Continuing Education Activity

Cardiovascular complications stemming from Epstein-Barr virus (EBV) infection, though relatively rare, carry significant implications, especially in immunocompromised individuals. These issues arise from a combination of direct viral toxicity and the immune system's response, leading to pathological changes such as myocardial necrosis and cardiac dilatation. The complications include coronary artery dilatation, coronary artery aneurysms, myopericarditis, acute myocardial infarction, valvular heart conditions, heart failure, pulmonary arterial hypertension, and more.

Left unaddressed, the complications lead to significant morbidity and mortality, underscoring the importance of timely and appropriate management. The appropriate treatment in a multidisciplinary care setting is necessary to optimize the care of patients with EBV-related myopericarditis. This activity reviews the evaluation and treatment of EBV-associated myopericarditis and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the signs and symptoms of EBV-associated myopericarditis.
• Select appropriate investigation modalities for establishing the diagnosis of EBV-associated myopericarditis. 
• Evaluate appropriate pharmacologic treatments for patients with myopericarditis caused by EBV.
• Collaborate with interprofessional team members, including specialists such as infectious disease clinicians, cardiologists, pathologists, and intensivists, and provide efficient, comprehensive, and coordinated care to patients with EBV-associated myopericarditis.

Introduction

Epstein-Barr virus (EBV) is a widely distributed virus from the herpesvirus family (human herpesvirus 4), containing a double-stranded DNA core enclosed by proteins.[1] EBV spreads through close contact between susceptible individuals and asymptomatic carriers of EBV. The primary source of virus transmission is through bodily fluids, primarily saliva.[2] Instances of spread are documented in the context of stem cell and organ transplantation and blood transfusion.[3] EBV can cause aggressive and catastrophic diseases in immunocompromised individuals, like chronic EBV disease, hemophagocytic lymphohistiocytosis, autoimmune phenomena, and some tumors (Hodgkin lymphoma, non-Hodgkin lymphoma, nasopharyngeal cancer, and Burkitt lymphoma).[4][5]

Cardiovascular manifestations and sequelae from EBV infection are less common yet significant, resulting from direct toxicity (lysing of host cells or cleavage of host proteins by viral proteases) and immune-mediated cellular injury. These complications have been noted in individuals whose immune systems are compromised. Complications include dilatation of the coronary artery, aneurysm of the coronary artery, progression of coronary artery disease, myopericarditis, valvular disease, and pulmonary hypertension, among others.[6] If not managed promptly and appropriately, fatal outcomes can occur.[7]

Etiology

EBV has an outer layer of glycoproteins. These are essential for binding to and infiltrating specific host cells, primarily B-cells and epithelial cells.[8] EBV mutates B-cells to duplicate genetic material. This process converts B-cells into memory B-cells, which can circulate in the bloodstream or remain inactive until an external trigger prompts the revival.[9]

B lymphocytes, T lymphocytes, epithelial cells, and myocytes are host cells for EBV. Unlike herpes simplex (HSV) or cytomegalovirus (CMV), EBV transforms B-cells without causing noticeable cell damage.[10] Given the latency of EBV, host factors such as immunosuppression may lead to virus reactivation, leading to clinical manifestations such as infectious mononucleosis and autoimmune phenomena.[8][11][12][13] Immunosuppression is associated with aggressive lymphoproliferative disorders in organ transplant recipients and other immunocompromised patients, first described in observations of EBV within tissue samples of lymphoma patients.[8][14]

Epidemiology

Approximately 90% to 95% of the global adult population has experienced EBV infection.[15] In the United States, one seroprevalence study estimated the prevalence of EBV among children and adolescents aged 6 to 19 to be 66.5%.[16] Specifically, children aged 6 to 8 exhibited an approximate 54% prevalence, while adolescents aged 18 to 19 displayed a prevalence of 82.9%. The Mexican-American children and adolescents in the study exhibited a higher EBV prevalence in comparison to their non-Hispanic black and white counterparts. In low and middle-income countries, the estimated population seroprevalence of EBV ranged from 92.1% to 94.8%, with the highest seropositivity in those aged >40 years.[17] In the United Kingdom, a seroprevalence study estimated an overall population prevalence of 85.3%, with females reaching seropositivity younger than males.[18] 

Other findings included higher seroprevalence in those with a white ethnicity, lower body mass index, and a non-smoking history. Factors such as larger household sizes, lower household incomes, decreased parental education, early life maternal deprivation, and foreign birth are all associated with a heightened prevalence of EBV infection among children and adolescents.[19][16]

