CALs associated with CAEBV infection, which primarily manifest as coronary artery dilatation (CAD) or CAAs, are diagnosed by measuring the diameter of the coronary lumen using echocardiography or coronary angiography. CAAs are typically defined as localized dilatations in which the diameter of the aneurysmal segment exceeds 1.5 times that of the adjacent normal artery (48). In recent years, the Z-score, which is calculated based on body surface area, has become the predominant evaluation metric for CALs, particularly in pediatric patients, as it demonstrates broader applicability than absolute coronary diameter measurements. Based on the Z-score, lesions were classified into 5 categories: normal, CAD-only, small CAA, medium CAA, and large or giant CAA (49). Although coronary atherosclerosis is the most common cause of coronary abnormalities in adults, pediatric cases involve both congenital and acquired etiologies, with Kawasaki disease (KD) being the predominant acquired factor (48). Literature reports indicate an 8.9% incidence of CALs in patients with CAEBV infection (39). Previous studies have paid limited attention to CAEBV-associated coronary lesions and have often overlooked this type of vascular pathology.

There were 22 articles (10–12, 19, 20, 22, 24, 27, 30–34, 36–41, 43, 44, 46) with 38 patients reporting CAEBV-associated CALs, 12 of which were Japanese (17 patients), 7 were Chinese (18 patients), and 1 article each for Morocco, Brazil, and Korea. Among these patients, 32 (84.2%) were children and 6 (15.8%) were adults, with 18 males (47.4%) and 20 females (52.6%). The median age was 6 years (range, 2–42 years), with the pediatric and adult subgroups showing median ages of 6 years (range, 2–16 years) and 25 years (range, 19–42 years), respectively. CALs frequently coexisted with other cardiovascular abnormalities: 12 patients (31.6%) presented with isolated CALs, whereas 26 (68.4%) exhibited coexisting cardiovascular damage. Of the 26 patients, 10 had additional vascular lesions such as multiple aneurysms in the aorta and branch vessels, 10 showed electrocardiographic (ECG) abnormalities, 8 had pericardial involvement, 7 demonstrated valvular regurgitation, 5 exhibited a sinus of Valsalva aneurysm, 4 progressed to myocardial infarction or heart failure, and 2 developed PAH.

Patients with CAEBV-associated CALs may exhibit diverse manifestations depending on the severity of the CALs and concurrent comorbidities, ranging from chest pain, congestive heart failure, acute coronary syndrome, and sudden death to being entirely asymptomatic. An elevated EBV viral load, fever, and cytopenia have been proposed as potential contributors to cardiovascular complications (27). The Coronary Artery Aneurysm Registry, the largest multicenter registry, reported a mortality rate of 15.3% and major adverse cardiac event rate of 31% in adults (50). However, no specific prognostic data have been reported for CAEBV infections with CALs. In our review, 52.6% of patients with CAEBV-associated CALs survived after treatment. Wei et al. reported that 30% of patients' coronary arteries with CALs returned to normal, and no patient died of CALs-related complications (39). Additionally, patients with CAEBV-associated CAAs with chronic total occlusion that underwent coronary artery bypass grafting (CABG) exhibited restoration of normal coronary circulation, as reported in the literature (46).

Diagnosing CALs is not inherently challenging; however, confirming whether CALs are attributable to CAEBV infection or KD, particularly incomplete KD, remains a diagnostically complex task. Kikuta et al. reported a high positivity rate for EBV-DNA polymerase chain reaction (PCR) testing in peripheral blood samples from patients with KD, suggesting that EBV infection may be a potential etiological contributor to KD (51). This complicates the differentiation between KD and CAEBV infection in patients with CALs. Definitive determination of the underlying cause of coronary damage is impossible unless coronary tissue is available for EBV DNA testing, a procedure that is rarely feasible in clinical practice. Because such biopsies are seldom performed in living patients owing to their invasiveness and risk, current diagnostic practices remain insufficient to definitively confirm whether lesions result from CAEBV infection or KD. In the absence of histopathological evidence, clinical symptoms and follow-ups may provide partial diagnostic guidance. Typically, KD coronary manifestations appear 7–10 days after disease onset, whereas in CAEBV infections, such manifestations may develop over time. The predominance of neutrophil activation in KD vs. lymphocyte activation in CAEBV infection may aid in the differentiation between these 2 conditions. Notably, many patients with KD lack the typical symptoms and only present with CAAs. Given the high risk of aneurysm rupture, intravenous immunoglobulin (IVIG) is administered when incomplete KD is suspected to prevent CAL progression (9). Further diagnostic evaluation should be performed based on persistent clinical manifestations after IVIG treatment.

