Diagnosis and Management of Pediatric Myocarditis

INTRODUCTION AND ETIOLOGY Myocarditis is a heterogeneous inflammatory disease of the myocardium, causing focal edema and injury, which may result in structural and functional abnormalities.1 The incidence varies between 0.8 and 2.13 cases per 100,000 with male predominance reported in children older than 6 years (approximately 2.5 times higher risk), and 2 peaks of occurrence: in children <2 years and in adolescents 13–18 years of age. In-hospital mortality is reported at 6.1%.2 Viruses are the leading cause of myocarditis in children, most commonly parvovirus B19, human herpes virus type 6 (HHV-6), enteroviruses and adenoviruses.3,4 Other etiologies include cytomegalovirus (CMV), Epstein Barr virus, hepatitis C, herpes simplex type 2, influenza, parainfluenza, SARS-CoV-2 and HIV, less frequent bacteria or other infectious pathogens, immune-mediated mechanisms and toxin exposure. Globally, the most frequent etiology is Trypanosoma cruzi (Chagas disease).4 Natural History and Clinical Features The clinical course depends on the location and extent of inflammatory infiltrates in the myocardium but also age and etiology. Clinical features vary from asymptomatic to cardiogenic shock and sudden cardiac death. The most common clinical presentations are acute heart failure, new arrhythmia and chest pain in adolescents. Poor weight gain, fever, irritability or listlessness, periodic episodes of pallor and diaphoresis with symptoms of congestive heart failure are typical in neonates and infants. Recent history of viral infection 10–14 days before presentation, general weakness, exercise intolerance, chest pain, diaphoresis, palpitations, decreased appetite, low-grade fever and respiratory symptoms related to heart failure are observed in older children. Investigations Elevated troponin T/I and N-terminal pro–B-type natriuretic peptide are often found at the time of diagnosis. Positive peripheral blood polymerase chain reaction (PCR) results and viral serology may be helpful to identify the causative pathogen. PCR can identify viral genome in peripheral samples and assess viral load qualitatively, however, the correlation of peripheral specimen and underlying disease is poor.1 Mahfoud et al5 analyzed the diagnostic value of virus serology in adult population and showed that serological evidence of infection by the same virus as detected in endomyocardial biopsy (EMB) was present only in 4% of tested population. Moreover, the high prevalence of viral pathogens in the population, and thus seropositivity and prolonged nasopharyngeal carriage, may result in the detection of a pathogen unrelated to myocarditis. Electrocardiogram and Chest Radiograph Electrocardiogram may commonly show repolarization abnormalities including elevation, flattening or lowering of the ST segment and tachycardia. Ventricular or supraventricular arrhythmias may be present. Ventricular arrhythmias are common in Coxsackie B, EBV and adenovirus myocarditis while atrioventricular blocks are often associated with HHV-6, CMV and Lyme disease.6,7 The cardiac silhouette in chest radiograph may be enlarged or within normal limits. Echocardiography and Cardiac Magnetic Resonance Left or biventricular dilation with reduced contractility is typical, but sometimes the size and function of ventricles are within normal limits. In fulminant myocarditis, thickening of the myocardium due to edema with significantly reduced ejection fraction is found. Myocarditis may be accompanied by pericardial involvement, predominantly in viral infections, causing accumulation of pericardial effusion, which rarely requires pericardiocentesis and drainage. PCR analysis of pericardial fluid can be helpful in determining etiology. Cardiac magnetic resonance if available is recommended for diagnosis.8 Diagnosis of myocardial inflammation is based on cardiac magnetic resonance Lake Louis criteria with the presence of both, myocardial edema and late gadolinium enhancement. Endomyocardial biopsy Dallas criteria (histologic inflammatory infiltrate different than ischemic necrosis), tissue PCR and immunohistochemistry are considered the gold standard for definitive diagnosis.1 Nonspecific patterns of infiltration, stains or suggestive histopathology and molecular detection of viral gene may be useful in identifying causative pathogen, for example, CMV inclusion bodies, enteroviruses infect and lyse cardiomyocytes, parvovirus B19 infects