Myopericarditis is infrequent in children and adolescents, with a projected occurrence rate of 1 to 2 cases per 100,000 individuals.[20] In cases of EBV associated with coronary disease, evidence is limited to observational studies or case reports, with one study of 299 patients with percutaneous coronary intervention indicating higher measures of pro-inflammatory cytokines and EBV-related proteins among all patients with acute myocardial infarctions.[21] In an anatomical study of 142 patients with cardiac dilation and histological evidence of myocarditis, 9 patients were found positive for EBV DNA.[22]

Pathophysiology

The progression of viral myocarditis-induced damage unfolds in 2 distinct phases. The initial phase spans roughly 1 week and is characterized by viral infiltration into the myocardium, viral replication, and subsequent cell lysis. Neutralizing antibodies are generated, leading to the elimination or attenuation of the virus by macrophages and natural killer cells during the innate immune response.[23][24]

Following this stage, the myocardium experiences an influx of inflammatory cells, accompanied by immune system activation that includes the production of antibodies targeting cardiac myocytes through an adaptive immune response driven by T cells. This phase endures for several weeks or months and is associated with varying extents of myocardial impairment, ranging from minimal to severe. Recovery may occur with the elimination of pathogens, but in susceptible individuals such as those with immune dysfunction, chronic inflammation, remodeling, dilated cardiomyopathy, and cardiac failure may occur.[24] In the murine model, characteristic pathological findings encompass multiple localized regions of myocyte loss, sheets of fibrosis, and diffusely scattered calcified deposits throughout all layers and chambers of the cardiac muscle.[23]

Histopathology

Pathologically, inflammatory cell infiltrates associated with or without myocyte necrosis are required to identify myocarditis when viewing stained heart tissue sections.[25] Autoantibodies to cardiac antigens, such as cardiac myosin, may be performed. Based on the associated clinical history and prodrome, findings may be consistent with either fulminant lymphocytic myocarditis or acute lymphocytic myocarditis.[26] Therefore, findings may suggest a viral etiology on histopathology. A concordant clinical history is required to confirm viral myocarditis.

History and Physical

The clinical presentation encompasses asymptomatic conditions to abrupt fatality attributable to either fulminant heart failure or malignant ventricular arrhythmias. The clinical presentation holds notable prognostic significance, and individuals with heart failure symptoms at the outset are markedly prone to requiring transplantation and facing cardiac mortality.[27]

Symptoms mostly resemble a cold, including fever, fatigue, cough, and odynophagia. Other symptoms encompass precordial chest pain, palpitations, polymyalgia, and asthenia.[28] Additionally, there is mild, non-radiating chest discomfort, breathlessness, dizziness, and decreased ability to exercise, all absent during rest.[29] The emergence of myocarditis in children and adults might be preceded by a viral prodrome characterized by symptoms like rash, myo-arthralgias, and gastrointestinal and respiratory issues, occurring anywhere from several days to a few weeks prior.[30][24][31]

In cases where pericardial involvement is predominant, individuals may describe the pain as sharp, exacerbated by coughing or deep breaths, and alleviated by assuming a forward-leaning position. When there is substantial myocardial engagement, the pain might be continuous, posing challenges while distinguishing it from myocardial ischemic pain, particularly among those with cardiovascular risk factors.[32] Additionally, they might exhibit prevalent symptoms of heart failure like breathlessness, orthopnea, swelling in the lower extremities, and fatigue. Infrequent symptoms encompass arrhythmias, syncope, and sudden cardiac arrest.[33]

Physical examination findings can vary but commonly include fever, a pericardial friction rub, and indications of heart failure. [34] Furthermore, enlarged cervical lymph nodes and tonsillar hypertrophy with exudates are present. Conversely, symptoms like hepatomegaly and splenomegaly are notably absent. Manifestations of systemic illness that might contribute to the underlying cause include autoimmune disorders, systemic lupus erythematosus, vaccinations, chemotherapy, and immune checkpoint inhibitor therapy.[35][36]

These subtle presentations can sometimes lead to complications abruptly, escalating into life-threatening scenarios. Myopericarditis exhibits diverse progression patterns, ranging from fatal outcomes attributed to severe systolic dysfunction or ventricular arrhythmias to extended development into dilated cardiomyopathy.[37] Upon discharge from inpatient care, vigilant monitoring for several weeks is imperative, especially in cases where the possibility of heart failure development persists.

