Viral myocarditis in pediatrics: A review of current diagnostic methods and future directions

Abstract

Viral myocarditis is the inflammation of heart myocytes resulting from viral infection. Incidence in the pediatric population could reach 2 per 100,000 per year, and COVID-19 infection is a significant risk factor, which increases the possibility of having an infection by 40 times. Early detection results in catching the disease early and consequently improves outcomes. Clinical presentation of viral myocarditis in children could vary from mild prodromal symptoms to severe heart failure. Clinical examination, electrocardiogram, and chest X-ray may give clues for physiological and structural signs usually associated with the disease. However, they are inconclusive as they lack both accuracy and specificity. Biomarkers used to track the disease usually lack sensitivity and specificity. Cardiac magnetic resonance (CMR) is the imaging of choice to diagnose viral myocarditis by showing edema and late gadolinium enhancement. Point-of-care ultrasound has been approved as a good imaging method for early detection. It can be used as an effective screening tool for high-risk patients. Positron emission tomography scan is very sensitive in detecting disease early in its acute phase, especially if combined with CMR. All imaging studies are prone to interpretation bias, leading to a misdiagnosis. Endomyocardial biopsy is the gold standard method for diagnosis. However, it is time-consuming and ineffective as an early detection tool. Artificial intelligence (AI) helps with interpretation, decreasing bias, improving accuracy, and saving time and manpower. With more research and evidence, adopting AI-based methods to diagnose myocarditis in pediatrics could offer early detection, reduce costs, and save time for early intervention. Genetics helps identify inflammatory pathways involved in vulnerable patients, and genetic therapy may suppress disease progression by mitigating these pathways. Research focused on children is highly encouraged, and collaboration between healthcare institutions to develop telemedicine-based programs is influential.

INTRODUCTION

Viral myocarditis is an inflammation of the heart muscle (myocardium) mediated by viral infections, either through direct viral invasion of the myocardium or triggered by viral antigens.[1] It remains a recognized cause of sudden cardiac death in children, with estimates indicating up to 12%.[2] Myocarditis is most commonly virally mediated, with a high prevalence of detection of enterovirus, adenovirus, parvovirus B19, and Epstein–Barr virus.[3] The presenting symptoms include chest pain, arrhythmias, and heart failure. As a result, it can lead to significant morbidity and mortality; however, most children with clinical myocarditis have a favorable prognosis. This article aims to highlight the merits, challenges, and suitable applications of current diagnostic methods of viral myocarditis in children. In addition, it explores emerging diagnostic innovations and provides recommendations to enhance the early detection of the disease.

The incidence of myocarditis varies significantly based on geographical and seasonal factors, with an estimated incidence of between 0.80 and 2.13 cases per 100,000.[2] Since the onset of the COVID-19 pandemic, a multisystem inflammatory syndrome in children linked to Severe acute respiratory syndrome coronavirus 2 has led to an estimated rise in the incidence of 17%–75% in affected children.[3] It has been proven that COVID-19 presents nearly a 40-fold increased risk for myocarditis compared with patients who did not have COVID-19.[4] Despite the severity of long-term outcomes, the mortality rate due to viral myocarditis remains low, with a survival rate of 93%.[5] However, this may depend on the patient’s age and other factors.

Early detection is crucial for improving outcomes as it facilitates resource management and implementation of specific therapeutic options, including pharmacologic and mechanical circulatory support.[6] Transthoracic echocardiography helps assess ventricular systolic function in children due to its ability to produce real-time images, portability, and ability to provide valuable diagnostic information relatively quickly. Currently, cardiac magnetic resonance (CMR) has emerged as an integral noninvasive imaging method with good sensitivity and specificity; the lack of ionizing radiation makes CMR particularly attractive as a potential “all-in-one” technique, decreasing the need for endomyocardial biopsy (EMB), which was previously used in the diagnosis of myocarditis.[3]

