Acute rheumatic fever (ARF) is an inflammatory condition manifested by the nonsuppurative sequelae of a preceding group A β-hemolytic streptococcal (GAS) pharyngitis. ARF involves the heart, central nervous system, joints, and skin and is the most common cause of acquired heart disease in many regions of the world. Historically, the relationship between streptococci and rheumatic fever was not evident; however, investigation over the past several decades has shown that only GAS infections are associated with ARF. Diagnosis of the disease relies on the identification of major and minor criteria that include clinical observations and laboratory data, an approach that has been modified occasionally since its introduction in 1944 by Jones.¹ The greatest impact of the illness lies in its potential to cause progressive valvular heart disease, which is more likely with recurrent episodes of ARF. Antibiotic prophylaxis is therefore important to minimize the likelihood of recurrent GAS pharyngitis.

EPIDEMIOLOGY

It is well accepted that the frequency of ARF has declined in part because of the use of antibiotics to treat pharyngitis. Investigations have shown that appropriate antimicrobial therapy has led to fewer episodes of ARF in the United States,^2-4 although the prevalence remains high in many parts of the world, especially in crowded populations of lower socioeconomic status.^5,6 Nevertheless, sporadic outbreaks have been identified in the United States among populations not thought to be at risk for such events.^7-11 Given the frequency of ARF as well as the clinical presentation among different populations, the Jones Criteria was modified recently to define the two populations more precisely.¹²

PATHOPHYSIOLOGY

Only GAS pharyngitis is rheumatogenic,¹³ and certain types of group A streptococci predispose to the development of ARF, based on the virulence of the organism. Group A streptococci with high concentrations of M protein, a component of the cell wall, are believed to be the most virulent strains and therefore the most likely to cause ARF. These types of streptococci often form mucoid-appearing colonies in culture. The number of M serotype GAS infections decreased in association with a similar decline in the incidence of ARF.¹⁴

The actual pathogenetic mechanism by which GAS pharyngitis leads to ARF is still somewhat speculative. The organism adheres to the pharyngeal mucosa, with subsequent destruction of epithelial cells. The immune reaction to this interaction results in both a humoral and a cell-mediated response to streptococcal antigens of the cell membrane. These antigens mimic those of cardiac tissue, whereas M proteins have similar antigenicity to myosin and sarcolemma,^15,16 as well as cartilage and synovium.¹⁷ The cross-reactivity may result in damage to these target tissues. In addition, the GAS carbohydrate components mimic antigens of cardiac valves, a possible explanation for valvular involvement in ARF.¹⁸ Cell-mediated involvement in the pathogenesis is supported by the presence of CD⁴⁺ helper cells in heart valves.¹⁹ It is possible that the M protein and streptococcal pyrogenic exotoxins may act as superantigens in the immune response.^20,21 A genetic basis for predisposition to development of rheumatic fever following GAS infection has been entertained for many years without definitive proof, but a recent report found the presence of potential rheumatic epitopes in the S2 region of human cardiac myosin.²²

The initial pathologic lesion in ARF is edema of the ground substance in connective tissue, with accompanying cellular infiltration of T and B lymphocytes. Degenerative deposition of eosinophils in these regions is described as fibrinoid necrosis. Although these pathologic findings are present early in the process, with the administration of anti-inflammatory therapy they regress. This stage of inflammation is followed by the more chronic and pathognomonic change known as the Aschoff body.²³ This pathologic lesion is characterized by an area of central necrosis encircled by mononuclear and polynuclear cells. Most observers link this lesion to connective tissue; however, at least one investigator has postulated that the Aschoff body is located in myocardial cells.²⁴ Some have posited that the lesion is the result of endothelial disruption of cardiac lymphatics.²⁵ Pathologic changes can be found in all layers of the heart. Myocarditis is seen microscopically in ARF, with inflammatory cells noted in perivascular regions as well as near areas of Aschoff bodies.²⁶ Though these changes are subclinical in many patients, other affected individuals may have pronounced heart failure in the acute phase of the disease. Pericardial inflammation is manifested as a serofibrinous reaction with pericardial fluid production. Although adhesions can ensue, constrictive changes are unlikely. Valvular inflammation is well described, involving primarily the aortic and mitral valves. Deposition of platelet fibrin collections is seen on the valve leaflets in the acute phase. Over many years, the leaflets may develop progressive fibrosis and contraction, as do the chordae tendineae of the mitral valve. These changes limit excursion of the valves, manifested as stenosis or a lack of coaptation of the leaflets and resulting regurgitation. The tricuspid and pulmonic valves are involved infrequently.

Joint inflammation is common in ARF, leading to the clinical manifestation of arthritis. Pathologically, a serous effusion is seen in the joint space, with inflammation of the articular surfaces; however, long-standing arthritis is not a sequela of the disease. Sydenham chorea is characterized pathologically by cellular infiltration and neuronal loss of the basal ganglia,^27-29 supported by findings of focal striatal enlargement by magnetic resonance imaging.³⁰ Anti–basal ganglia antibodies have been demonstrated in the sera of patients with Sydenham chorea in both acute and chronic settings.³¹ Subcutaneous nodules are located over the extensor surfaces of the large joints, typically the elbows and knees, and are composed of fibrinoid necrosis similar to that seen in Aschoff bodies. These nodules are rarely seen clinically in this era.