Evaluation

Laboratory Studies

Atypical lymphocytosis is typically evident in peripheral smears.[8] Serological testing is generally used to ascertain whether a patient has exposure to EBV. Routine viral serology tests are not typically beneficial for the diagnostic process, as their outcomes seldom influence treatment decisions. In determining acute infection with EBV, a heterophile antibody test can detect immunoglobulin M (IgM) antibodies targeting EBV. False positive results may occur due to the cross-reactivity of IgM with other viral infections, hematological malignancies, and autoimmune disorders.[38] Despite these caveats, utilizing heterophile antibody testing as an initial approach is advantageous due to the affordability, rapidity, and sensitivity range of 63% to 84% and specificity range of 84% to 100%.[39] 

Given the challenges of using serological markers to diagnose EBV infection, polymerase chain reaction (PCR) methods have been demonstrated to accurately detect primary EBV infection and reactivation in sera without heterophile antibodies.[38] Sensitivity and specificity among pediatric populations with infectious mononucleosis were 77% (95% CI 66-86%) and specificity 98% (95% CI 93-100%) respectively.[40] Furthermore, PCR may be applied to paraffin-embedded tissues with assay sensitivities as low as 50 copies of EBV DNA per reaction.[41] PCR has replaced culture as the primary means of detecting EBV in tissue.[42]

Myopericarditis can result in elevated levels of inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, white blood cells, and cardiac biomarkers.[43] A comprehensive blood analysis is recommended for all patients to rule out thyroid disorders and hepatitis and assess renal function. This approach thoroughly evaluates the patient's overall health and contributing factors.[44] 

Electrocardiogram

Characteristic electrocardiogram patterns in pericarditis encompass a widespread, concave elevation of ST segments and PR depression. These alterations, generalized T-wave modifications, or inversions can vary depending on the extent of myocardial engagement. While ST-segment alterations are generally diffuse, localized ECG shifts (inferolateral or anterolateral) can also manifest contingent on the degree of involvement. Frequent arrhythmias involve supraventricular or ventricular ectopic beats and brief episodes of ventricular arrhythmias.[45][46]

Chest Radiography

Pericardial effusion may manifest as a rounded cardiac silhouette on a chest X-ray. Echocardiography typically confirms effusion, constriction, or tamponade.[47]

Echocardiogram

The echocardiographic characteristics of myocarditis are non-specific. However, as a part of the routine evaluation, an echocardiogram is ordered, which may reveal normal heart function along with a minimal or absent pericardial effusion. The echocardiographic presentation can resemble various patterns, including dilated, hypertrophic, restrictive, or right ventricular cardiomyopathy, along with manifestations similar to coronary artery disease. Additionally, the echocardiogram assesses the functioning of both the left and right ventricles and identifies any abnormalities related to valvular heart disease.[48]

Coronary Angiography

When there is suspicion of acute coronary syndrome, and the clinical presentation is reminiscent of coronary artery disease, this diagnostic approach is considered the definitive method to exclude its presence. In cases where traditional contraindications are not applicable, CT coronary angiography (CTCA) might be an alternative. For young patients exhibiting typical myopericarditis symptoms, coronary angiography is typically unnecessary. However, for individuals with risk factors associated with atherosclerotic cardiovascular disease, distinguishing between myopericarditis and myocardial ischemia through non-invasive testing is challenging. In such instances, cardiac catheterization is required to rule out acute coronary syndrome.[49][44]

Cardiac Magnetic Resonance Imaging

Cardiac MRI is a promising technique for assessing individuals suspected of having myocarditis. The revised Lake Louis criteria now encompass T1 and T2 criteria for diagnosing myocarditis. T1 imaging reveals an elevated T1 relaxation time, while T2 imaging demonstrates an increased T2 relaxation time or Signal Intensity (SI). In addition, gadolinium-enhanced CMR sequences unveil irregular hyperenhancement patterns within the myocardial tissue.[50] Such changes are associated with a higher rate of mortality, including sudden cardiac death.[51]