Treatment of myocarditis varies according to the stage of the disease. Myocarditis progresses through 3 stages. The first stage involves direct injury to the myocardium. In the second phase, cardiomyocyte injury is caused by immune-mediated responses. Therefore, immunomodulatory therapies may prove effective. The third stage comprises either recovery or further disease progression to Dilated Cardiomyopathy (DCM) due to ongoing inflammation or overwhelming injury in the acute phase. Therefore, in some cases, immunomodulatory treatment may be considered. The most commonly used immunomodulators include intravenous immunoglobulin (IVIG), corticosteroids, azathioprine, and anakinra. IVIG administration may be regarded as adjuvant management in acute myocarditis. Recent meta-analyses suggest that IVIG treatment improves left ventricular ejection fraction and reduces in-hospital mortality among the pediatric population. High-dose steroids in conjunction with IVIG showed overall transplant-free survival of 92.5%, without reporting significant side effects.[7]

PATHOPHYSIOLOGY

It is mandatory to understand the progress of the disease to gain new insights regarding new diagnostic tools. Viral myocarditis is an inflammatory disease of the myocardium caused commonly by enteroviruses, adenoviruses, parvovirus B19, and human herpesvirus 6, less commonly by human immunodeficiency virus.[8] The pathophysiology of viral myocarditis is related to the interaction between viral infection and the immune response, which leads to direct injury to the myocardium and triggers an inflammatory response.[8,9] The progression of the disease occurs in phases:

• Phase 1: Viral entrance through host cellular pathways. For example, coxsackievirus and adenovirus enter through the transmembrane coxsackie and adenovirus receptor. Parvovirus B19 infects endothelial cells via erythrocyte P antigen and integrin αvβ1 as a co-receptor[8,9,10]

• Phase 2: Replication of the virus and stimulation of the host’s innate immunity and cell necrosis. In the case of coxsackievirus, the virus releases protease 2A, which stimulates the release of intracellular antigens, including myosin. This activates the host immune response, represented by natural killer cells, T lymphocytes, and macrophages. During this stage, increased production of cytokines along with antibodies to the virus can cause more damage to the myocardium. This phase may last weeks to months[8,10]

• Phase 3: Recovery, further cell injury, or cell death, which may progress to DCM. Enterovirus causes direct damage to the myocardium, leading to systolic dysfunction. Parvovirus B19 affects the endothelium, compromising tissue perfusion and leading to ischemia and systolic dysfunction.[8,9]

Risk factors for viral myocarditis include genetic factors such as the Human Leukocyte Antigen-DQ locus and CD4 polymorphisms. Environmental factors, such as malnutrition, selenium deficiency (Keshan disease), sex hormones, and age,[8] can also increase the risk of developing viral myocarditis.

The difference in approach between a patient in phase 2 versus a patient in Phase 3 of the disease process lies in the diagnostic methods, treatment focus, and prognosis. In Phase 2 of viral myocarditis, due to immunological activation, the diagnosis is made through EMB, a few days to weeks after symptom resolution. Noninvasive tools, though less sensitive and specific, include intercellular adhesion molecule-1, cardiac-specific autoantibodies like anti-α-myosin, and imaging techniques such as gallium-and indium-labeled anti-myosin antibody scans. Treatment focuses on immunomodulatory therapies to control inflammation, and the prognosis is favorable with early management. In contrast, Phase 3 of the disease is managed similarly to idiopathic DCM and congestive heart failure. Diagnosis relies on clinical history and examination, with echocardiography used for follow-up and monitoring heart function and remodeling. Treatment at this stage aims to prevent heart failure with anti-failure drugs such as angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and spironolactone. An implantable defibrillator may be needed for patients with life-threatening arrhythmias.[11]

TRADITIONAL DIAGNOSTIC METHODS AND LIMITATIONS

Myocarditis can present in various clinical profiles, often presenting with reduced ventricular function, heart failure symptoms, and a preceding viral infection, making diagnosis challenging due to its varied clinical manifestations.[12] The diagnosis of pediatric myocarditis is especially challenging because of the variable clinical presentation, ranging from asymptomatic patients with only subtle findings on an electrocardiogram to fulminant cardiac failure and sudden death.[5]

Laboratory markers, including inflammatory markers (C - reactive protein or erythrocyte sedimentation rate), may be elevated but are neither sensitive nor specific, and normal levels do not exclude myocarditis.[13] Cardiac troponins and natriuretic peptides are often elevated. However, troponins are sensitive indicators of myocardial damage but lack specificity for myocarditis. Natriuretic peptide levels are associated with cardiac dysfunction and heart failure but are nonspecific for myocarditis.[12] Antibodies to cardiac myosin were detected in some pediatric myocarditis patients, remaining present even after myocardial recovery.[14] However, their sensitivity and specificity are challenged by many nonspecific antibodies arising from broader tissue damage, complicating their use as reliable biomarkers for myocarditis.[15] Chest X-ray findings are consistent with heart failure.[5] Nevertheless, given the low accuracy and high probability of interpretation bias, chest X-rays may not diagnose viral myocarditis accurately.