endothelial cells and HHV-6 and EBV replicate in immune cells. Given the focal nature of myocarditis, multiple EMB samples are recommended to detect viral nucleic acids to minimize the risk of false-negative results. EMB should be performed in children with a severe clinical course for treatment decisions.9,10 Implementation of antiviral therapy or restrictions of immunosuppression are determined based on the causative agent. Management of Myocarditis Initial management depends on the severity of the clinical course regardless of the etiology, and may include management of heart failure, serious arrhythmias and conduction disorders in accordance with the current guidelines.1 Targeted treatment is summarized in Table 1. TABLE 1. - Publications on Targeted-treatment Therapies in Pediatric Myocarditis Sample Size (No.) Age (y) Etiology Grounds for Diagnosis Treatment Reference Number and First Author Viral myocarditis 67 0–28 d Viral Clinical IVIG Yen et al11 40 0–15 Viral Clinical/CMR/EMB IVIG, corticosteroids Schauer et al12 8 1–14 Varied Clinical/CMR IVIG, corticosteroids, Anakinra Maunier et al13 - - Viral - Oseltamivir Rodríguez et al14 Vaccine-associated myocarditis Children 543 13–17 Immunological Clinical/CMR NSAIDs, IVIG, corticoids, vasoactive medications, Oster et al15 5 15–17 Immunological CMR - Puchalski et al16 Toxin-induced myocarditis 2 cases 9 y; 5 y Cephalosporin-induced acute hypersensitivity Autopsy - Chikwava et al17 3 cases 8; 12; 17 years Hypersensitivity due to antitubercular drugs Clinical Steroids, IVIG Dhochak et al18 CMR, cardiac magnetic resonance; NSAIDs, nonsteroidal anti-inflammatory drugs. In patients with an asymptomatic or benign course of myocarditis and good general condition spontaneous resolution is usually observed. They initially require bed rest, followed by repeated echocardiograms after the acute phase, focused on monitoring and prevention of dilated cardiomyopathy (DCM) development in the future. To reduce the risk of remodeling and DCM, use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor antagonist and β-blocker should be considered. For patients with a markedly decreased ejection fraction and heart failure symptoms inotropic support, with phosphodiesterase-3 inhibitor (milrinone) should be considered. Beta-blockers are especially recommended for patients demonstrating tachycardia and/or arrhythmias.1 Management of Fulminant Myocarditis The most severe course of myocardial disease may present as fulminant myocarditis. Its precise etiology remains unknown, but the most identified etiological agents are viruses such as parvovirus B19, coxsackievirus B3 and CMV. The rapid progression of heart failure, hemodynamic instability and cardiogenic shock due to fulminant myocarditis requires advanced mechanical ventilatory and circulatory support. Management options include extracorporeal membrane oxygenation, ventricular assist devices or Impella pump allowing for successful bridging to recovery or heart transplantation. Both extracorporeal membrane oxygenation and ventricular assist device strategies may be life-saving options for this patient population.19,20 Viral and Other Pathogen Etiology Identification of the viral genome by EMB allows for the use of specific antiviral treatment, although its efficacy in myocarditis remains unproven and the risk–benefit ratio for the procedure must be evaluated on an individual basis. Identifying the possible infectious cause of myocarditis in peripheral samples, such as blood, stool, nasopharyngeal or throat specimens, in patients who are not appropriate for EMB, should be considered in the decision on antimicrobial treatment. The treatment may be especially beneficial in the early stages of the disease when replication and direct myocardial injury take place. Data in adults with viral myocarditis caused by influenza A suggest that early antiviral drugs may reduce mortality and improve prognosis,14 however, there are no analogous data in pediatric populations. The first-line oral therapy in children is oseltamivir. It is most effective when introduced within 48 hours from the onset of symptoms and usual duration of therapy is 5 days in uncomplicated cases. A single dose of intravenous peramivir may be considered in hospitalized patients over 6 months of age. Other antiviral agents should be directed against the specific etiology if known; for example, ganciclovir and valganciclovir for CMV and HHV-6, acyclovir for herpes