INTRODUCTION — The potential complications of group A Streptococcus (GAS) pharyngeal infection include both suppurative (eg, peritonsillar abscess, otitis media, sinusitis) and inflammatory, nonsuppurative conditions. Acute rheumatic fever (ARF) is one of the nonsuppurative complications (others include scarlet fever and acute glomerulonephritis [AGN]). There is a latent period of two to three weeks following the initial pharyngitis before the first signs or symptoms of ARF appear [1]. The disease presents with various manifestations that may include arthritis or arthralgia, carditis, chorea, subcutaneous nodules, and erythema marginatum.
The epidemiology and pathogenesis of ARF are reviewed here. The clinical manifestations, diagnosis, treatment, and prevention of this disorder are discussed separately. (See "Acute rheumatic fever: Clinical manifestations and diagnosis" and "Acute rheumatic fever: Treatment and prevention".)
Other complications of streptococcal tonsillopharyngitis are also discussed separately. (See "Complications of streptococcal tonsillopharyngitis".)
EPIDEMIOLOGY — Rheumatic fever and rheumatic heart disease are diseases of poverty and economic disadvantage. In developing areas of the world, severe disease caused by group A Streptococcus (GAS; eg, ARF, rheumatic heart disease, glomerulonephritis, and invasive infections) is estimated to affect over 33 million people [2] and is the leading cause of cardiovascular death during the first five decades of life [3]. ARF can occur at any age, although most cases occur in children 5 to 15 years of age [4-6]. Worldwide, based upon conservative estimates, there are approximately 470,000 new cases of ARF and 275,000 deaths attributable to rheumatic heart disease each year [2,3,7,8]. Most cases occur in low- and middle-income countries and among Indigenous groups [9]. Regions with the highest rates are likely to have the least accurate data with substantial underreporting.
The mean incidence of ARF is 19 per 100,000 school-aged children worldwide [10], but it is lower (≤2 cases per 100,000 school-aged children) in the United States and other developed countries [11,12]. In many low- and middle-income countries and in certain Indigenous populations, such as those in Australia and New Zealand, the incidence of ARF is substantially higher, with some of the highest rates reported in Indigenous Australians at 153 to 380 cases per 100,000 children aged 5 to 14 years [5].
The higher incidence in developing countries is primarily explained by environmental factors, especially household overcrowding, which favors increased transmission of GAS [13], and in smaller part by routine use of antibiotics for acute pharyngitis. From time to time, localized outbreaks of ARF occur [14-19]. These may be associated with specific strains of GAS, though this alone cannot explain overall variations in the incidence of rheumatic fever [20]. (See "Evaluation of acute pharyngitis in adults" and "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis".)
Up to 3 percent of episodes of untreated acute streptococcal pharyngitis were followed by ARF during epidemics in the mid-1900s. In contrast, the incidence of ARF is substantially less (approximately 1 percent) during times of endemic infections [21].
PATHOGENESIS — The pathogenic mechanisms that lead to the development of ARF remain incompletely understood. Streptococcal pharyngeal infection is clearly required, and genetic susceptibility may be present. Within this framework, molecular mimicry is thought to play an important role in the initiation of the tissue injury.
Following group A Streptococcus (GAS) pharyngeal infection, activation of the innate immune system leads to GAS antigen presentation to T cells (figure 1). B and T cells respond through production of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody and activation of CD4+ T cells. In susceptible individuals, there is a cross-reactive immune response thought to be mediated by molecular mimicry that involves both humoral and cellular components of the adaptive immune system. This cross-reactive response results in the clinical features of rheumatic fever including transient arthritis due to the formation of immune complexes, chorea due to binding of antibody to basal ganglia, and carditis due to antibody binding and infiltration of T cells. Studies of the pathogenesis of ARF have been constrained by the lack of a suitable animal model, although a Lewis rat model of valvulitis and chorea has been used for some time [22,23].
Role of Streptococcus pyogenes — Significant epidemiologic evidence indirectly implicates GAS in the initiation of disease, although evidence for the direct involvement of GAS in the affected tissues of patients with ARF is lacking:
●Outbreaks of ARF closely follow epidemics of streptococcal pharyngitis or scarlet fever with associated pharyngitis [24,25].
●Adequate treatment of a documented streptococcal pharyngitis reduces the incidence of subsequent ARF by nearly 70 percent [26,27].
●Appropriate antimicrobial prophylaxis prevents the recurrence of disease in patients who have had ARF [28-30].