Electrocardiograph (ECG) often reveals diffuse ST-segment elevations or T-wave changes in over half of patients, with around 25% experiencing premature ventricular contractions, especially polymorphic ones, indicating potential myocarditis, whereas conduction abnormalities may suggest specific myocarditis types.[13] ECG has low sensitivity (47%) and unknown specificity for diagnosing myocarditis, but it is widely used as a simple, noninvasive initial screening tool despite its limitations in accuracy.[16]

Echocardiography is the primary imaging tool for assessing cardiac structure and function in suspected myocarditis cases. Its real-time imaging and portability are particularly beneficial for quickly evaluating children with potential hemodynamic instability.[12] Severe LV dysfunction is the most frequent echocardiographic finding in myocarditis.[14] While echocardiography is moderately sensitive and specific, it has limitations in differentiating myocarditis from other cardiomyopathies;[12] however, it is essential for ruling out other causes of the acute presentation.[13]

ADVANCED DIAGNOSTICS AND REAL-WORLD APPLICATION

Viral myocarditis in children can quickly become severe, mimicking other cardiac and respiratory conditions, so rapid treatment is crucial to reduce mortality. Modern methods such as CMR, EMB, and positron emission tomography (PET) scans are used. Since 1990, CMR has been a specific tool for identifying heart inflammation, showing edema and patterns of late gadolinium enhancement (LGE), depending on the disease phase. Importantly, CMR helps determine the need for extracorporeal membrane oxygenation, ventricular assist devices, and transplants, and it assesses death risk[9,17] CMR imaging has an overall sensitivity of 76%, specificity of 54%, and accuracy of 68% for diagnosing myocarditis. It is more effective for acute myocarditis, with a sensitivity of 81%, compared to chronic myocarditis, which has a sensitivity of 63%.[18]

EMB is critical for diagnosing patients with suspected viral myocarditis, especially in severe cases or when initial treatments fail. It is essential to rule out ongoing viral infections before starting immunosuppression, as the precise diagnosis is vital for personalized treatment. Persistent viruses worsen heart function, but their removal improves it.[9] According to the American College of Cardiology, CMR imaging and EMB are the gold standard diagnostic tests for diagnosing viral myocarditis, starting with CMR because it is noninvasive.[19]

Fluorodeoxyglucose-18 (FDG) is used in PET scans to detect cancer and inflammation by highlighting active metabolic areas. Cardiac-gated FDG-PET is used primarily for cardiac sarcoidosis but can also detect acute myocarditis. Due to the high glucose consumption of the heart muscle, patients follow a special diet to enhance the detection of inflammation areas. PET/magnetic resonance imaging (MRI) offers detailed analysis, and recent studies show FDG uptake in COVID-19 recovery patients linked to MRI anomalies. Future research focuses on new PET tracers like CXCR4, which targets inflammation. PET scans are more effective when used with CMR than alone.[20] One prospective study investigated the use of PET-computed tomography (CT) compared to CMR with LGE in 65 patients with suspected myocarditis. It showed that the sensitivity and specificity of PET-CT were 74% and 97%, respectively, with an overall accuracy of 87% as compared to CMR.[21]

Preparing for PET/CT scans in children needs careful planning, especially if the child requires sedation. The team should ensure all sedation steps are completed beforehand and allow about 45 min for the sedative to take effect. Good communication is key to ensure the child is positioned correctly and everyone knows how long the scan will take. After the scan, the team should quickly check the images (in about 5–10 min) to see if more pictures are needed. This helps avoid doing another scan when the sedative starts to wear off. With good preparation and teamwork, managing sedation can be smooth, leading to fewer delays and better images.[22]

Fulminant myocarditis is a rare and life-threatening condition. Rapid diagnosis and treatment are crucial, as patients may require medications or devices to support heart function until recovery or transplantation. However, with early detection and good care, more than 90% will fully recover with minimal long-term sequelae.[23] Effective management necessitates specialized resources and a multidisciplinary healthcare team. Training frontline healthcare providers to recognize fulminant myocarditis early improves patient outcomes and prevents serious complications.

