Pediatric Myocarditis

Myocarditis is defined by the World Health Organization/International Society and Federation of Cardiology as "an inflammatory disease of the myocardium and is diagnosed by established histological, immunological, and immunohistochemical criteria." When myocarditis is associated with cardiac dysfunction, it is termed inflammatory cardiomyopathy.¹ While myocarditis most often has an infectious etiology, other possible causes include autoimmune disease, toxins, and hypersensitivity reactions.² It is most often due to a viral infection in developed countries. In Central and South America, myocarditis is commonly caused by Trypanosoma cruzi infection.²

Myocarditis poses an interesting dilemma for the emergency physician. Classically, patients present with heart failure (HF) a few weeks after a viral illness; however, many patients do not present with the classic symptoms.² The diagnosis can be difficult secondary to a variety of presentations which can range from an asymptomatic, subclinical presentation to acute fulminant myocarditis characterized by cardiovascular collapse and even sudden death.^3,4 In addition, symptomatic patients often present with signs and symptoms that have a very broad differential diagnosis including predominantly respiratory or gastrointestinal symptoms.

Myocarditis is associated with dilated cardiomyopathy and can lead to significant morbidity and mortality.^3,4,5 Just as the clinical presentation can be quite varied, so too can the prognosis. Therefore, the emergency physician must have a high index of suspicion for this very difficult diagnosis and potentially deadly disease entity.

— Ann M. Dietrich, MD, FAAP, FACEP, Editor

Epidemiology

Myocarditis can at times be asymptomatic and has a varied presentation; consequentially, it often goes undiagnosed and its true incidence is unknown.⁶ A chart review of patients seen in a pediatric emergency department in Taiwan found that 27 of the 224,435 patients seen in the study period were diagnosed with myocarditis, making the incidence at that institution’s emergency department 1.2 cases per 10,000 visits, with the majority of those affected being male.⁷ A nationwide study by Saji et al predicted the annual incidence in Japan to be 0.24 cases per 100,000 population.⁸

A U.S. study by Ghelani et al identified 514 pediatric patients with acute myocarditis from April 2006 to March 2011 using the Pediatric Health Information System database and found a bimodal age distribution with a predominance of males (64% overall), especially in the > 12 year old age group where males accounted for 80.9%. Whites accounted for 41.4%, blacks for 22.4%, and Hispanics for 17.7% of the study population.³

During the recent influenza A/H1N1 pandemic, myocarditis was a frequent complication worldwide. Often, pediatric patients requiring admission to pediatric ICUs had associated myocarditis, which also put these children at higher risk for death.^9,10,11,12

Etiology

Although there are a multitude of infectious and noninfectious causes of myocarditis, the most common etiology in the United States is viral.⁶ Common viral pathogens associated with myocarditis include enteroviruses such as coxsackievirus, adenovirus, parvovirus B19, human herpes virus 6, Epstein-Barr virus, hepatitis C virus, and influenza.^4,13,14 There has been a trend over the past 2 decades from enteroviruses and adenoviruses as the primary cause to parvovirus and human herpesvirus 6 (see Figure 1).² Additionally, cytomegalovirus, measles, mumps, herpes zoster, and mycoplasma pneumonia all have been identified as less common infectious etiologies of myocarditis.⁸ There are several less common non-infectious etiologies of myocarditis as well including autoimmune diseases, drug reactions, and hypersensitivity reactions. Table 1 reviews the various infectious and non-infectious etiologies of myocarditis.