The onset of ARF occurs after a variable latent period—typically, 10 to 30 days—following streptococcal pharyngitis; however, many patients give no history of a preceding pharyngitis. In particular, when the primary manifestation of the illness is chorea, the latent period from the streptococcal infection can be as long as 6 months. The diagnosis is established by meeting the criteria established by Jones,¹ modified in 1992³² and again in 2015¹² (Table 57-1). A history of appropriate therapy for streptococcal pharyngitis does not preclude the diagnosis, since ARF has occurred following GAS treatment.^33,34

Early in the disease, complaints may center on a migratory polyarthritis involving the large joints, including the knees, wrists, elbows, and ankles. Fever between 38°C and 39°C is often an accompanying sign. The cardiac examination is notable for tachycardia at rest exacerbated by the fever, but the heart rate is also generally elevated in afebrile patients who have carditis. The precordium is hyperdynamic in the face of the fever-associated tachycardia, myocardial dysfunction, moderate mitral or aortic regurgitation, or the additive effects of mitral and aortic regurgitation producing left ventricular volume overload. The most common murmur is a blowing pansystolic regurgitant murmur heard best at the apex and left lower sternal border with radiation to the axilla. When the regurgitation is moderate or greater, the diastolic rumble of relative mitral stenosis (Carey Coombs murmur) is present at the apex, sometimes best heard with the patient rotated in the left lateral recumbent position using the bell of the stethoscope. High-frequency diastolic murmurs of aortic regurgitation are heard best using the diaphragm of the stethoscope with the patient seated and leaning forward, with the breath held in expiration. In patients with heart failure, S₃ gallops are present, heard best at the apex with the bell. A three-component pericardial friction rub is heard in the presence of serofibrinous pericarditis, although the sound may be muted when a moderate to large effusion is present. Cardiac tamponade is extremely rare in ARF. Pulses and perfusion are well maintained, except in the unusual case of severe myocardial decompensation.

Erythema marginatum is a serpiginous, salmon-colored eruption characterized by lesions with clear centers over the extremities and trunk. It is evanescent, noted more frequently during febrile episodes or after a bath or shower. Although subcutaneous nodules were once a classic part of the description of ARF, they are now infrequent findings. When present, they are nontender, knobby lesions usually palpated over the extensor surfaces of the elbows or knees, but can also occur around wrists, ankles or spine.

Sydenham chorea is a purposeless, involuntary movement disorder of the extremities and face that is exacerbated during periods of stress. Irritability and emotional outbursts are common. The onset may be gradual, but the symptoms may persist for many months, making speech or writing difficult and thereby limiting attendance at school. Carditis and arthritis are generally not noted in combination with chorea. The neurologic signs resolve without long-term sequelae.

Given the frequency of ARF in certain populations at higher risk, additional criteria have been adopted by the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease. The presence of subclinical carditis, monoarthritis, and polyarthralgia now constitute major criteria, while monoarthralgia and fever >38° are new minor categories.

The differential diagnosis of ARF is wide, given the systemic nature of its manifestations. Arthritis is present in many acute illnesses, including juvenile idiopathic (rheumatoid) arthritis, post-streptococcal arthritis, Lyme disease, septic arthritis, infective endocarditis, leukemia, and sickle cell disease. These diseases can be identified by careful consideration of the constellation of history, physical findings, and laboratory tests, including complete blood count with smear, blood cultures, and joint aspiration. Some consider post-streptococcal arthritis to be a separate entity from ARF, but others consider these two disorders to be different presentations of a common disease. Implications for the prevention of recurrence make this an important but controversial point of distinction.

The diagnosis of ARF relies on criteria derived from the physical examination and laboratory findings. In the setting of a preceding GAS infection, patients with two major manifestations or one major manifestation and two minor manifestations (see Table 57-1) meet the criteria for the diagnosis of ARF. Because the index of suspicion is higher in an individual with previous ARF, the diagnosis of recurrent ARF is accepted if, in the presence of a preceding streptococcal infection, one major or two minor manifestations are present.

Fever is present in virtually all patients with ARF and should be documented carefully during hospitalization as a marker of the inflammatory process. In addition, the erythrocyte sedimentation rate and C-reactive protein level, nonspecific indicators of inflammation, are elevated in ARF. In a patient with chorea, however, both values might be normal, because the condition can follow the inciting event by a number of months. In the setting of severe heart failure, the erythrocyte sedimentation rate may be within the normal range, but the C-reactive protein is usually elevated. Both values improve after the institution of anti-inflammatory therapy and are useful for following the course of the acute illness.

Laboratory tests that support the likelihood of a preceding streptococcal infection are important for establishing the diagnosis of ARF. All patients should have throat cultures to identify the presence of a GAS infection. Because throat cultures are often negative after patients have been treated, however, and because signs of ARF may not appear until some time after the streptococcal infection, streptococcal antibody tests are useful to establish a recent infection.³⁵ The antistreptolysin test (ASO) identifies the presence of an antibody to streptolysin O, an extracellular product of β-hemolytic streptococci. ASO titers less than 250 Todd units are considered normal; titers of 500 Todd units or more are considered positive. Values falling between 250 and 500 units are supportive but not diagnostic of a preceding infection. Elevated titers of other serologic tests, including anti-deoxyribonuclease B (anti-DNAase B), antihyaluronidase, and antistreptokinase, suggest a preceding streptococcal infection and may be helpful when ASO titers are not definitive. In the setting of chorea, these tests may be normal, given the latent period between streptococcal exposure and the onset of neurologic signs.