Patients with CAEBV infection may develop vascular involvement that extends beyond CALs. These changes are characterized by dilated or stenotic alterations in any segment of the aorta and its branch arteries, including the subclavian, vertebral, superior mesenteric, and common iliac arteries. Studies have reported the occurrence of multiple aneurysms in patients with CAEBV infection, not only in the coronary arteries, but also in the splenic, superior mesenteric, common hepatic, left gastric, celiac trunk, bilateral intercostal, subclavian, carotid, vertebrobasilar systems, and thoracoabdominal aorta (40, 43). Clinical presentations vary according to lesion severity, ranging from asymptomatic to life-threatening complications, such as intracranial hemorrhage due to vascular rupture, acute cardiac tamponade resulting from aneurysm rupture, or cardiocerebrovascular arrest (40).

We identified 13 articles (11, 12, 22, 25, 30, 33, 34, 36, 37, 40, 41, 43, 47) reporting multiple CAEBV-associated aneurysms involving 14 patients. These 13 articles included 6 Japanese studies (7 patients), 4 Chinese studies (4 patients), and a single case each from Morocco, Brazil, and India. The cohort consisted of 9 pediatric patients (64.3%) and 5 adult patients (35.7%), with a male-to-female ratio of 5:9 (35.7% vs. 64.3%). The overall median age was 10 years (range, 2–42 years), stratified as 5 years (range, 2–16 years) for the pediatric subgroup and 36 years (range, 19–42 years) for the adult subgroup.

Distinguishing CAEBV-associated vasculopathy from Takayasu arteritis (TA) is critical despite overlapping features such as aortic branch vessel stenosis, occlusion, or dilatation. TA, a type of vasculitis potentially associated with genetic or immune dysregulation, is characterized by distinct histopathological features, including granulomatous inflammation of the arterial walls in the active phase, which may progress to panarteritis with minimal inflammation and adventitial fibrosis in the chronic stages (52, 53). TA predominantly affects young women aged 20–40 years and presents with pulse deficits, blood pressure discrepancies, vascular bruits, and elevated inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, but usually lacks autoantibodies. In contrast, CAEBV-related vasculopathy results from persistent EBV infection and is characterized by systemic lymphocytic infiltration. Histopathological hallmarks include perivascular atypical lymphocyte infiltration, destruction of the medial elastic lamina at vascular bifurcations with a moth-eaten appearance, and EBV-encoded RNA (EBER) positivity along with elevated EBV DNA levels in affected vessels (11). CAEBV-associated vascular lesions exhibit a broader age distribution, primarily affecting pediatric and adolescent populations, with the involvement of medium or small arteries. These lesions are often accompanied by systemic manifestations, such as fever, hepatosplenomegaly, and lymphadenopathy. Timely differentiation is imperative because of the distinct therapeutic approaches and prognoses associated with these entities.

A subset of patients with CAEBV infection may exhibit ECG abnormalities including tachycardia, atrial fibrillation, atrioventricular block, junctional escape beats, premature contractions, and ST-T changes. These abnormalities may result from the direct viral infiltration of cardiomyocytes or conduction pathways, leading to myocardial degeneration or conduction disturbances. Autopsy has revealed EBER-positive cells surrounding the degenerated myocardium in CAEBV-infected patients, with instances of transient ventricular fibrillation (10). Case reports have further associated EBV-related myocarditis with atrioventricular block, suggesting that persistent EBV infection may induce cardiomyocyte degeneration, thereby triggering arrhythmias or acute circulatory failure (54). Alternatively, ECG abnormalities may secondarily reflect heart structural remodeling, as observed in CAEBV-associated PAH. Severe PAH often leads to right ventricular enlargement and septal shift, which manifests as right axis deviation and complete right bundle branch block (31).

We retrieved 10 articles with 14 patients (19, 24, 26, 27, 31, 38, 39, 41, 42, 47) documenting CAEBV-associated ECG abnormalities, 5 of which were Japanese (5 patients), 4 were Chinese (8 patients), and 1 was Indian. Of the included patients, 10 were pediatric (71.4%) and 4 were adults (28.6%). There were 7 males (50.0%) and 7 females (50.0%). The overall median age was 9 years (range, 1–45 years), with a median of 7 years (range, 1–14 years) in the pediatric subgroup and 37 years (range, 36–45 years) in the adult subgroup.

