Etiology

The epidemiology of acute rheumatic fever is identical to that of group A streptococcal upper respiratory tract infections. As is the case for streptococcal sore throat, acute rheumatic fever most often occurs in children: the peak age-related incidence is between 5 and 15 years. Most initial attacks in adults take place at the end of the second and beginning of the third decades of life. Rarely, initial attacks occur as late as the fourth decade and recurrent attacks may be seen even later; attacks have been documented in the fifth and sixth decades.

Epidemiologic risk factors classically associated with individual attacks and especially with outbreaks of acute rheumatic fever include lower standards of living, especially crowding; the disease has been more common among socially and economically disadvantaged populations. However, the outbreaks in the United States in the late 1980s and early 1990s cannot be explained entirely by these factors. The large Utah outbreak of almost 300 cases during 7 years affected patients in primarily middle-class families with ready access to medical care. Therefore, one can conclude that the organism itself as well as the degree of host/herd immunity to the prevalent serotypes in an affected community is equally important risk factors.

Studies have shown that approximately 3 percent of individuals with untreated group A streptococcal pharyngitis will develop rheumatic fever. The epidemiology of rheumatic fever is also influenced by the serotypes of group A streptococci present in a population. The concept of "rheumatogenecity" of specific strains is largely based upon epidemiologic evidence associating certain serotypes with rheumatic fever. Mucoid or highly encapsulated strains have been associated with rheumatic fever.

Pathogenesis

More than half a century ago the pioneering studies of Lancefield differentiated beta-hemolytic streptococci into several serologic groups. This ultimately led to the association of infection by the group A organism of the oropharynx (not of other sites) and the subsequent development of acute rheumatic fever. However, the mechanism(s) responsible for the development of rheumatic fever after an infection remains elusive. Historically, approaches to understanding the pathogenesis of rheumatic fever have been grouped into three major categories:

1) direct infection by the group A streptococcus;

2) a toxic effect of streptococcal extracellular products on the host tissues;

3) an abnormal or dysfunctional immune response to one or more as yet unidentified somatic or extracellular antigens produced by all (or perhaps only by some) group A streptococci.

There is insufficient evidence to support direct infection of the heart as the inciting event. Additionally, while toxins such as streptolysin O and others have been postulated to be responsible for this sequel, there is relatively little convincing evidence at the present time. Major efforts have focused on an abnormal immune response by the human host to one or more group A streptococcal antigens. The hypothesis of "antigenic mimicry" between human and bacterial antigens has been studied extensively and has concentrated on two interactions. The first is the similarity between the group-specific carbohydrate of the group A streptococcus and the glycoprotein of heart valves; the second involves the molecular similarity between either streptococcal cell membrane or streptococcal M protein and sarcolemma or other moieties of the human myocardial cell. The possibility of a predisposing genetic influence in some individuals is one of the most tantalizing of the incompletely understood factors that might contribute to the susceptibility to rheumatic fever. The precise genetic factors influencing the attack rate have never been adequately defined. Observations have been described that support the concept that this nonsuppurative sequel to a group A streptococcal infection results from an abnormal immune response by the human host. Thus differences in immune responses to streptococcal extracellular antigens have been reported, with a unique surface marker on non-T lymphocytes of rheumatic fever patients.