simplex virus, cidofovir for adenovirus and combination drug regimens for HCV and HIV.1 Enteroviruses are a leading cause of severe myocarditis in neonates. Currently, there are no approved antiviral drugs against enteroviruses, however, an early intravenous immunoglobulin (IVIG) therapy may be beneficial.11 Unfortunately, available data are derived from other clinical manifestations of enteroviral infection and there is limited evidence for direct IVIG effectiveness in myocarditis. Antiviral treatment for COVID-19 is reserved for children at highest risk of severe illness, including myocarditis. Intravenous remdesivir and orally administered paxlovide (nirmatrelvir/ritonavir) are approved for children and should be used in accordance with the current guidelines.21 In complicated courses, immunomodulatory treatment with intravenous immunoglobulin (in standard dose of 1 g/kg) and steroids should be considered.21 It is worth mentioning that after the COVID-19 infection, myocardial damage associated with immune dysregulation (pediatric inflammatory multisystem syndrome) may occur. In these cases, immunomodulatory therapy with IVIG and acetylsalicylic acid or combined with corticosteroids is the first-line treatment. In patients with pediatric inflammatory multisystem syndrome (multisystem inflammatory syndrome in children) refractory to initial treatment with IVIG and steroids, anakinra [recombinant interleukin-1 (IL-1) receptor antagonist] should be considered.22 Appropriate antimicrobial treatment is indicated in Lyme disease, tuberculosis, Mycoplasma pneumoniae and parasitic infections. Immunomodulatory Treatment Myocarditis progresses through 3 stages. The first stage involves direct injury of 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 progression of the disease to DCM due to ongoing inflammation or overwhelming injury in the acute phase, therefore, in some cases, immunomodulatory treatment may be considered. The most used immunomodulators include IVIG, corticosteroids, azathioprine and anakinra. IVIG administration may be considered as adjuvant management in acute myocarditis. Recent meta-analyses suggest that IVIG treatment improved left ventricular ejection fraction and reduced in-hospital mortality.23 High-dose steroids in conjunction with IVIG showed overall transplant-free survival of 92.5%, without reporting significant side effects.12 On the other hand, a Taiwanese registry study showed no significant effects of high-dose steroid or IVIG therapy on survival and long-term mortality.24 Further randomized multicenter studies to validate immune modulation therapy in pediatric myocarditis are needed, however due to limited incidence, varied etiology and heterogenous clinical course, they may be difficult to conduct. Anakinra is a recombinant human IL-1 receptor antagonist which neutralizes the biological activity of IL-1. Its successful use has been described in a series of case reports enhancing the recovery from both acute and chronic myocarditis.13,25 A randomized study comparing anakinra versus placebo for the treatment of acute myocarditis (ARAMIS, ClinicalTrials.gov Identifier: NCT03018834) is currently underway. Noninfectious Inflammatory Conditions as a Cause of Myocarditis Myocarditis could be a manifestation of many noninfectious inflammatory disorders including lupus erythematous, rheumatic fever, rheumatoid arthritis, ulcerative colitis, Crohn’s disease and Kawasaki disease. The underlying disorder treatment is a first-line management after excluding other potential causes of myocarditis.1,26 The special myocarditis form, often related to above mentioned inflammatory conditions, is giant cell myocarditis. It should be always suspected in patients with rapid general condition deterioration unresponsive to standard therapy and is characterized by unfavorable prognosis. Vaccines and Myocarditis Immunization against influenza or SARS-CoV-2 reduces the incidence of myocarditis caused by these pathogens. A temporal and presumed link between myocarditis and several vaccines, including smallpox, tetanus, influenza remains unproven.27 Stronger evidence exists for SARS-CoV-2 vaccines (particularly mRNA vaccines).15,26 However, myocarditis following mRNA COVID-19 (C-VAM) vaccines is a rare complication and the probability of myocarditis occurrence is up to 7 times less frequent in vaccinated than unvaccinated patients.28 Cases of C-VAM have been described, mostly in adolescents and young