Diagnostic imaging is essential for diagnosing fulminant myocarditis. Echocardiography is usually the first test to check how well the left ventricle works. It can also show problems with the right ventricle and thickening of the heart wall in severe cases. CMR is the most accurate noninvasive method for diagnosing myocarditis, but it may not be practical for very ill patients. Scintigraphy can detect myocarditis, but it is not commonly used anymore because its accuracy can vary.[23]

Point-of-care ultrasound (POCUS) is an excellent example of a noninvasive and beneficial diagnostic method that can enhance the early identification and diagnosis of heart problems and direct treatment for critically ill patients. The American Academy of Pediatrics recently released the first policy statement supporting the use of POCUS by pediatric emergency physicians. The following case study demonstrates how useful it is in real life: A 5-year-old girl arrived at the emergency department (ED) with vague myocarditis, including fever, vomiting up to 10 times a day (non-bilious and non-bloody), sore throat, poor appetite, insomnia, and mild cough. In addition, she was experiencing lethargy, increasing tachypnea, and deteriorating mental status. Her condition improved once fluids were discontinued, and an adrenaline drip was initiated. Then the pediatric cardiac intensive care unit (PCICU) admitted her. Both ECG and chest radiograph were performed. Quick POCUS and physical examination were done. Troponin results showed a high level at 30.40 ng/mL (normal is <0.03 ng/mL); the patient was diagnosed with myocarditis with cardiogenic shock based on POCUS.[24] An electrocardiogram is abnormal in most cases, but not specific. The gold standard for diagnosis is a cardiac biopsy, which is rarely performed before the patient’s death. POCUS is a new, quick, and simple technique that can be utilized as soon as a patient arrives, even before any lab tests are made. POCUS can aid in the early detection of heart conditions and improve the outcomes of children in the emergency room.

Therefore, using POCUS on critically ill patients who exhibit vague symptoms can improve the sensitivity and effectiveness of identifying myocarditis early in the ED and directing the resuscitation team appropriately.[24] Until more cutting-edge testing methods are merged, this investigation may be a helpful screening tool for high-risk patients.

An echocardiogram is the best first test for infants who might have myocarditis because it is safe. CMR can provide more detailed images but has some challenges, like needing sedation and taking a long time. 18F-FDG-PET scans are not usually used because they involve radiation and can show high activity in the heart. A heart tissue biopsy is the most accurate test, but it is only done if other tests do not give clear answers. Identifying and treating severe myocarditis is crucial for better recovery.[25]

DIAGNOSTIC INNOVATIONS AND FUTURE DIRECTION

As artificial intelligence (AI) technology has pervaded most aspects of diagnostic medicine, it has specifically added a qualitative leap in diagnosing myocarditis.[26] As we have mentioned, CMR is a noninvasive and sensitive diagnostic method; however, the interpretation of films requires experts and qualified personnel, which makes imaging studies prone to interpretation bias. AI helps with interpretation, decreasing bias, improving accuracy, and saving time and manpower. Some limitations exist, such as the fact that it can be affected by the quality of the CMR, the variability of the patient’s presentation, and the number of dataset centers used.[27] However, these can be considered relatively manageable issues with more data to be obtained. Not only CMR but also AI participated in the interpretation of ECG. In a study involving 1040 ECG results, the authors used the improved quantum genetic algorithm with the optimized backpropagation neural network to detect ECG changes, especially in myocarditis patients.[28] Features of abnormal ECG changes have been detected with 99.6% accuracy and 99.5% sensitivity [Table 1]. With more research and evidence, adopting AI-based methods to diagnose myocarditis in pediatrics could offer early detection, reduce costs, and save time for early intervention.

Table 1.