Pathophysiology

The pathogenesis of myocarditis is poorly understood due to the complex nature of the disease and its various etiologies (see Figure 2). Most knowledge is based on animal models of coxsackie and adenoviral infections.¹⁸ Viral myocarditis can be described in three distinct phases: the viral phase, the autoimmune phase, and dilated cardiomyopathy.¹⁵

Phase 1 – The Viral Phase. Phase 1 commences with the entry of the virus. Coxsackievirus and adenovirus enter the cardiac myocyte via a common receptor, the coxsackie adenoviral receptor (CAR).¹⁶ Lysis of the cardiomyocyte then triggers the innate immune response.¹⁷ Cardiac myocyte injury is mediated by both the direct viral effect as well as the immune response.¹⁸ Most patients recover from phase 1 without entering the second phase.¹⁷ However, if the immune system does not downregulate once viral proliferation is controlled, phase 2, autoimmune disease, results.¹⁵

Phase 2 – The Autoimmune Phase. If the immune system is not down regulated, the host’s tissue is targeted by T cells, cytokine activation, and cross-reacting antibodies.¹⁵ This is the autoimmune phase. If the virus is not cleared or the inflammatory process continues, the patient may progress to phase 3.¹⁷

Phase 3 – Dilated Cardiomyopathy. Phase 3 is characterized by the development of dilated cardiomyopathy (DCM). This can occur in patients in whom the virus is not cleared or the inflammatory process is not appropriately down regulated. Persistence of the inflammatory process can lead to remodeling and subsequent development of DCM.¹⁹

Clinical Features

History. Myocarditis can be difficult to diagnose because patients present with a wide variety of symptoms and can have very non-specific complaints. Children can present with predominantly respiratory or gastrointestinal symptoms and may have no cardiac complaints. Older children are more likely than younger children to present with cardiac symptoms.⁴ See Table 2 for signs and symptoms of myocarditis.

Physical exam. Physical exam findings consistent with myocarditis are also varied. Fever, tachycardia, bradycardia, hypotension, tachypnea, respiratory distress, lethargy, gallop, murmur, hepatomegaly, and poor perfusion are physical exam findings that may be present in patients with myocarditis, all of which are non-specific. Infants often present with hypoxia (SpO2 < 95%) and poor perfusion.⁴ Children aged 1-5 years are often febrile and tachycardic; hepatomegaly is present in more than half of this age group. Poor perfusion and lethargy are again common in these children. Hypotension, lethargy, and poor perfusion are the most common exam findings in children over the age of 6 years. Twenty-one percent of this age group had a gallop or murmur and 42% had hepatomegaly.⁴ Table 3 reviews physical exam findings seen in myocarditis.

The Canadian Cardiovascular Society (CCS) released recommendations based on a consensus panel regarding commonly seen symptoms in pediatric myocarditis. According to the CCS, "myocarditis should always be considered in the differential diagnosis of children who present with a viral prodrome and nonspecific respiratory or abdominal symptoms associated with tachycardia, hypotension, or cardiac rhythm abnormalities, even in the absence of cardiomegaly on chest x-ray."²⁰

Diagnostic Evaluation

Electrocardiogram (ECG). An electrocardiogram should be performed in all patients with clinically suspected myocarditis. There is no single finding that is specific for myocarditis, however, an abnormality on ECG is frequently found.

Common abnormalities seen on ECG include sinus tachycardia, heart block, ST or T-wave abnormalities, axis deviation, decreased voltage, and arrhythmias including ventricular tachycardia.^4,21,22 Transplant-free survival is associated with the absence of ST changes.¹³ See Table 4 for ECG changes seen in myocarditis and Figure 3 for ECG findings in myocarditis.

The European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases recommends a 12-lead ECG be performed for all patients with suspected myocarditis.²³

20 The ESC provides no specific recommendation on the use of IVIG due to lack of multicenter randomized studies.²³

Immunoadsorption. While not universally available, the use of immunoadsorption in adult patients with inflammatory cardiomyopathy has been shown to improve left ventricular systolic function and decrease left ventricular end-diastolic diameter at 6 months.³⁴ The ESC gives no recommendation on the use of immunoadsorption due to lack of evidence.²³

Immunosuppression. Immuno-
suppression in the treatment of myocarditis is, in general, controversial. However, immunosuppression for the treatment of specific entities, including giant cell and eosinophilic myocarditis, has been well established.^2,17

Studies on immunosuppression for the treatment of myocarditis have included prednisone either alone or in combination with azathioprine or cyclosporine.^23,35 Favorable response has been seen primarily in virus-negative and giant cell myocarditis.²³

