The incidence of acute rheumatic fever varies with geographic location and the population studied but, in general, ranges from 3 to 61 per 100,000 school children. The highest incidence occurs in children aged 5 to 14 years. This condition is rare in children younger than 4 years but does occur. Acute rheumatic fever is most common during winter and spring, a seasonal variation similar to that of streptococcal pharyngitis.

The incidence of initial attacks of acute rheumatic fever is increased in disadvantaged populations, presumably because of crowded living conditions that facilitate the spread of streptococcal infection.

Streptococcus is composed of a core of cytoplasm surrounded by a cytoplasmic membrane and a cell wall, which in turn is surrounded by a capsule that constitutes the external surface of the organism. The capsule is composed of hyaluronate, which is nonantigenic. The cell wall is composed of three layers: The outermost protein layer, the middle carbohydrate layer, and the innermost mucopeptide protoplast layer.

The protein layer contains the proteins designated M, T, and R. The M protein is the most important because it determines the virulence of the organism, stimulates the formation of opsonizing and precipitating antibodies, and may impede phagocytosis. Lancefield classified group A β-hemolytic
streptococci into serologic types on the basis of the M protein. Acute rheumatic fever can result from infection by any of the serotypes of group A β-hemolytic streptococci, unlike glomerulonephritis, which is associated with only a limited number of the serotypes. Antibodies produced against the M protein antigen can impart long-lasting immunity against reinfection by that specific serotype. The middle layer of the cell wall, the carbohydrate layer, provides the group specification of the Streptococcus. N-Acetylglucosamine is the group-specific carbohydrate for group A β-hemolytic streptococci. The mucopeptide innermost layer of the cell wall forms the skeletal component of the cell and is responsible for the shape of the cell. The cytoplasmic membrane is an antigenic lipoprotein, which cross-reacts with several mammalian tissue antigens, including human glomerular basement membrane.

The Streptococcus produces a number of extracellular products, some of which are involved in the disease-causing effects of the microorganism. Erythrogenic toxin is pyrogenic and is responsible for the rash of scarlet fever. Streptolysin O is cardiotoxic and leukotoxic and is responsible for the hemolysis of erythrocytes. Streptolysin O elicits an antibody response (producing antistreptolysin O) in 70% to 85% of infected individuals, and this forms the basis of a useful assay of invasive streptococcal infection. Early and effective antibiotic treatment of streptococcal infections can suppress this antibody response. The antigenicity of streptolysin O is inhibited by lipid extracts (probably cholesterol) of rabbit skin, and this property may be responsible for the lack of association between streptococcal skin infections and acute rheumatic fever. Free cholesterol neutralizes streptolysin O, but serum cholesterol, not in a free state, is a poor inhibitor of streptolysin O. Streptolysin S produces the hemolysis characteristic of β-hemolytic streptococci when cultured on sheep blood agar. Extracellular proteinase can cause myocardial necrosis. Streptokinase activates plasma proteins and converts plasminogen to plasmin. Diphosphopyridine nucleotidase elicits an antibody response (producing anti–diphosphopyridine nucleotidase) in 87% of patients with acute rheumatic fever and is a useful adjunct to the antistreptolysin O titer in identifying patients with invasive streptococcal disease. There are four deoxyribonucleases (I, II, III, and IV), all of which are antigenic. Deoxyribonuclease II is produced in the largest quantities in response to group A β-hemolytic streptococcal infection and is the most consistent of the deoxyribonucleases. Antideoxyribonuclease antibodies are useful indicators of invasive streptococcal disease.

Although it is clear that invasive group A β-hemolytic streptococcal infection is causally related to acute rheumatic fever, the pathogenesis of this relationship is unclear. Most likely, acute rheumatic fever is an autoimmune disease in which invasive streptococcal infection evokes an antibody response from the host, and this antibody attacks antigenically similar host tissues. Four streptococcal–host cross-reactive antigen–antibody systems have been identified: (i) Cardiac myofiber smooth muscle antigen cross-reacting with streptococcal cell wall and cell membrane antigen, (ii) heart valve fibroblast antigen cross-reacting with streptococcal cell membrane antigen, (iii) subthalamic and caudate nuclei antigen cross-reacting with streptococcal cell membrane antigen, and (iv) heart valve and connective tissue antigen cross-reacting with streptococcal group A carbohydrate antigen. Although heart-reactive antibody can be identified in patients with acute rheumatic fever, these antibodies can at times also be identified in patients with streptococcal infection but without acute rheumatic fever.

It is possible that streptococcal extracellular products play a role in the pathogenesis of acute rheumatic fever. Although some of these products are cardiotoxic, the effects of these toxins in vitro do not mimic the chronic granulomatous lesions seen in acute rheumatic fever.