Sensitivity, specificity, and accuracy of using artificial intelligence in diagnosing various heart diseases. Summarized from Lei Wu et al. Study[28]

Classification Task	Method	Sensitivity (SEN)	Specificity (SPE)	Accuracy (ACC)	F-measure (F-MEA)
Myocarditis vs. Normal	ADE-BPNN	0.9927	0.9910	0.9954	0.9982
	BPNN	0.9795	0.9835	0.9790	0.9857
	CNN	0.9673	0.9724	0.9759	0.9669
	SVM	0.9711	0.9670	0.9687	0.9751
	RF	0.9690	0.9618	0.9700	0.9706
Myocarditis vs. Abnormal	ADE-BPNN	0.9899	0.9923	0.9957	0.9844
	BPNN	0.9738	0.9809	0.9883	0.9720
	CNN	0.9692	0.9755	0.9730	0.9649
	SVM	0.9657	0.9681	0.9698	0.9703
	RF	0.9589	0.9608	0.9697	0.9625
Myocarditis vs. MI	ADE-BPNN	0.9851	0.9900	0.9936	0.9876
	BPNN	0.9796	0.9813	0.9754	0.9794
	CNN	0.9780	0.9724	0.9751	0.9733
	SVM	0.9684	0.9620	0.9799	0.9669
	RF	0.9557	0.9539	0.9574	0.9560
Myocarditis vs. PMI	ADE-BPNN	0.9875	0.9867	0.9940	0.9827
	BPNN	0.9719	0.9750	0.9890	0.9783
	CNN	0.9755	0.9692	0.9756	0.9718
	SVM	0.9631	0.9589	0.9718	0.9653
	RF	0.9602	0.9517	0.9631	0.9576

ADE: Adaptive differential evolution, BPNN: Backpropagation neural network, CNN: Convolusional neural network, SVM: Support vector machine, RF: Random forest

In 2020, Peretto et al. described how telemedicine can enhance the care of myocarditis patients. They developed the Myocarditis Disease Unit (MDU), which is a multidisciplinary team specializing in diagnosing and following myocarditis patients, aiming for optimum outcomes. After the era of the COVID-19 pandemic, the idea of combining telemedicine with the MDU (tele-MDU) allowed obtaining consultant reports, sharing reports with patients, regulating updates regarding patients’ follow-up and upcoming tests and visits, and organizing a multidisciplinary discussion about the patients’ updates.[29] We believe telemedicine could add to the diagnosis of myocarditis in pediatric patients, especially in remote areas. Setting platforms for multidisciplinary personnel would facilitate data transfer, particularly imaging, and attaining a second opinion, particularly in low-resource areas. Healthcare institutions should collaborate to initiate and develop such platforms.

Advanced genetic testing, such as Next-Generation Sequencing (NGS), has been proven to help with identifying pathogens and anticipating prognosis in inflammatory cardiac diseases.[30] In myocarditis, applying NGS helps identify different kinds of transcripts for viruses. Distinguishing the virus lytic transcript can give a picture of the degree of inflammation that can happen, and consequently, anticipate clinical presentation.[31] Genetics helps identify inflammatory pathways involved in vulnerable patients, and genetic therapy may suppress disease progression by mitigating these pathways. Genetics is a substantial aspect of early detection of viral myocarditis in the future; nevertheless, pediatric patients’ unique presentation and causative pathogens in articulation with different age groups should be addressed in future research.

CONCLUSIONS

Diagnosing viral myocarditis in children remains challenging due to its diverse clinical presentations and overlap with other pediatric conditions. However, recent advancements in imaging technologies – such as cardiac MRI, PET scans, and POCUS – have significantly improved early detection and risk stratification, helping identify children who may require more intensive treatment and monitoring.

While traditional diagnostic methods such as ECG, echocardiography, and laboratory markers remain important, they often lack the accuracy and specificity needed for a definitive diagnosis.

Emerging tools such as AI, genetic testing, and telemedicine offer substantial promise in enhancing diagnostic precision and accessibility, especially in low-resource settings. Integrating these innovations within a multidisciplinary clinical framework is essential for timely diagnosis, personalized intervention, and improved outcomes in pediatric patients with viral myocarditis. Continued research and interprofessional collaboration are crucial to refine these approaches and ensure their effective integration into standard clinical practice.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.