eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology

Myocarditis, Viral

Author: Edwin Rodriguez-Cruz, MD, Assistant Professor, Department of Pediatrics, San Juan Bautista Medical School and Medical Center; Consulting Interventional/Clinical Pediatric Cardiologist, Department of Prediatrics, Hospital El Maestro and San Juan Bautista Medical Center; Consulting Interventional/Clinical Pediatric Cardiologist, Department of Cardiology, Cardiovascular Center of Puerto Rico and the Caribbean and Veterans Affairs Hospital and Medical Center of Puerto Rico
Coauthor(s): Robert D Ross, MD, Co-Director of Pediatric Cardiology Fellowship Program, Department of Pediatrics, Division of Pediatric Cardiology, Professor, Children's Hospital of Michigan and Wayne State University
Contributor Information and Disclosures

Updated: Oct 9, 2008

Introduction

Background

Myocarditis is an inflammatory disorder of the myocardium with necrosis of the myocytes and associated inflammatory infiltrate.¹ It is usually caused by a viral infection, particularly adenovirus and enterovirus infections (eg, coxsackievirus), although many infectious organisms commonly seen in infants and children have been implicated. Occasionally, myocarditis may be a manifestation of drug hypersensitivity or toxicity. 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):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.

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 arterial pressures, resulting in increasing hydrostatic forces. These increased forces lead to both pulmonary edema and congestive heart failure. Without treatment, this process may progress to end-stage cardiac failure and death.

Frequency

International

Myocarditis is a rare disease. The World Health Organization reports that 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.

Mortality/Morbidity

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%). Complete recovery of ventricular function has been reported in as many as 50% of patients. Some patients develop chronic myocarditis (ongoing or resolving), dilated cardiomyopathy, or both and may eventually require cardiac transplantation.

Race

No racial predilection is observed.

Sex

No sex predilection is observed in humans, 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.

Age

No age predilection is noted. Younger patients, especially newborns and infants, and immunocompromised patients may have increased susceptibility to myocarditis.

Clinical

History

• Clinical presentation widely varies. In mild forms, few or no symptoms are noted. In severe cases, patients may present with acute cardiac decompensation and progress to death.
  • Heart failure: This is the most common presenting picture in all ages. The condition of patients who present with heart failure may rapidly deteriorate even with supportive care. Neonates and young children have higher mortality rates than older patients. Rapid supportive care with blood pressure support, afterload reduction, and control of arrhythmia may prevent early death.
  • Chest pain: Although rare in young children, this may be the initial presentation for older children, adolescents, and adults. Chest pain may be due to myocardial ischemia or concurrent pericarditis.
  • Arrhythmia: Patients can present with any type of dysrhythmia, including atrioventricular conduction disturbances. Sinus tachycardia is typical and the rate is faster than expected for the degree of fever present, which is typically low-grade. Junctional tachycardia is also seen and can be difficult to control medically.
  • Dilated cardiomyopathy: The debate continues over whether myocarditis progresses to dilated cardiomyopathy. Many investigators believe that dilated cardiomyopathy is a direct result of a previously burned-out myocarditis episode.
• Initial symptoms in infants include the following:
  • Irritability
  • Lethargy
  • Periodic episodes of pallor
  • Fever
  • Hypothermia
  • Tachypnea
  • Anorexia
  • Failure to thrive
• Older children present with similar symptoms and may experience lack of energy and general malaise.
• Parents may refer to a recent, nonspecific, flulike illness, GI symptoms, poor feeding, or rapid breathing.

Physical

Signs of diminished cardiac output, such as tachycardia, weak pulse, cool extremities, decreased capillary refill, and pale or mottled skin may be present. Heart sounds may be muffled, especially in the presence of pericarditis. An S₃ may be present, and a heart murmur caused by atrioventricular valve regurgitation may be heard. Hepatomegaly may be present in younger children. Rales may be heard in older children. Jugular venous distention and edema of the lower extremities may be present.

• Neonates
  • Neonates may seem irritable, be in respiratory distress, and exhibit signs of sepsis.
  • Somnolence, hypotonia, and seizures can be associated if the CNS is involved.
  • Hypothermia or hyperthermia, oliguria, elevated liver enzymes and elevated BUN and creatinine levels caused by direct viral damage, low cardiac output, or both may be present.
• Infants
  • Signs include failure to thrive, anorexia, tachypnea, tachycardia, wheezing, and diaphoresis with feeding.
  • In severe cases, low cardiac output may progress to acidosis and death.
  • End-organ damage may develop because of direct viral infestation or because of low cardiac output.
  • CNS involvement may also develop.
• Adolescents
  • Presentation may be similar to that of younger children but with a more prominent decrease in exercise tolerance, lack of energy, malaise, chest pain, low-grade fever, arrhythmia, and cough.
  • End-organ damage and low cardiac output may be present.

Causes

• Infecting organisms
  • 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) for the diagnosis, parvovirus B19 and human herpesvirus-6 are the most frequent pathogens in patients with acute myocarditis.³
  • 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
    • Influenza and parainfluenza
    • Measles
    • Mumps, associated with endocardial fibroelastosis (EFE)
    • Parvovirus B19
    • 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 B3.⁴ 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 clear the virus from the system.
  • NK cells also induce 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 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.
  • Enzymatic cleavage by viral proteins of cytoskeletal proteins appears to play a role in development of dilated cardiomyopathy.
  • Apoptosis appears to play a role in the 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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