A recent meta-analysis by Lu et al examined the role of immunosuppressive treatment for myocarditis in adults and children and included nine articles (609 patients; 342 treated with immunosuppression and 267 treated conventionally). The group receiving immunosuppressive treatments had improved left ventricular ejection fraction (LVEF) at short- and long-term follow-up and decreased left ventricular end diastolic diameter at short-term follow-up. There was no difference in mortality or need for transplantation. The authors concluded that while immunosuppressive therapy may be beneficial, more large randomized controlled trials (RCTs) are needed.³⁵

A recent Cochrane systematic review by Chen et al looked more specifically at the use of corticosteroids for viral myocarditis and included eight RCTs and 719 participants. There was no significant difference in mortality between the steroid and control group. LVEF was improved in the short-term in the corticosteroid group. The authors concluded that corticosteroids do not reduce mortality, but they may improve cardiac function. They note, however, that this finding is questionable due to the size and quality of the trials and large-scale RCTs are needed.³⁶

Even without compelling evidence to support the use of corticosteroids for the treatment of myocarditis in children, administration of steroids is not uncommon. Some studies show associated increased mortality or transplantation and no change in survival.^3,8

Recommendations regarding the use of steroids for myocarditis have been set forth by the CCS, the Heart Failure Society of America (HFSA), as well as the ESC. Corticosteroids as a routine treatment for myocarditis are not recommended by the CCS or the HFSA.^20,27 The ESC has set forth more specific recommendations as shown in Table 8.²³

Mechanical ventilation and circulatory support and transplantation. Assistance of the pediatric patient’s respiratory system and mechanical circulatory support are commonly required in pediatric patients with myocarditis. Extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs) have significant risks of complication, but can be life-saving and are often used as a bridge to transplantation or recovery. ECMO-associated complications include bleeding, limb ischemia, neurologic injury, multi-system organ failure, renal failure, sepsis, and circuit complications.²² ECMO use in patients with acute fulminate myocarditis and hemodynamic collapse is the first-line mechanical circulatory support system due to ease and rapidity of set up, especially during CPR, when compared with VADs.³⁷

The CCS recommends "for fulminant myocarditis, mechanical circulatory support should be considered. Invasive therapies are considered acceptable considering the prospect of spontaneous recovery."²⁰ The ESC recommendations state: "In patients with hemodynamic instability, a mechanical cardio-pulmonary assist device may be needed as a bridge to recovery or to heart transplantation" and "cardiac transplantation should be deferred in the acute phase, because recovery may occur, but can be considered for hemodynamically unstable myocarditis patients, including those with giant cell myocarditis, if optimal pharmacological support and mechanical assistance cannot stabilize the patient."²³

Disposition. Due to the complicated nature of myocarditis and significant risk of clinical deterioration, patients often require admission to an intensive care unit or unit with capabilities to monitor patients for dysrhythmias and hemodynamic instability.^3,20 Additionally, hospitalization at a facility with the ability for cardiac catheterization and EMB should be considered.²³

Additional Aspects

Misdiagnosis. Because of the varied presentation of myocarditis, the potential for misdiagnosis is high. Most commonly, myocarditis is misdiagnosed as a respiratory tract infection; sepsis and seizure are other common misdiagnoses.⁴

Outcome/Prognosis. Although there is potential for complete recovery from myocarditis, the diagnosis is associated with high rates of transplantation and mortality, especially in cases caused by parvovirus B19 and those that progress to fulminant myocarditis.^3,8,13,22 The overall mortality of pediatric myocarditis is 7.3%.³ The rate of death or transplantation is higher for children younger than age 12 years as compared to older children.³ Children with parvovirus B19 myocarditis have a worse prognosis. The rate of transplant-free survival for these children is only 32%.¹³ In a study of 20 patients with acute fulminant myocarditis, the survival rate was 85%; one of the survivors in this study underwent transplantation.²²