Endomyocardial Biopsy

Endomyocardial biopsy (EMB) is warranted in select cases of severely ill patients who demonstrate clinical deterioration after standard supportive treatment. EMB is the gold standard for diagnosis. According to the consensus scientific statement of the European Society of Cardiology, the American Heart Association, and the American College of Cardiology, a class I indication for performing EMB in myocarditis is in cases of new-onset heart failure lasting less than 2 weeks, involving preserved ventricle dimensions but compromised hemodynamics.[52] Additionally, EMB is indicated as a class I procedure for patients experiencing new-onset heart failure lasting 2 weeks to 3 months, characterized by dilated ventricles, tachyarrhythmia or bradyarrhythmia, and a lack of response to therapy within 1 to 2 weeks.[53]

Treatment / Management

For the majority of patients, the overall prognosis of this condition is favorable, and long-term complications are rare. The available data to inform the management of myopericarditis are currently limited.[54] Viral myopericarditis is mainly supportive and follows the general management of myopericarditis. 

Hemodynamically Unstable Patients

Patients presenting with a life-threatening condition should be directed to specialized facilities equipped with the capacity for hemodynamic monitoring, cardiac catheterization, expertise in EMB, and cardiac surgery. In instances of hemodynamic instability, the implementation of a mechanical cardio-pulmonary assist device is necessary to bridge either recovery or heart transplantation.[55] The consideration for cardiac transplantation should be postponed during the acute phase, as there is a potential for spontaneous recovery. However, this option is considered for hemodynamically unstable myocarditis patients, including those with giant cell myocarditis, if optimal pharmacological support and mechanical assistance fail to stabilize the patient.[56]

Hemodynamically Stable Patients 

For patients experiencing stable heart failure, the recommended treatment includes diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-adrenergic blockers. If individuals continue to show symptoms of heart failure despite receiving optimal care, one should consider adding aldosterone antagonists.[57] 

When the initial manifestation resembles pericarditis symptoms, and the left ventricular function remains intact, the first-line treatment involves Nonsteroidal anti-inflammatory drugs (NSAIDs). However, in cases where substantial myocardial involvement is evident, NSAIDs are approached cautiously due to their potential to exacerbate myocardial function and cardiac failure.[58] In such instances, NSAIDs are administered at minimal dosages to avoid compromising myocardial health.[44]

Arrhythmia

Ventricular or atrial arrhythmias and heart block are potential complications of acute myocarditis. In hemodynamically stable tachyarrhythmia without signs of peripheral hypoperfusion, β-blocker therapy is advised. Patients with sustained ventricular arrhythmias are recommended amiodarone and dofetilide as suitable treatment options. When necessary, heart block is addressed by implementing a temporary pacemaker followed by a permanent pacemaker. As the acute phase subsides, standard recommendations include an implantable cardioverter defibrillator during the chronic stage.[49]

Avoidance of Exercise 

During acute myocarditis, physical activity should be restricted. Patients are discouraged from engaging in competitive sports for at least 3 to 6 months following the acute episode. Subsequent guidance hinges on regular follow-up involving clinical evaluation, echocardiography, and Holter monitoring.[59][60]

Immunomodulatory Therapy

There is no approved antiviral therapy, but vaccination is a future possibility.[61]

In cases of myocarditis that do not respond to standard heart failure treatments, including both viral and autoimmune types, especially those driven by autoantibodies, intravenous immunoglobulin (IVIG) may be employed to minimize adverse effects.[62]

Immunosuppressive Therapy

The safety and effectiveness of immunosuppressive regimens for myocarditis are studied using steroids alone, combined with azathioprine or cyclosporine A, azathioprine, and steroids. Limited information is available regarding the use of other medications. Reports on treatment outcomes primarily focus on chronic cases that are negative for viral involvement.[56]

Differential Diagnosis

Acute Coronary Syndrome 

Cardiovascular magnetic resonance imaging is vital in distinguishing between different causes of acute coronary syndromes. This significance is pronounced due to the vague and overlapping signs and symptoms, which resemble those of other conditions like myopericarditis.[63] The viral prodrome of EBV-associated myocarditis rules out acute coronary syndrome.

Chagas Heart Disease (CHD)

As a result of the protozoan parasite Trypanosoma cruzi, CHD is the primary cause of known infectious myocarditis globally, albeit concentrated within the Americas.[64] CHD comprises 2 distinct clinical phases: the acute phase, which emerges shortly following infection and persists for 4 to 8 weeks, and the chronic phase, which evolves over 10 to 30 years. The PCR is the most sensitive diagnostic tool in the acute phase of Chagas disease.[65] In around one-third of cases, the chronic phase develops from asymptomatic to symptomatic.

