Pediatric Viral Myocarditis

Updated: Aug 26, 2015
  • Author: Edwin Rodriguez-Cruz, MD; Chief Editor: Howard S Weber, MD, FSCAI  more...
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Overview

Background

Myocarditis, a disease of adult and pediatric patients, is an inflammatory disorder of the myocardium that is typically caused by a viral infection. Necrosis of the myocytes and associated inflammatory infiltrate are seen in this disorder. (See Etiology.) [1]

Myocarditis particularly arises from adenovirus and enterovirus infections (eg, coxsackievirus), although many infectious organisms commonly seen in infants and children have been implicated in the disease. Occasionally, myocarditis may be a manifestation of drug hypersensitivity or toxicity. (See Etiology.)

Although the use of myocardial biopsy is debated, suspected myocarditis can be classified into the following 3 types based on pathologic findings as defined in the Dallas Criteria (1987) (See Workup.) [2] :

  • Active myocarditis - Characterized by abundant inflammatory cells and myocardial necrosis
  • Borderline myocarditis - Characterized by an inflammatory response that is too sparse for this type to be labeled as active myocarditis; degeneration of myocytes not demonstrated with light microscopy
  • Nonmyocarditis

If an active or borderline inflammatory process is found, follow-up biopsy findings can be subclassified into ongoing, resolving, or resolved myocarditis. (See Workup and Treatment.)

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Pathophysiology

Myocarditis generally results in a decrease in myocardial function, with concomitant enlargement of the heart and an increase in the end-diastolic volume caused by increased preload. Normally, the heart compensates for dilation with an increase in contractility (Starling law), but because of inflammation and muscle damage, a heart affected with myocarditis is unable to respond to the increase in volume.

In addition, inflammatory mediators, such as cytokines and adhesion molecules, as well as apoptotic mechanisms, are activated. The progressive increase in left ventricular end-diastolic volume increases left atrial, pulmonary venous, and pulmonary arterial pressures, resulting in increasing hydrostatic forces. These increased forces lead to pulmonary edema and congestive heart failure. Without treatment, this process may progress to end-stage cardiac failure and death.

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Etiology

Adenovirus and Ebstein-Barr virus have been considered the most common viruses that cause myocarditis. However, studies have found that, using polymerase chain reaction (PCR) assay for the diagnosis, parvovirus B19 and human herpesvirus 6 are the most frequent pathogens in patients with acute myocarditis. [3, 4, 5]

Infecting organisms include the following:

  • Coxsackievirus types A and B (especially type B)
  • Adenovirus (most commonly types 2 and 5)
  • Cytomegalovirus
  • Echovirus
  • Epstein-Barr virus
  • Hepatitis C virus
  • Herpes virus
  • Human immunodeficiency virus (HIV)
  • Influenza and parainfluenza [6]
  • Measles
  • Mumps, associated with endocardial fibroelastosis (EFE)
  • Parvovirus B19 [5]
  • Poliomyelitis virus
  • Rubella
  • Varicella

Murine model

The coxsackievirus and adenovirus receptor acts as the receptor for the 4 most common viruses that cause human myocarditis: type C (type 2 and type 5) adenovirus and coxsackievirus B3 and B4. Coxsackievirus B serotypes 1-6 have been associated with human myocarditis, but the most serious cases have been attributed to types 3 and 4.

In 1973, Lerner and Wilson developed an animal model of myocarditis using mice inoculated with coxsackievirus B3. [7] This model was characterized by an early and a late phase. Following inoculation of the mice with the virus, initial replication of the virus occurred, with maximum replication within 3-5 days. By day 5, focal myocyte necrosis was evident. On day 7, most mice showed no further inflammation, and no organisms could be recovered; however, some mice showed ongoing, worsening inflammation similar to that seen in humans.

The primary response to the early phase of viral infection is the release of natural killer (NK) cells, which lyse infected myocytes. This helps to clear the virus from the system.

NK cells also induce the expression of major histocompatibility complex antigens on myocytes by releasing cytokines, which prepare the NK cells to interact with T lymphocytes. Animal models depleted of NK cells develop a more severe form of myocarditis.

The late phase, or second wave of T lymphocytes (CD4, CD8), begins approximately 1 week after the mouse has been inoculated with the virus. T lymphocytes can injure cells in the following 3 ways:

  • Stimulation of cytotoxic T cells
  • Production of antibody and antibody-dependent myotoxicity
  • Direct antibody and complement formation

These ongoing processes are considered to be genetically mediated autoimmune processes. Two different strains of cytolytic T cells have been recognized; one strain attacks virus-infected myocytes and the other strain attacks uninfected cells.

Apoptosis, as well as enzymatic cleavage by viral proteins of cytoskeletal proteins, appears to play a role in development of dilated cardiomyopathy.

Various kinds of autoantibodies have been found in as many as 60% of patients with myocarditis. These include complement-fixing antimyolemmal antibodies, complement-fixing antisarcolemmal antibodies, antimyosin heavy chain antibodies, and anti–alpha myosin antibodies. Although their role in the disease is not completely understood, their presence may serve as a marker for diagnosing myocarditis in the future.

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Epidemiology

Myocarditis is a rare disease. The World Health Organization (WHO) reports that the incidence of cardiovascular involvement after enteroviral infection is 1-4%, depending on the causative organism. Incidence widely varies among countries and is related to hygiene and socioeconomic conditions. Availability of medical services and immunizations also affect incidence. Occasional epidemics of viral infections have been reported with an associated higher incidence of myocarditis. Enteroviruses (eg, coxsackievirus, echovirus) and adenoviruses, particularly types 2 and 5, are the most commonly involved organisms.

No sex predilection is observed in humans in viral myocarditis, but some research in laboratory animals suggests that the disease may be more aggressive in males than in females. Certain strains of female mice had a reduced inflammatory process when treated with estradiol. In other studies, testosterone appeared to increase cytolytic activity of T lymphocytes in male mice.

No age predilection is noted in viral myocarditis. However, younger patients, especially newborns and infants, as well as immunocompromised patients, may have increased susceptibility to myocarditis.

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Prognosis

Studies give a wide spectrum of mortality and morbidity statistics. With suspected coxsackievirus B, the mortality rate is higher in newborns (75%) than in older infants and children (10-25%). [8]

Complete recovery of ventricular function has been reported in as many as 50% of patients. Some patients develop chronic myocarditis (ongoing or resolving), and an association has been suggested between myocarditis and the development of dilated cardiomyopathy. Those who develop dilated cardiomyopathy may require a heart transplant.

Viral myocarditis may be a fatal disease during pregnancy; however, pregnant women are not at a higher risk of developing viral myocarditis compared with the general population.

Complications

Complications of myocarditis may include the following:

  • Arrhythmia
  • Congestive heart failure
  • Thromboembolism
  • Further decrease in ventricular function
  • Dilated cardiomyopathy
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