adult males shortly after the second mRNA type vaccine dose. The course of the disease is usually mild and self-limiting. Echocardiography shows either normal or mildly impaired left ventricular systolic function with a tendency to normalize within a few days.15,16 Supportive and symptomatic analgesic treatment with paracetamol is usually sufficient, as spontaneous recovery is the norm. Rarely, supplementary therapy with angiotensin-converting enzyme inhibitors and β-blockers and escalation treatment (as described) may be required.15,16 There is some evidence that extending the interval between SARS-CoV-2 doses to 8 weeks reduces the risk of C-VAM and should be considered especially in higher risk population (teenage boys and young men).29 There is no evidence that new SARS-CoV-2 variants are responsible for a higher incidence of myocarditis, but the number of C-VAM cases after updated vaccination’s introduction is lower.30 It should be strongly emphasized that the benefits of vaccination outweigh the risk of C-VAM in pediatric population, and vaccination should be recommended to every eligible patient. However, in patients with C-VAM history, due to the lack of strong data proving vaccination safety after C-VAM incident current guidelines generally suggest that no further COVID vaccines of any type should be administered.31 Antibiotic-associated Myocarditis Recognized rare causes of myocardial injury involve exposure and intoxication with many chemicals, including antibiotics. Based mostly on case reports, a presumed relationship between myocarditis and use of antibiotics, such as ampicillin and anti-TB drugs (rifampicin, isoniazid and streptomycin) has been rarely described.17,18 In these situations, myocardial damage may develop as a result of drug-induced excessive cell-mediated immune response, resulting in myocardium destruction.1 After excluding other etiologies, the antibiotic-associated myocarditis should be considered and immediate drug discontinuation should be the first-line treatment. CONCLUSION Pediatric myocarditis remains a challenging condition with diverse etiologies and varied clinical course. Tailored management strategies, ranging from supportive care to specific antiviral or immunosuppressive therapies are essential for improving patient outcomes. Further studies are needed to enhance the treatment of pediatric myocarditis. Key principles of myocarditis management in children are summarized in Table 2. TABLE 2. - Key Principles of Myocarditis Management in Children General care • Bed rest is mandatory for all patients.• Acute myocarditis is often a self-limiting disease and supportive treatment is sufficient in a mild course of the disease.• Recommendations for all patients with myocarditis include withdrawal from competitive sports for 3–6 mo until active inflammation subsides and myocardial injury markers normalize.• Before returning to intense physical activity thorough cardiologic evaluation should be performed. Cardiologic treatment • Early introduction of ACE-I as a prevention of myocardial fibrosis is recommended.• Beta-blockers are recommended for tachycardia and may be considered for arrhythmia treatment.• Heart failure management should be carried out in accordance with current guidelines using an ACE-I or an ARB, a mineralocorticoid receptor antagonist, and a β blocker. Therapy should be continued for 6 mo.• In advanced heart failure, phosphodiesterase-3 inhibitor (milrinone) is a first-line therapy. Catecholamines, diuretics, ventilatory and circulatory support may be necessary.• In fulminant myocarditis, ECMO, VAD or Impella pump allow for bridge to recovery or heart transplantation. Targeted care • When viral etiology is proven, targeted antiviral treatment is an option including oseltamivir for Influenza A, B, ganciclovir and valganciclovir for CMV and HHV-6, acyclovir for herpes simplex, cidofovir for adenovirus, remdesivir and paxlovide for COVID-19 and various drugs for HCV and HIV.• In the second phase of myocarditis, immunoglobulins, corticosteroids and anakinra may be beneficial.• Immunosuppressive treatment at an early stage is recommended in giant cell myocarditis and immune-mediated diseases.• COVID-19 mRNA vaccine-associated myocarditis is usually mild and self-limiting; in severe course immunomodulatory treatment may be considered. ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; ECMO, extracorporeal membrane oxygenation; VAD, ventricular assist device.