Version May 2024
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 — In low-resource 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, and rheumatic heart disease is the leading cause of cardiovascular death during the first five decades of life [2]. ARF can occur at any age, although most cases occur in children 5 to 15 years of age [3-5]. Worldwide, based upon conservative estimates, there are approximately 470,000 new cases of ARF and 320,000 deaths attributable to rheumatic heart disease each year [6-9]. Most cases occur in low- and middle-income countries and among indigenous populations, with risk factors including overcrowding and limited access to health care [10]. 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 [11], but it is lower (≤2 cases per 100,000 school-aged children) in the United States and other high-resource countries, having declined since the middle of last century [12-14]. 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 [4].
The higher incidence in low-resource countries is primarily explained by environmental factors, especially household overcrowding, which favors increased transmission of GAS [15], and in smaller part by routine use of antibiotics for acute pharyngitis. Overcrowding is also a strong risk factor for ARF in high-resource countries, including New Zealand, where household crowding was associated with a fourfold increased risk [16]. From time to time, localized outbreaks of ARF occur [17-22]. They may be associated with specific strains of GAS, though this alone cannot explain overall variations in the incidence of rheumatic fever [23]. (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 [24].
PATHOGENESIS
Overview — The pathogenic mechanisms that lead to the development of ARF remain incompletely understood. 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 [25,26]. Streptococcal pharyngeal infection clearly plays a roll, although the antecedent pharyngitis is often mild and not recollected. The number of streptococcal infections (both pharyngeal and skin infection) may also be important, with repeated infections possibly priming the immune system. Genetic susceptibility may be present. Within this framework, tissue injury is thought to be caused by an autoimmune process generated by cross-reactive antibodies and T cells between group A Streptococcus (GAS) antigens and human tissue.
Immune response to infection — Following 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. A linked IgG3-C4 response appears to be important [27]. In susceptible persons, there is a cross-reactive immune response. This may 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, chorea, and carditis due to antibody binding and infiltration of T cells.
Role of Streptococcus pyogenes — Although evidence for the direct involvement of GAS in the affected tissues of patients with ARF is lacking, significant epidemiologic evidence indirectly implicates GAS in the initiation of disease:
●Outbreaks of ARF closely follow epidemics of streptococcal pharyngitis or scarlet fever with associated pharyngitis [28,29].
●Adequate treatment of a documented streptococcal pharyngitis reduces the incidence of subsequent ARF by nearly 70 percent [30,31].
●Appropriate antimicrobial prophylaxis prevents the recurrence of disease in patients who have had ARF [32-34].
●Most patients with ARF have elevated antibody titers to antistreptococcal antigens (streptolysin O, anti-deoxyribonuclease B, hyaluronidase, streptokinase), whether or not they recall an antecedent sore throat [35].
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 three classes based upon differences in the C repeat regions of the M protein [36]. Pharyngeal strains typically have patterns A to C, impetigo strains show pattern D, and "generalist" strains (both pharyngeal and impetigo) are pattern E [37,38]. (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 [17,32,39,40]. 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 [41]. Thus, a shift in the prevalence of so-called rheumatogenic emm types does not appear to fully explain the decrease in ARF.
Other data, particularly from outside the US, suggest that there are no specific rheumatogenic strains [42,43]. A systematic review of cases of ARF from around the world found 73 different emm types distributed across the GAS phylogeny associated with ARF, and only 12 percent of cases were associated with "rheumatogenic" strains [43]. These data led the authors to challenge the concept of rheumatogenicity. As an example, a study in Hawaii observed that 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 [44].
The role of pharyngeal and skin infection — Streptococcal pharyngitis is the only streptococcal infection that is clearly associated with ARF. The role of streptococcal skin infection (impetigo, pyoderma) in ARF remains unclear. GAS impetigo has not been proven to directly lead to ARF, but epidemiologic evidence in certain populations suggests some sort of role along the causal pathway [42].
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 documented outbreaks of impetigo that caused acute glomerulonephritis (AGN) but almost never caused ARF [45,46]. A study of patients in Trinidad with ARF or 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 [46]. The presence of impetigo was associated with AGN but did not influence the incidence of ARF. Impetigo strains are able to colonize the pharynx but may not elicit as strong an immunologic response to the M protein moiety as pharyngeal strains [47,48].
Nevertheless, epidemiologic data and clinical experience in high-risk populations have challenged the theory that GAS skin infection does not play a role in the causal pathway of ARF. Aboriginal Australian and Pacific Island populations have very high rates of ARF, but pharyngeal carriage of GAS and symptomatic GAS tonsillopharyngitis are uncommon [42,49-55]. A case-control study of ARF in New Zealand observed that ARF risk was increased after both self-reported sore throat (odds ratio 2.3) and skin infection (odds ratio 2.5) [16]. A retrospective study of nearly two million throat and skin swabs in New Zealand found that ARF risk among Māori and Pacific Peoples increased following GAS detection in both throat and skin swabs (relative risk of 4.8 and 5.1 following a GAS-positive throat swab or skin swab, respectively) [56]. Two main hypotheses have been suggested to explain the link between GAS skin infection and ARF. One hypothesis is that there is a direct initiation of ARF after skin infection, and a second is that repeated episodes of GAS pyoderma may prime the immune system before an episode of GAS pharyngitis directly triggers ARF [49]. However, these hypotheses are unproven and require further exploration for confirmation.
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 cross-react with host antigens [57-62]. 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 [63].
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 [58-61]. In a rodent model, immunization with recombinant streptococcal M protein type 6 leads to development of both valvulitis and focal cardiac myositis [25]. 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 cross-reactivity in animal or human subjects [64].
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 [60]. 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 [61]. 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 [65]. 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 [65].
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 [62]. 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 [66-69]. ARF appears to be a highly heritable disease [70], 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) [71].
Polymorphisms in several genes encoding immune proteins are associated with ARF susceptibility. Large-scale, genome-wide association studies (GWAS) of rheumatic heart disease in multiple populations in over 20 countries in Africa, the Pacific, South Asia, Europe, and northern Australia are underway or completed [72-74]. The first GWAS, conducted among 2582 persons 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 [75]. The second GWAS, conducted among 1263 persons in indigenous communities of Australia, found variation at the class II region of the human leukocyte antigen [76], consistent with previous smaller studies [77-79]. The third study, of 2622 persons in South Asian or Europe, identified a susceptibility signal in the class III region of the human leukocyte antigen [80]. The fourth study, of 4809 participants from eight countries in Africa, identified a single risk locus among Black African persons at 11q24.1, an intergenic region containing long noncoding transcripts [81]. A meta-analysis of Black and multiracial persons identified several suggestive susceptibility signals including the same immunoglobulin heavy-chain locus identified in the Oceania GWAS [81].
SUMMARY
●Definition – Acute rheumatic fever (ARF) is a delayed, nonsuppurative sequela of infection with group A Streptococcus (GAS). (See 'Introduction' above.)
●Epidemiology – Most cases of ARF occur in children 5 to 15 years of age. ARF is more common in low-resource than high-resource countries. (See 'Epidemiology' above.)
●Pathogenesis – The pathogenic mechanisms that lead to the development of ARF remain incompletely understood. Streptococcal pharyngeal infection is required, and 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.
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