Cardiac Tamponade

Pericarditis frequently involves pericardial effusion, which could progress to cardiac tamponade.[66] Cardiac tamponade is a condition that arises when there is a sudden and excessive buildup of fluid within the pericardial cavity. 

Prognosis

Differentiating acute myopericarditis from pericarditis is essential. Common viruses, including parvovirus B19, adenovirus, herpes viruses, hepatitis viruses, human immunodeficiency virus, and enteroviruses, can induce heart inflammation, leading to acute pericarditis and myocarditis.[67] EBV rarely contributes to these conditions in individuals with intact immune systems.[13] The prognosis can be jeopardized by heart failure, particularly in cases of severe onset. Due to the diverse clinical manifestations of EBV, the severity of such manifestations, and the interplay with host immune factors, the prognosis of EBV-related myopericarditis can vary. In general, patients experiencing acute decompensated heart failure, persistent arrhythmias, and a left ventricular ejection fraction below 50%, or those necessitating inotropic agents, vasopressors, or mechanical cardiac assistance, are more likely to encounter unfavorable cardiovascular outcomes.[68][69]

Complications

Complications may vary according to the interplay between EBV and the host immune system, but known sequelae of viral (including EBV) related cardiac manifestations include:

• Coronary artery dilatation[70]
• Coronary artery aneurysm[71]
• Valvular heart disease[72]
• Acute myocardial infarction[21]
• Pulmonary arterial hypertension[73]
• Left ventricle dysfunction[24]
• Right ventricle failure[74]
• Arrhythmia[33]
• Death secondary to the above

Deterrence and Patient Education

Patients with EBV infection should be informed about potential complications, which range from asymptomatic conditions to life-threatening outcomes such as coronary artery dilation, valvular heart disease, and heart failure.[6] However, these fatal complications can be prevented with prompt and appropriate management. Transmission of EBV occurs primarily through close contact with infected individuals, mainly saliva.[2] Regular precautions that include awareness and personal hygiene prevent viral transmission. 

Patients who develop myopericarditis and are hemodynamically unstable must have a timely referral to a highly specialized cardiac center. Other patients should receive symptomatic management following the principles of heart failure treatment. Patients with heart failure are more susceptible to unfavorable cardiac complications, so close monitoring and proper medical care are crucial. Timely and thorough cardiac evaluation is paramount to detecting potential complications and providing appropriate interventions. 

In summary, educating patients about the potential complications of EBV infection, emphasizing the importance of transmission prevention, ensuring timely referrals for severe cases, and implementing appropriate management strategies can contribute to better outcomes and a reduced risk of complications.

Enhancing Healthcare Team Outcomes

Patients with EBV-associated myocarditis face a significant risk of mortality when not promptly and effectively treated. Therefore, early management is crucial for reducing morbidity and mortality. The care of individuals with EBV-associated myocarditis demands a collaborative approach involving healthcare professionals to provide patient-centered care and enhance overall outcomes.

A multidisciplinary team, including cardiologists, emergency medicine clinicians, critical care clinicians, advanced practitioners, nurses, pharmacists, physiotherapists, and other healthcare providers, should possess the clinical skills and knowledge to diagnose and manage EBV-associated myocarditis. The condition involves expertise in recognizing diverse clinical presentations and proficiency in diagnostic techniques such as echocardiography, cardiac MRI, and endomyocardial biopsy.[75][76] Furthermore, educating patients and caregivers about the condition's origins, symptoms, and utilization of diagnostic tools is vital in preventing cardiac complications and reducing morbidity.

A strategic approach involving evidence-based strategies to optimize treatment plans while minimizing adverse effects is crucial. Ethical considerations should steer decision-making, ensuring that informed consent is secured and patient autonomy is honored in the decision-making process. Every healthcare professional should be conscious of their responsibilities and contribute unique expertise to the patient's care plan, fostering a multidisciplinary approach.

Effective interprofessional communication is paramount, allowing for seamless information exchange and collaborative decision-making among team members. Care coordination is vital in ensuring that the patient's path from diagnosis to treatment and follow-up is effectively managed, minimizing errors and improving patient safety. By embracing these principles of skill, strategy, ethics, responsibilities, interprofessional communication, and care coordination, healthcare professionals can deliver integrated patient-centered care.

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Disclosure: Rakesh Das declares no relevant financial relationships with ineligible companies.

Disclosure: Andrew Nguyen declares no relevant financial relationships with ineligible companies.