Sudden Death. Myocarditis can present as sudden death in childhood. Frequently diagnosed at autopsy, myocarditis is an etiology of sudden unexpected cardiac death and sudden unexpected death due to an infectious disease.^38,39 Myocarditis has also been identified as an etiology of sudden death in sports-related deaths.⁴⁰

Follow-up. Patients with myocarditis may fully or partially recover. Relapses may occur. In those patients whose disease does not resolve, dilated cardiomyopathy may develop. Patients with myocarditis require long-term follow-up with clinical reassessment, ECGs, and repeat echocardiograms.²³ Patients with suspected myocarditis with mild symptoms should be followed closely as well due to potential for progression to severe illness.²⁰

Summary

Myocarditis serves as a diagnostic challenge for the emergency physician in the pediatric population. Given the varied nature of presentation, the breadth of the clinical spectrum, and the limitations in treatment options, emergency physicians must keep a high index of suspicion for myocarditis. Figure 5 reviews the basics in diagnosis and treatment of myocarditis in children.⁴¹

References

1. Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996;93:841-842.

2. Canter CE, Simpson KP. Diagnosis and treatment of myocarditis in children in the current era. Circulation 2014;129:115-128.

3. Ghelani SJ, Spaeder MC, Pastor W, et al. Demographics, trends, and outcomes in pediatric acute myocarditis in the United States, 2006 to 2011. Circ Cardiovasc Qual Outcomes 2012;5:622-627.

4. Shu-Ling C, Bautista D, Kit CC, Su-Yin AA. Diagnostic evaluation of pediatric myocarditis in the emergency department: A 10-year case series in the Asian population. Pediatr Emerg Care 2013;29:346-351.

5. Camargo PR, Okay TS, Yamamoto L, et al. Myocarditis in children and detection of viruses in myocardial tissue: implications for immunosuppressive therapy. Int J Cardiol 2011;148:204-208.

6. Vallejo JG. Myocarditis. In: Cherry JD, et al, eds. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases. 7th ed. Philadelphia: Elsevier Saunders; 2014:381-400.

7. Hsiao HJ, Hsia SH, Wu CT, et al. Clinical presentation of pediatric myocarditis in Taiwan. Pediatr Neonatol 2011;52:135-139.

8. Saji T, Matsuura H, Hasegawa K, et al. Comparison of the clinical presentation, treatment, and outcome of fulminant and acute myocarditis in children. Circ J 2012;76:1222-1228.

9. Tokuhira N, Shime N, Inoue M, et al. Mechanically ventilated children with 2009 pandemic influenza A/H1N1: Results from the National Pediatric Intensive Care Registry in Japan. Pediatr Crit Care Med 2012;13:e294-298.

10. Randolph AG, Vaughn F, Sullivan R, et al. Critically ill children during the 2009-2010 influenza pandemic in the United States. Pediatrics 2011;128:e1450-1458.

11. Altmann M, Fiebig L, Buda S, et al. Unchanged severity of influenza A(H1N1)pdm09 infection in children during first postpandemic season. Emerg Infect Dis 2012;18:1755-1762.

12. Kuchar E, Nitsch-Osuch A, Karpinska T, et al. Pandemic influenza in the 2009/2010 season in central Poland: The surveillance study of laboratory confirmed cases. Respir Physiol Neurobiol 2013;187:94-98.

13. Molina KM, Garcia X, Denfield SW, et al. Parvovirus B19 myocarditis causes significant morbidity and mortality in children. Pediatr Cardiol 2013;34:390-397.

14. Schultz JC, Hilliard AA, Cooper LT Jr, Rihal CS. Diagnosis and treatment of viral myocarditis. Mayo Clin Proc 2009;84:1001-1009.

15. Liu PP, Mason JW. Advances in the understanding of myocarditis. Circulation 2001;104:1076-1082.

16. Bergelson JM, Cunningham JA, Droguett G, et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 1997;275:1320-1323.

17. Shauer A, Gotsman I, Keren A, et al. Acute viral myocarditis: current concepts in diagnosis and treatment. Isr Med Assoc J 2013;15:180-185.

