Introduction

Acute rheumatic fever (ARF) is a delayed autoimmune reaction that follows a group A β‐hemolytic Streptococcus pyogenes infection. This immune reaction most commonly follows group A streptococcal pharyngitis, but is also seen in skin infections [1]. It is a multiorgan disease that affects the heart, joints, brain, skin, and subcutaneous tissue. The clinical manifestations of ARF are summarized in the recently updated Jones criteria for the diagnosis of ARF [2]. The adverse effect on the cardiovascular system causes rheumatic heart disease (RHD), which is responsible for the mortality and the majority of morbidity related to ARF. Despite the virtual disappearance of ARF/RHD from the developed world, its human, social, and economic costs remain a significant burden in many low‐ and middle‐income countries (LMICs).

Epidemiology

Acute rheumatic fever was once very common in North America and Europe, but is now rarely seen by physicians who practice in developed countries. The incidence of ARF began to decline in the nineteenth century, preceding the availability of penicillin [3]. This change was attributed to decreased crowding, and improvements in hygiene, sanitation, nutrition, and overall living standards. With the introduction of penicillin in the mid‐twentieth century, the incidence of ARF further decreased and in many places it is now virtually nonexistent. However, in developing nations, ARF remains the most common cause of acquired heart disease in children and young adults. LMICs and some indigenous populations of the developed world continue to struggle with the scourge of ARF and its long‐term consequences.

In 2019, there were estimated to be over 40 million prevalent cases of RHD worldwide and over 10 million disability‐adjusted life years due to RHD [4]. The true prevalence of RHD is likely greater due to subclinical or echocardiography‐positive disease that commonly goes undetected [5–8]. Children aged between 5 and 15 years are at the greatest risk of a primary episode of ARF [1], but prevalence studies in RHD‐endemic regions of the world frequently report cases in children as young as 2–3 years of age [4,9]. Onset of a primary episode of ARF is rare beyond the fourth decade of life. RHD is a chronic disease resulting in heart valve damage due to single or multiple recurrent episodes of ARF. Therefore, presentation with RHD commonly occurs in late adolescent and young adult age groups.

There is no established gender difference for ARF; however, RHD occurs more commonly in females, with a relative risk of about 1.5–2 compared with males [10]. This may be due to increased exposure to streptococcal infections related to child rearing, physiologic changes during pregnancies, lack of access to preventive care, or different host susceptibility. RHD in pregnancy causes significant morbidity and mortality to mothers and fetuses [11]. A recent international registry project found that pregnant women with RHD had a 2% mortality rate, while 50% of those with severe mitral stenosis (MS) and 23% of those with moderate MS developed heart failure and significant morbidity in the perinatal period [12].

Historically, RHD was noted to cluster in families: a meta‐analysis of twin studies showed a pooled concordance risk for ARF of 44% in monozygotic twins and 12% in dizygotic twins, giving an estimated heritability of 60% [13]. In the 1980s and 1990s, several reports linked RHD to the human leukocyte antigen (HLA) locus on chromosome 6, followed by reports implicating other candidate regions in the genome [14]. Most recently, the search for susceptibility loci has been reinvigorated by the use of genome‐wide association studies (GWAS), through which millions of variants can be tested for association in thousands of individuals. Early findings implicate the HLA‐DQA1 to HLA‐DQB1 regions, as well as the immunoglobulin heavy chain locus, including the IGHV4‐61 gene segment, on chromosome 14 [15].

Multiple environmental factors, such as seasonal variation, household size, rural/urban location, poverty level, and nutrition, have been studied and found to be associated with ARF, but the relative contribution of each factor has been difficult to discern. Underlying most studies is a common connection between ARF and poverty [16]. Conflicting studies have shown higher rates of ARF in rural areas, while others show highest rates in urban slums. Features common to both populations are poverty and overcrowding. Household overcrowding has been the most consistent and important factor detected across multiple studies and is likely the most modifiable factor [17,18].

Pathophysiology

The association between ARF and group A β‐hemolytic streptococcal infection is well established. However, the exact pathogenesis of ARF remains incompletely understood. The classical disease model is based on a complex interaction between a susceptible host, a virulent bacterium, and an environment conducive to bacterial infection. The current hypothesis attributes the delayed autoimmune reaction of ARF to molecular mimicry between the host and the streptococcus [1]. Particular streptococcal proteins (e.g., M protein and N‐acetylglucosamine) share homologous sequences with human tissues such as myosin and laminin. As a result, the immune reaction that occurs in response to group A streptococcal infection can lead to the formation of cross‐reactive antibodies and T cells in susceptible hosts. Cross‐reactive antibodies attach to native laminin in valvar endothelium and to other tissues, allowing the entry of primed T helper cells to trigger an autoimmune reaction [19]. Inflammation then leads to neovascularization and further recruitment of T cells.

Diagnostic criteria for acute rheumatic fever

In 1944, T. Duckett Jones established clinical diagnostic criteria for ARF, specifically to avoid overdiagnosis. Over the last 75 years, the Jones criteria have been modified and updated, most recently in 2015 (Table 40.1) [20]. Earlier updates through 1992 were changed to become more specific and less sensitive for ARF in a continuing effort to avoid overdiagnosis at a time when ARF in industrialized countries had declined so dramatically. However, underdiagnosis in RHD endemic regions has been increasingly recognized as a barrier to disease control. The 2015 Jones criteria include specific language about different criteria for low‐ and high‐risk populations, similar to guidelines from Australia (Table 40.2) [2,21]. Thus, the latest Jones criteria are consistent with other guidelines that have attempted to increase diagnostic sensitivity in RHD‐endemic regions.

Most significantly, the 2015 Jones criteria now include echocardiography for the diagnosis of valvulitis in agreement with the most recent Australian guidelines. It has been shown that auscultation is neither sensitive nor specific for mild mitral or aortic regurgitation. Both the Australian diagnostic guidelines and the 2015 Jones criteria include subclinical valvulitis as a major criterion for ARF. Subclinical valvulitis refers to echocardiographic evidence of mild mitral and/or aortic valve regurgitation that is not audible in otherwise asymptomatic children and adults.

Clinical course of rheumatic fever and rheumatic heart disease

Up to 80% of patients with a primary episode of ARF have carditis. The overall risk of developing long‐term RHD following the first episode of ARF is approximately 60–65% [22]. The risk of progression to chronic severe RHD depends upon two factors: (i) the severity of carditis at presentation; and (ii) the number of ARF recurrences following the primary episode [1]. Recurrence of ARF is most common in the first 5 years after the initial episode and may occur in up to 75% of patients who do not receive regular secondary prophylaxis. Secondary prophylaxis consists of the continuous delivery of antibiotics to prevent recurrent episodes of ARF, usually with monthly benzathine penicillin G injections or daily oral penicillin. The benefits of secondary prophylaxis have been recognized since the 1950s [23]. Continuous adherence to secondary prophylaxis leads to a reduction in recurrent episodes of ARF, improvement in the severity of RHD (including complete regression of mild valvulitis within 5–10 years in up to 70% of cases), and reduced mortality. Despite these preventive measures, RHD remains a common cause of morbidity and is one of the most frequent indications for valve intervention.