 2017 [8]. However, the exact incidence is difficult to determine as myocarditis has a variable clinical presentation mimicking other conditions and can coexist with other cardiac or systemic diseases. Furthermore, there is limited availability of advanced cardiac imaging or endomyocardial biopsy, which can also contribute to confirming its diagnosis. Thus, the actual cases of myocarditis are believed to be significantly underestimated [9].

#### **2.1 Infectious**

Infectious causes remain the most frequent causes of myocarditis globally with viral etiology more common in the developed countries of North America and Europe, while bacterial, protozoal, fungal, and other rare pathogens are responsible for most cases in the developing countries of Africa, Asia, and South America [10]. A comprehensive list of currently identified infectious causes of myocarditis can be found in **Table 1**.

Bacterial myocarditis is rare, but the most common cause is *Staphylococcus aureus* and Streptococcal species [16]. The prevalence is difficult to determine with few studies published reporting 0.2–1.5% from cardiac biopsy samples post-mortem [17]. Furthermore, its prevalence has been shown to be more common in the setting of sepsis with or without concomitant endocarditis. The pathogenesis typically involves direct bacterial invasion into cardiac myocytes or by pathogenic toxins (common with clostridium or diphtheria). Cardiac dysfunction of either the left or right ventricle subsequently develops from severe sepsis (mediated by increased circulating cytokines), myocardial inflammation/necrosis, direct action from toxins and in the later stages, ventricular remodeling.

Viral myocarditis is by far the most common etiology with an incidence in the range of 10–22 per 100,000 individuals [18]. The pathogenesis follows a similar course of other pathogens that involve direct myocardial invasion with three distinct *The Evaluation of Myocarditis in the Post-Covid-19 Era: Pearls and Perils for the Clinician DOI: http://dx.doi.org/10.5772/intechopen.110395*


#### **Table 1.**

*Infectious causes of myocarditis [11–15].*

phases: acute, subacute, and chronic. Each phase is characterized by a distinct process with variable transitional periods. In phase 1 (acute), the virus gains access into the target organ tissue and triggers an immune response. This may progress into phase 2 (subacute), an autoimmune phase involving autoreactive T-cells, cytokines, and cross-reacting antibodies predominant after the full or partial resolution of the initial infection. Finally, in phase 3 (chronic), there is progressive remodeling often from autoimmune injury to the myocardium resulting in a persistent or often dilated cardiomyopathy [18, 19].

The **acute phase** includes the first days following infection where viral replication occurs within the heart and other organs. Viral entry is largely facilitated by specific receptors that vary based on the pathogen. For instance, Measles virus entry depends on the major reovirus receptor JAM-A, SARS-CoV-2 utilizes the spike protein to bind the ACE2 receptor and in Group B coxsackieviruses (CVB) viral entry is mediated via two host receptors, decay-accelerating factor (DAF) and coxsackievirus-adenovirus receptor (CAR). In the case of coxsackievirus, these receptors are expressed in cardiac myocytes and pancreatic cells. Animal models have demonstrated the important role they play in so much that targeted deletion of these receptors is protective against CVB-induced pancreatitis and myocarditis [20]. Following initial viral entry, the virus causes cell lysis and spreads infection to adjacent cells through release of packaged virions. The cardiomyocyte injury triggers an innate immune response increasing the levels of cytokines and infiltration of immune cells into the damaged tissue (seen in **Figure 1**).

Approximately 1 week following infection, the **subacute**, autoimmune phase develops in response to the immune dysregulation caused by myocyte injury via molecular mimicry of the viral antigens to host cardiac proteins [22]. It should be noted that acute reduction in LV function along with hemodynamic compromise can occur during acute and subacute phases. The constant activation of T cells, increased levels of cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1,

#### **Figure 1.**

*Fulminant Myocarditis (FM) pathological phenotypes. a–c representative HE staining of EMB samples of FM patients showed lymphocyte FM (a), eosinophilic FM (b), and giant cell FM (c). d–f IHC staining showed massive T lymphocyte (CD45RO) infiltrated into myocardium (d). Macrophage (CD68) can also be observed (e). Few B lymphocytes (CD20) can be seen in EMB samples (f). From [21]. Copyright © Hang et al. Distributed under the terms of the Creative Commons Attribution 4.0 International License.*

and IL-6, may lead to persistent and recurrent myocardial damage causing further impairment of the heart's contractile function and progressive remodeling, which is seen in the chronic phase of the disease.

In the final, **chronic phase** of the disease, the cumulative effect of the virus either through direct cytotoxic or subsequent autoimmune damage initiates a process of myocardial remodeling that can lead to dilated cardiomyopathy. In most cases by the chronic stage, the virus has been cleared and inflammation subsided, but in some cases the chronic phase is associated with a persistent viral infection and ongoing autoimmune responses. In myocarditis patients with chronic symptoms and inflammation, parvovirus B19 (PVB19) and human herpesvirus 6 (HHV6) genomes predominate in EMB samples with approximately 30% of patients having multiple viral infections [23].