18. Schultheiss HP, Kühl U, Cooper LT. The management of myocarditis. Eur Heart J 2011;32:2616-2625.

19. Sagar S, Liu PP, Cooper LT Jr. Myocarditis. Lancet 2012;379:738-747.

20. Kantor PF, Lougheed J, Dancea A, et al. Presentation, diagnosis, and medical management of heart failure in children: Canadian Cardiovascular Society guidelines. Can J Cardiol 2013;29:1535-1552.

21. Eisenberg MA, Green-Hopkins I, Alexander ME, Chiang VW. Cardiac troponin T as a screening test for myocarditis in children. Pediatr Emerg Care 2012;28:1173-1178.

22. Teele SA, Allan CK, Laussen PC, et al. Management and outcomes in pediatric patients presenting with acute fulminant myocarditis. J Pediatr 2011;158:638-643.

23. Caforio AL, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34:2636-2648.

24. Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol 2012;59:779-792.

25. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: A JACC white paper. J Am Coll Cardiol 2009;53:1475-1487.

26. Ziólkowska L, Kawalec W, Biernatowicz M, et al. The usefulness of scintigraphy with (99m)Tc-anti-granulocyte antibody for diagnosis and follow-up in children with myocarditis. Kardiol Pol 2012;70:1243-1249.

27. Lindenfeld J, Albert NM, Boehmer JP, et al. Executive Summary: HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail 2010;16:e1-194.

28. Cooper LT, Baughman K, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: A scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. J Am Coll Cardiol 2007;50:1914-1931.

29. Maron BJ, Ackerman MJ, Nishimura RA, et al. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol 2005;45:1340-1345.

30. Kühl U, Lassner D, von Schlippenbach J, et al. Interferon-beta improves survival in enterovirus-associated cardiomyopathy. J Am Coll Cardiol 2012;60:1295-1296.

31. Drucker NA, Colan SD, Lewis AB, et al. Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation 1994;89:252-257.

32. Klugman D, Berger JT, Sable CA, et al. Pediatric patients hospitalized with myocarditis: A multiinstitutional analysis. Pediatr Cardiol 2010;31:222-228.

33. Foerster SR, Canter CE, Cinar A, et al. Ventricular remodeling and survival are more favorable for myocarditis than for idiopathic dilated cardiomyopathy in childhood. An outcomes study from the Pediatric Cardiomyopathy Registry. Circ Heart Fail 2010;3:689-697.

34. Bulut D, Scheeler M, Wichmann T, et al. Effect of protein A immunoadsorption on T cell activation in patients with inflammatory dilated cardiomyopathy. Clin Res Cardiol 2010;99:633-638.

35. Lu C, Qin F, Yan Y, et al. Immunosuppressive treatment for myocarditis: A meta-analysis of randomized controlled trials. J Cardiovasc Med (Hagerstown) 2014; Jul 4 [Epub ahead of print].

36. Chen HS, Wang W, Wu SN, Liu JP. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev 2013;10:CD004471.

37. Hsu KH, Chi NH, Yu HY, et al. Extracorporeal membranous oxygenation support for acute fulminant myocarditis: Analysis of a single center’s experience. Eur J Cardiothorac Surg 2011;40:682-688.

38. Ilina MV, Kepron CA, Taylor GP, et al. Undiagnosed heart disease leading to sudden unexpected death in childhood: A retrospective study. Pediatrics 2011;128:e513-520.

39. Morentin B, Suárez-Mier MP, Aguilera B, et al. Clinicopathological features of sudden unexpected infectious death: Population-based study in children and young adults. Forensic Sci Int 2012;220:80-84.

40. Suárez-Mier MP, Aguilera B, Mosquera RM, Sánchez-de-León MS. Pathology of sudden death during recreational sports in Spain. Forensic Sci Int 2013;226:188-196.

41. Das BB. Role of endomyocardial biopsy for children presenting with acute systolic heart failure. Pediatr Cardiol 2014;35:191-196.