Case Analysis

The cause of death in this case was overwhelming viral pneumonitis and fulminant viral myocarditis, causing CHF and terminal fatal arrhythmia. The damage in the heart had been present for at least a month prior to this child's demise, as indicated by the extensive fibrosis in areas of persistent active inflammation. The signs of CHF were evident from the fluid accumulation in the pleural spaces, pericardial and abdominal cavities, and the acute and chronic dilatation of the central veins in the liver. The presence of large atypical mononuclear cells in the heart and lung, as well as the adenoviral intranuclear inclusions, confirms the viral etiology of this illness.

Myocarditis in infants and young children is almost always due to a specific viral infection of the heart, which leads to inflammatory injury and myocardial cell necrosis. In, contrast myocarditis in older immunocompetent children and adults, is frequently an immune-mediated disease. Myocarditis is usually suspected in cases of unexplained onset of CHF and arrhythmia, after a respiratory (upper respiratory infection or URI) or systemic febrile illness. The viral etiology may be suggested by epidemiologic clustering of cases during seasonal epidemics of certain viruses (enteroviruses), diagnostic serologic studies, and the application of molecular techniques, like in situ hibridization and polymerase chain reaction (PCR), to detect genomic sequences in tissue samples such as endomyocardial biopsies. Other rare causes of myocarditis include, bacterial infections of the heart, which result from direct extension to myocardial tissue with microabscesses, or from toxin-mediated injury (e.g. diphtheria). Occasionally, contiguous spread from the endocardium or pericardium can occur, most commonly from pneumonic foci.

This girl presented with fever, episodes of vomiting and respiratory distress. Her pediatrician ascribed these non-specific symptoms to a viral syndrome, and decided just to follow her clinically. This approach is fairly common in pediatric medicine. Even if a child is symptomatic, but is overall stable with adequate cardiovascular and neurologic function, he or she will be monitored over time. Still, consideration of several facts may be warranted. First, the issue of intermittent fevers may be of importance. Fever represents a non-specific host response to an on-going process, which can be significant or trivial. What define the importance of the fever are concomitant symptoms and their progression and/or resolution. In this case, if the fever had been daily or frequent, it should have prompted a more thorough physical exam and laboratory analyses to detect potentially treatable conditions. The crucial elements to evaluate include the height of the fever, associated signs and symptoms (particularly rashes, change in mental status, respiratory signs and hemodynamic stability), and response to therapy (e.g. antibiotics, antipyretic drugs).

In the beginning of the illness, her main symptom was vomiting (there is no mention of change in bowel habits, or rashes). Enteroviruses predominantly cause fever, gastrointestinal, respiratory and skin manifestations. Therefore, it is conceivable that her symptoms were due to an enteroviral infection. The turning point came when she began developing respiratory complaints, and on physical exam she had signs of pulmonary compromise characterized by coarse breath sounds and rales. Clues that this illness perhaps represented more than a self-limited viral syndrome include the progressive involvement of new organ systems. Other diagnoses to consider are progressive lung involvement such as significant pneumonia with or without effusion, diffuse interstitial lung disease, sepsis syndrome, hereditary cardiomyopathies or congenital heart disease.

The clinical history, physical examination and pathologic findings of the heart definitely excluded the possibility of a common pediatric illness of unknown etiology, Kawasaki's disease. This entity is a non-infectious, immune-mediated disorder, which afflicts infants and young children. It is a systemic vasculitis that affects the small and medium muscular arteries, resulting in fever, rash, mucositis, lymphadenopathy, and the hallmark coronary artery inflammation. Other potential fatal conditions in children, that may present subacutely, are those related to toxic ingestions or toxin-mediated illnesses. Again, in the absence of epidemiologic and clinical history, and with the strong pathologic evidence of myocarditis, it is very unlikely that there was a different cause that may have resulted in this child's death.

Even though the majority of myocarditis episodes end up being idiopathic, of those identified with a specific etiology, viruses account for a significant number of cases. Coxsackie B viruses, are small stranded RNA viruses, which have a natural affinity for the myocardium by interacting with specific receptors on the myocardial cell surface, and can be identified in 2540% of acute cases (mostly types B2-B5). The determinant for host susceptibility is the lack of serotype-specific antibodies. Neonates are particularly prone to viral myocarditis due to both Coxsackie B and ECHO (enteric cytopathogenic human orphan) viruses. Clusters of neonatal cases may occur when mothers lack specific antibodies to the prevalent strains. Affected neonates will present with feeding difficulty, listlessness, and respiratory distress. Cyanosis, fever and hepatosplenomegaly may occur in 50-75% of babies. The mortality rate may reach 75%, and is associated with multiorgan failure.

Cardiac scarring occurs over a fixed period of time, with at least 2 weeks required for collagen to deposit in the tissues. The estimation that the girl's disease had been on-going for at least a month prior to her death was predicated on the findings of organizing inflammation, necrosis, and fibrosis in the heart. Additionally, the enlargement of the heart requires weeks to develop. Thus, well before this child presented to the emergency room, she already had extensive cardiac involvement. Because it often is a silent condition, it is of no surprise that there were no specific features suggesting the diagnosis of myocarditis in this girl. The initial clinical presentation is often a vague flu-like or gastrointestinal illness. In this case, there was a respiratory infection (pneumonitis), in addition to the cardiac inflammation. By the time she was brought to the emergency room, the severity of the damage to the heart was so overwhelming, that her chances for survival were negligible. Since viral myocarditis is a generalized disease, the extent of the lesion can be extrapolated from the massive injury in the sections examined. These sections were obtained at random, and the diffuse and extensive involvement is a statistical confirmation that the remainder of the heart was equally affected.

Finally, it is likely that in our case, the initial infection was respiratory, given the typical adenoviral nuclear inclusions in the bronchial epithelium; and then the virus spread to the heart via the blood stream. Although, adenoviral myocarditis is uncommon, co-infection with other pathologic agents cannot be excluded.

Suggested Readings

1 Penninger JM, Bachmaier K. Review of microbial infections and the immune response to cardiac antigens. J Infect Dis. 2000; 181 Suppl 3:S498-504.

2 Huber SA, Gauntt CJ, Sakkinen P. Enteroviruses and myocarditis: viral pathogenesis through replication, cytokine induction, and immunopathogenicity. Adv Virus Res. 1998; 51:35-80.

3 Bowles NE, Towbin JA. Molecular aspects of myocarditis. Curr Opin Cardiol. 1998; 13:179-84.

Figure 58. Myocarditis, histologic section. Numerous inflammatory cells are present in the myocardium. Viable myocytes and striations are still present (arrow) (Hematoxylin and Eosin, 40X)

Figure 58. Myocarditis, histologic section. Numerous inflammatory cells are present in the myocardium. Viable myocytes and striations are still present (arrow) (Hematoxylin and Eosin, 40X)

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