Acute rheumatic fever (ARF) is a multisystem disease resulting from an autoimmune reaction to infection with group A streptococcus. Although many parts of the body may be affected, almost all of the manifestations resolve completely. The exception is cardiac valvular damage [rheumatic heart disease (RHD)], which may persist after the other features have disappeared.
ARF and RHD are diseases of poverty. They were common in all countries until the early twentieth century, when their incidence began to decline in industrialized nations. This decline was largely attributable to improved living conditions—particularly less crowded housing and better hygiene—which resulted in reduced transmission of group A streptococci. The introduction of antibiotics and improved systems of medical care had a supplemental effect. Recurrent outbreaks of ARF began in the 1980s in the Rocky Mountain states of the United States, where elevated rates persist.
The virtual disappearance of ARF and reduction in the incidence of RHD in industrialized countries during the twentieth century unfortunately was not replicated in developing countries, where these diseases continue unabated. RHD is the most common cause of heart disease in children in developing countries and is a major cause of mortality and morbidity in adults as well. It has been estimated that between 15 and 19 million people worldwide are affected by RHD, with approximately one-quarter of a million deaths occurring each year. Some 95% of ARF cases and RHD deaths now occur in developing countries.
Although ARF and RHD are relatively common in all developing countries, they occur at particularly elevated rates in certain regions. These “hot spots” are sub-Saharan Africa, Pacific nations, Australasia, and the Indian subcontinent (Fig. 322-1). Unfortunately, most developing countries do not currently have coordinated, register-based RHD control programs, which are proven to be cost-effective in reducing the burden of RHD. Enhancing awareness of RHD and mobilizing resources for its control in developing countries is an issue requiring international attention.
Prevalence of rheumatic heart disease in children aged 5–14 years. Circles within Australia and New Zealand represent indigenous populations, and also Pacific Islanders in New Zealand. (From JR Carapetis et al: Lancet Infect Dis. Copyright 2005, with permission from Elsevier.)
ARF is mainly a disease of children aged 5–14 years. Initial episodes become less common in older adolescents and young adults and are rare in persons aged >30 years. By contrast, recurrent episodes of ARF remain relatively common in adolescents and young adults. This pattern contrasts with the prevalence of RHD, which peaks between 25 and 40 years. There is no clear gender association for ARF, but RHD more commonly affects females, sometimes up to twice as frequently as males.
Based on currently available evidence, ARF is exclusively caused by infection of the upper respiratory tract with group A streptococci (see Chap. 136). Although classically, certain M-serotypes (particularly types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29) were associated with ARF, in high-incidence regions, it is now thought that any strain of group A streptococcus has the potential to cause ARF. Potential role of skin infection and of groups C and G streptococci are currently being investigated.
Approximately 3–6% of any population may be susceptible to ARF, and this proportion does not vary dramatically between populations. Findings of familial clustering of cases and concordance in monozygotic twins—particularly for chorea—confirm that susceptibility to ARF is an inherited characteristic. Particular human leukocyte antigen (HLA) class II alleles appear to be strongly associated with susceptibility. Associations have also been described with high levels of circulating mannose-binding lectin and polymorphisms of transforming growth factor β1 gene and immunoglobulin genes. High-level expression of a particular alloantigen present on B cells, D8-17, has been found in patients with a history of ARF in many populations, with intermediate-level expression in first-degree family members, suggesting that this may be a marker of inherited susceptibility.
When a susceptible host encounters a group A streptococcus, an autoimmune reaction results, which leads to damage to human tissues as a result of cross-reactivity between epitopes on the organism and the host (Fig. 322-2). Cross-reactive epitopes are present in the streptococcal M protein and the N-acetylglucosamine of group A streptococcal carbohydrate and are immunologically similar to molecules in human myosin, tropomyosin, keratin, actin, laminin, vimentin, and N-acetylglucosamine. It is currently thought that the initial damage is due to cross-reactive antibodies attaching at the cardiac valve endothelium, allowing the entry of primed CD4+ T cells, leading to subsequent T cell-mediated inflammation.
Pathogenetic pathway for acute rheumatic fever and rheumatic heart disease.(From JR Carapetis et al: Lancet 366:155, 2005. Copyright 2005, with permission from Elsevier.)
There is a latent period of ∼3 weeks (1–5 weeks) between the precipitating group A streptococcal infection and the appearance of the clinical features of ARF. The exceptions are chorea and indolent carditis, which may follow prolonged latent periods lasting up to 6 months. Although many patients report a prior sore throat, the preceding group A streptococcal infection is commonly subclinical; in these cases it can only be confirmed using streptococcal antibody testing. The most common clinical presentation of ARF is polyarthritis and fever. Polyarthritis is present in 60–75% of cases and carditis in 50–60%. The prevalence of chorea in ARF varies substantially between populations, ranging from <2% to 30%. Erythema marginatum and subcutaneous nodules are now rare, being found in <5% of cases.
Up to 60% of patients with ARF progress to RHD. The endocardium, pericardium, or myocardium may be affected. Valvular damage is the hallmark of rheumatic carditis. ...