●Most patients with ARF have elevated antibody titers to at least one of three antistreptococcal antigens (streptolysin "O," hyaluronidase, and streptokinase), whether or not they recall an antecedent sore throat [31].
Bacterial strain specificity — Bacterial genetic factors may be an important determinant of the site of GAS infection. There are five chromosome patterns of emm genes, labeled A to E, that code for M and M-like cell surface virulence proteins. GAS fall into two main classes based upon differences in the C repeat regions of the M protein [32]. Pharyngeal strains typically have patterns A to C, whereas almost all impetigo strains show D and E patterns [33]. (See "Group A streptococcus: Virulence factors and pathogenic mechanisms", section on 'M and M-like proteins' and "Group A streptococcus: Virulence factors and pathogenic mechanisms", section on 'Ig-binding M-like proteins'.)
Certain emm types (types 3, 5, 6, 14, 18, 19, 24, and 29), all belonging to pattern A to C, were implicated in outbreaks of rheumatic fever in the United States in the 1960s and have been termed "rheumatogenic" strains of GAS [14,28,34,35]. The decrease in the incidence of ARF in the US from the 1960s to the present correlated with the replacement of rheumatogenic types by nonrheumatogenic types. However, the prevalence of rheumatogenic strains decreased two- to fivefold, whereas the reduction in the incidence of ARF over the same period was ≥20-fold [36]. Thus, a shift in the prevalence of so-called rheumatogenic emm types does not appear to fully explain the decrease in ARF.
Other data suggest that there are no specific rheumatogenic strains [37]. Several different M serotypes were isolated from patients seen during a mid-1980s outbreak of ARF in Utah [38]. When data outside the continental US are considered, classic rheumatogenic strains are less frequently observed. For example, in a study in Hawaii, 8 of 63 patients with ARF had GAS isolated on throat swab at presentation (emm types 65/69, 71, 92, 93, 98, 103, and 122); none of these emm types are classically associated with ARF, and all belong to emm pattern D or E [39]. Similar data are available from Ethiopia and India [40-42].
Importance of pharyngitis — Streptococcal pharyngitis is the only streptococcal infection that is clearly associated with ARF, although streptococcal pyoderma appears capable of triggering the condition in tropical areas [37]. Streptococcal skin infections (such as impetigo or pyoderma) have not been proven to lead to ARF. In addition, viral pharyngitis and pharyngitis caused by other bacteria do not result in ARF. A few theories have tried to explain why ARF is only associated with streptococcal pharyngitis, but the exact explanation remains obscure. The pharyngeal site of infection, with its large repository of lymphoid tissue, may be important in the initiation of the abnormal host response to those antigens cross-reactive with target organs.
There are many documented outbreaks of impetigo that caused glomerulonephritis but almost never caused ARF [43,44]. In addition, a study of patients in Trinidad with ARF or acute glomerulonephritis (AGN) diagnosed during an outbreak of scabies and secondary impetigo found that the streptococcal strains colonizing the skin in patients with impetigo were different from those associated with ARF [44]. The presence of impetigo was associated with AGN but did not influence the incidence of ARF. Impetigo strains do colonize the pharynx. However, they do not appear to elicit as strong an immunologic response to the M protein moiety as the pharyngeal strains [45,46]. This observation may prove to be an important factor, especially in light of the known cross-reaction between various streptococcal structures and mammalian proteins.
Challenging this theory is the fact that rates of ARF are high in Aboriginal Australian and in Pacific Island populations, but pharyngeal carriage of GAS and symptomatic GAS tonsillopharyngitis are uncommon [47-53]. Group G and group C streptococci have been identified frequently in the throat but less so in the pyoderma lesions of Australian Aboriginals and Pacific Islanders [52]. Such findings have led to the hypothesis that ARF may arise from GAS pyoderma or from pharyngitis due to non-GAS strains that inherited certain GAS antigens or enzymes that are important for initiating ARF. This hypothesis requires further exploration for confirmation.
Several factors may affect the site of infection. Bacterial factors are discussed above (see 'Bacterial strain specificity' above). Another factor affecting localization to the pharynx may be CD44, a hyaluronic acid binding protein that appears to act as a pharyngeal receptor for GAS. After intranasal inoculation, GAS colonize the oropharynx in wild-type mice but not transgenic mice that do not express CD44 [54]. This finding has not been studied in humans.