CAEBV-related ECG abnormalities may present asymptomatically or with symptoms, such as chest tightness, palpitations, or syncope. ECG exhibits nearly 100% diagnostic accuracy in detecting CAEBV-associated arrhythmias, providing direct visualization of the heart rate, rhythm patterns, and specific arrhythmia subtypes. This modality facilitates timely therapeutic decision-making and plays a critical role in longitudinal monitoring, thereby justifying routine ECG evaluation in all patients with CAEBV infection.

Pericardial effusion or cardiac tamponade may occur in patients with CAEBV infection, either as an isolated condition or as part of the systemic involvement. While pericardial effusion can result from numerous etiologies, including idiopathic causes and infections, particularly viral pathogens such as coxsackievirus and echovirus (55, 56), a small-scale Japanese study identified pericardial involvement in 20% of patients with CAEBV infection (27).

We found 8 articles (21, 22, 24, 27, 39, 42, 43, 47) comprising 14 patients reporting CAEBV-associated pericardial pathologies; 4 were from Japan (7 patients), 2 from China (5 patients), and 1 each from Brazil and India. Of these 14 patients, 10 were pediatric (71.4%) and 4 were adults (28.6%). There were 5 males (35.7%) and 9 females (64.3%). The overall median age was 13 years (range, 3–37 years), with pediatric patients aged 6 years (range, 3–16 years) and adult patients aged 29 years (range: 19–37 years).

Clinical manifestations range from asymptomatic presentation to chest tightness, dyspnea, cardiac tamponade, and even cardiac arrest, depending on the severity of the effusion. CAEBV-related pericardial effusion is usually exudative, with cytological analysis revealing EBV positivity, metagenomic next-generation sequencing demonstrating elevated EBV-DNA levels, and flow cytometry showing predominantly mature T cell populations. Notably, some studies have observed disproportionately high EBV-DNA loads in effusions with minimal cellular components, suggesting that viral replication originates from adjacent tissues rather than the direct infiltration of EBV-infected lymphocytes into the pericardium (24, 57). Echocardiography achieves nearly 100% diagnostic accuracy in detecting pericardial effusion and plays a pivotal role in monitoring and guiding pericardiocentesis. Echocardiography is sufficient for diagnosing pericardial effusion in most patients. However, computed tomography (CT) or magnetic resonance imaging (MRI) may occasionally be used to supplement the evaluation, with CT attenuation values potentially offering additional insights into the composition of the effusion.

PAH associated with CAEBV infection is a rare complication characterized by elevated pulmonary artery pressure, and clinically manifests as progressive dyspnea, edema, and right-sided heart failure. Although PAH can occur in both pediatric and adult populations, it is more commonly observed in adults and typically presents as an isolated PAH.

Our review identified 7 articles (28, 29, 31, 34, 35, 38, 45) with 10 patients reporting CAEBV-associated PAH: 6 from Japan (9 patients) and 1 from China. Among the 10 patients, 2 were pediatric (20%) and 8 were adults (80%), with a male-to-female ratio of 4:6 (40% vs. 60%). The overall median age was 32 years (range, 6–69 years), with pediatric cases aged 6–9 years, and the median age of the adult subgroup was 38 years (range, 23–69 years). Both pediatric patients had CALs, whereas among the adults, 7 exhibited isolated PAH and 1 developed heart failure.

The clinical classification of PAH comprises 5 groups, and CAEBV-associated PAH is categorized as group 5, which is characterized by unclear and multifactorial pathogenic mechanisms (58). In all patients with CAEBV-associated PAH, right heart catheterization revealed elevated pulmonary vascular resistance and normal pulmonary capillary wedge pressure, indicative of precapillary pulmonary hypertension. The diagnosis of PAH is relatively straightforward, and echocardiography is the primary tool for evaluating pulmonary artery pressure by measuring the tricuspid regurgitation velocity. Right heart catheterization remains the gold standard for definitive diagnosis. When diagnosing PAH, it is crucial to systematically exclude common etiologies across all PAH groups. Once these causes have been ruled out, rare etiologies such as CAEBV infection should be considered. Conversely, in patients with CAEBV infection and PAH, the aforementioned etiological groups must be excluded before attributing PAH to CAEBV-induced pathogenesis.

Patients with CAEBV infection may develop valvular dysfunction as the disease progresses, although its precise pathogenesis remains unclear. Potential mechanisms could involve EBV-mediated valvular damage or result from cardiac pathologies such as cardiomyopathy, myocardial infarction, papillary muscle displacement and dysfunction, or arrhythmia-induced valvular abnormalities. In our review, we found that CAEBV-associated valvular regurgitation predominantly affected the mitral, tricuspid, and aortic valves.

Five articles reporting CAEBV-related valvular dysfunction comprising 9 patients were reviewed. There were 3 Chinese studies (37, 39, 41) (7 patients), and 1 study each with 1 patient from Japan (25) and India (47). The cohort included 8 pediatric and 1 adult patients, with a male-to-female ratio of 3:6. The overall median age was 10 years (range, 4–37 years), stratified as 7 years (range, 4–14 years) in the pediatric subgroup and 37 years in the adult subgroup. Aortic regurgitation was observed in 7 patients, mitral regurgitation in 5, and tricuspid regurgitation in 2. No isolated valvular regurgitation was observed. Instead, among the pediatric cases, 7 coexisted with CALs, 1 with aortic sinus dilatation, and the adult case presented with both a ventricular aneurysm and vascular involvement.

Echocardiography is the primary non-invasive diagnostic modality for valvular heart disease, enabling real-time assessment of valve morphology, function, and hemodynamics as well as semiquantitative evaluation of the severity of stenosis and regurgitation. Cardiac magnetic resonance (CMR) can accurately quantify regurgitant volumes and evaluate myocardial fibrosis or scarring. Digital subtraction angiography (DSA) provides precise measurements of transvalvular pressure gradients, cardiac output, and valve orifice area; left ventriculography enables direct visualization of regurgitant severity and evaluation of coronary involvement. CT primarily aids in detecting valvular calcification and excludes coronary artery disease, offering additional anatomical characterization in complex cases.

CAEBV-associated myocarditis and cardiomyopathy have rarely been reported. Chen et al. reported 7 patients with EBV-related myocarditis, with only 1 definitively associated with CAEBV infection (9). Our review identified one case each of CAEBV-associated myocarditis and dilated cardiomyopathy (23, 26) one each from Japan and Germany, both involving adult males.

The definitive diagnosis of CAEBV-related myocarditis remains challenging, typically necessitating endomyocardial biopsy for viral genome identification through PCR. However, myocardial biopsies are seldom performed in clinical practice because of the risks involved. As a result, diagnosis relies on clinical manifestations and ancillary tests such as cardiac biomarkers, ECG, echocardiography, angiography, and CMR. In CAEBV-associated myocarditis, elevations in troponin I/T, creatine kinase, and CRP levels may occur, although these findings are not specific. ECG may reveal ST-segment deviations and bundle branch blocks, suggesting myocardial injury. Although echocardiographic findings are usually variable and nonspecific, they can assist in excluding alternative etiologies.

CAEBV with myocardial involvement may lead to ventricular aneurysm formation. Raghuram et al. reported a patient with CAEBV presenting with a left ventricular apical pseudoaneurysm accompanied by thrombus formation with no evidence of abnormal coronary arteries. CMR revealed an apical pseudoaneurysm with wall thinning and transmural late gadolinium enhancement, suggesting myocardial fibrosis (47). Angiography and coronary CT angiography play a crucial role in distinguishing these aneurysms from postinfarction variants because aneurysms following infarction are typically confined to territories supplied by occluded coronary arteries (59).

Heart failure is defined as a clinical syndrome resulting from structural or functional cardiac abnormalities that impair left ventricular ejection fraction, leading to reduced cardiac output and elevated intracardiac pressure. It may develop secondary to CAEBV-related complications including CALs, myocarditis, myocardial ischemia, arrhythmias, PAH, or valvular regurgitation. The clinical manifestations include chest tightness, dyspnea, exercise intolerance, and edema. We identified 7 patients with heart failure (23, 26, 27, 29, 38) (4 adults and 3 children; 2 males and 5 females). The overall median age was 28 years (range, 3–45 years), with a median of 11 years (range, 3–16 years) for pediatric patients and 36 years (range, 28–45 years) for adult patients.

Diagnosis of heart failure integrates clinical signs and symptoms with elevated B-type natriuretic (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, although determining the underlying etiology remains essential. Echocardiography is the primary diagnostic modality and can comprehensively assess cardiac structure and systolic and diastolic function while excluding valvular, cardiomyopathic, ischemic, or congenital etiologies. CMR precisely quantifies left ventricular systolic function and diagnoses cardiomyopathy- or myocarditis-related heart failure. ECG can be used to diagnose arrhythmia and ischemic cardiomyopathy, while DSA is used to evaluate coronary artery disease, which is a potential cause of heart failure. Invasive hemodynamic monitoring is indicated for patients with acute decompensated heart failure and suspected cardiogenic shock, providing a precise assessment of volume status and cardiac function.