Molecular mimicry — Molecular mimicry implies structural similarity between some infectious or other exogenous agent and human proteins, such that antibodies and T cells activated in response to the exogenous agent react with the human protein. In ARF, antibodies directed against GAS antigens crossreact with host antigens [55-60]. In addition, human heart-intralesional T cell clones react with meromyosin, myosin, and valve-derived proteins, leading to an immunologic response to cardiac tissue and production of inflammatory cytokines [61].
Carditis — The alpha-helical protein structures found in M protein and N-acetyl-beta-D-glucosamine (NABG, the immunodominant carbohydrate antigen of GAS) share epitopes with myosin, and antibody crossreactivity has been demonstrated in humans [56-59]. In a rodent model, immunization with recombinant streptococcal M protein type 6 leads to development of both valvulitis and focal cardiac myositis [22]. There do not appear to be cross-reactive responses against the N-terminal and A-repeat regions of the M protein. These regions are responsible for type-specific immunity and have been used in GAS vaccine studies with no evidence of crossreactivity in animal or human subjects [62].
In one study, monoclonal antibodies generated from tonsillar or peripheral blood lymphocytes of patients infected with GAS cross-reacted with myosin and certain other proteins [58]. In addition, antimyosin antibodies purified from patients with ARF cross-reacted with GAS and M protein. Similar antibodies were present in much lower concentrations in some normal subjects.
In a later report, a monoclonal antibody directed against myosin and NABG was isolated from a patient with rheumatic carditis [59]. The antibody was cytotoxic for human endothelial cell lines and reacted with human valvular endothelium. This reactivity was inhibited by myosin>laminin>NABG. The reactivity with the extracellular matrix protein laminin may explain the reactivity against the valve surface.
Autoreactive T cells appear to play an important role in the formation of Aschoff nodules in cardiac valves. Vascular cell adhesion molecule 1 (VACM1) appears to be the link between humoral and cellular immunity at the valve surface [63]. VCAM1 is upregulated on the surface of the valve endothelium following binding of cross-reactive antibodies. This leads to adherence of T cells (predominantly CD4+) to the endothelium, with subsequent infiltration of these cells into the valve resulting in the formation of granulomatous lesions (Aschoff bodies) underneath the endocardium [63].
Chorea — Molecular mimicry may also be involved in the development of Sydenham chorea in patients with ARF. In an animal model, monoclonal antibodies that caused chorea bound to both NABG and mammalian lysoganglioside [60]. Exposure of cultured human neuronal cells to either monoclonal antibodies or serum from patients with chorea led to induction of calcium/calmodulin protein kinase. Exposure to serum from patients following streptococcal infection that was not complicated by chorea did not have this effect on neuronal cells. (See "Sydenham chorea".)
Genetic susceptibility — The concept that ARF might result from a host genetic predisposition has intrigued investigators for more than 100 years [64-67]. ARF appears to be a highly heritable disease [68], and susceptibility to ARF is most likely polygenic.
A meta-analysis of twin studies found that the pooled proband-wise concordance risk was 44 percent in monozygotic twins and 12 percent in dizygotic twins. The association between zygosity and concordance was strong, with an odds ratio of 6.4 (95% CI 3.4-12.1) [69].
Polymorphisms in several genes encoding immune proteins are associated with ARF susceptibility. Large-scale, genome-wide association studies of rheumatic heart disease in multiple populations in over 20 countries in Africa, the Pacific, and northern Australia are underway or completed [70,71]. The first study, conducted among 2582 individuals in seven countries in Oceania, observed a susceptibility signal in the immunoglobulin heavy chain locus suggesting a central role of humoral immunity in the pathogenesis of rheumatic fever [72]. The second study, conducted among 1263 individuals in indigenous communities of Australia, found variation at the class II region of the human leukocyte antigen [73], consistent with previous smaller studies [74-76].
SUMMARY
●Acute rheumatic fever (ARF) is a delayed, nonsuppurative sequela of infection with the group A Streptococcus (GAS). (See 'Introduction' above.)
●Most cases of ARF occur in children 5 to 15 years of age. ARF is more common in developing than developed countries. (See 'Epidemiology' above.)
●The pathogenic mechanisms that lead to the development of ARF remain incompletely understood. Streptococcal pharyngeal infection is required, and molecular mimicry due to activation of autoreactive B and T cells by GAS antigens is thought to play an important role in the initiation of the tissue injury. Genetic susceptibility may also be a factor. (See 'Pathogenesis' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge John B Zabriskie, MD, who contributed to earlier versions of this topic review.