Fever and arthritis are the two most common initial presenting features of acute rheumatic fever. Three fourths of patients with acute rheumatic fever have joint pain. Classically, the large joints, such as knees, ankles, elbows, and wrists, are involved and are tender, swollen, and erythematous. The pain migrates from one joint to another, each joint being involved for approximately 1 to 5 days. The arthritis persists for 2 to 4 weeks. In general, the severity of the joint symptoms is inversely proportional to the severity of cardiac involvement.

Carditis occurs in 40% to 50% of patients with the first attack of acute rheumatic fever. It may be the presenting feature but more commonly occurs after the onset of arthritis. The endocardium, myocardium, and pericardium may be involved. Carditis may be recognized by the appearance of a new significant cardiac murmur, such as mitral regurgitation or aortic regurgitation, cardiomegaly, or signs and symptoms of congestive heart failure or pericarditis. Congestive heart failure may present initially as fatigue, anorexia, unexplained shortness of breath, or cough. Chest pain may be the first manifestation of pericarditis. Carditis may be insidious and be apparent only by the presence of tachycardia that is disproportionate to the fever during sleep. Also, arrhythmia may be the first manifestation of carditis.

Chorea is a late manifestation of acute rheumatic fever, but the latter condition must be considered in the differential diagnosis of patients with chorea, particularly those aged between 7 and 14 years. Rheumatic chorea is more common in girls than boys and is a rare manifestation of acute rheumatic fever after puberty.

Erythema marginatum is an unusual manifestation of acute rheumatic fever but, if present, is helpful in establishing the diagnosis, particularly in association with other manifestations of the disorder. Erythema marginatum is not pathognomonic for acute rheumatic fever because it can also occur as a manifestation of drug reactions. Erythema marginatum occurs predominantly on the trunk and medial aspect of the proximal parts of the extremities. The eruption begins as pink-colored, slightly raised nonpruritic macules. The borders of the lesions migrate peripherally as the central areas assume normal skin appearance. Heat applied to the skin can accentuate the appearance of erythema marginatum.

Subcutaneous nodules occur in 7% to 20% of patients with acute rheumatic fever. They occur on extensor surfaces, over the spine, and on the scalp. They are nontender, nonpruritic, firm, painless masses. Usually, the diagnosis of acute rheumatic fever would already have been established by the time the subcutaneous nodules appear. In general, subcutaneous nodules occur in patients with relatively severe carditis.

Acute rheumatic fever also may present with abdominal pain, epistaxis, or pneumonia. There have been cases where patients with unsuspected acute rheumatic fever have undergone laparotomy because of an incorrect diagnosis of acute appendicitis.

Many conditions share the clinical manifestations of acute rheumatic fever (see Table 12.1). Many of these conditions are acute self-limiting processes that do not require long-term prophylaxis and are unassociated with an increased risk of cardiac dysfunction. Although it is important to identify a person with acute rheumatic fever, it is equally important not to mislabel patients who do not have acute rheumatic fever. To assist in this distinction, the Jones criteria were developed in the 1940s. The diagnosis of acute rheumatic fever can be made if the patient exhibits two of the major manifestations or one major manifestation and two minor manifestations and has evidence of previous streptococcal infection (see Table 12.2).

It must be stressed that evidence of a streptococcal infection must be present in addition to the major and minor manifestations. The one exception is the diagnosis of acute rheumatic fever on the basis of an otherwise unexplained chorea. In this case, evidence of
current or prior streptococcal infection is not necessary. A throat culture and appropriate antistreptococcal enzyme assays should be performed on all patients with suspected acute rheumatic fever to detect any evidence of streptococcal infection. The antistreptolysin O antibody titer is abnormally elevated or an increase or decrease of more than two tube dilutions can be documented in 70% to 85% of patients with acute rheumatic fever. A single value of 500 U is considered indicative of streptococcal infection, and a value of 333 U is of borderline significance. If the antistreptolysin O titer is 333 U or less, additional antistreptococcal antibody assays should be performed. These include antideoxyribonuclease II, anti–nicotinamide adenine dinucleotidase, antihyaluronidase, and antistreptokinase. When the levels of three different streptococcal antibodies are measured, >95% of patients with acute rheumatic fever will have abnormal elevation of at least one. The streptozyme test includes an assay for antibodies against five extracellular antigens of group A β-hemolytic streptococci (streptolysin O, hyaluronidase, streptokinase, deoxyribonuclease II, and nicotinamide adenine dinucleotidase). Unfortunately, false-positive streptozyme test results are common, and the streptozyme test should not be used as a screening test. The streptozyme test is useful in conjunction with a negative or borderline antistreptolysin O titer. A negative result of the streptozyme test and a negative or borderline antistreptolysin O titer indicate that streptococcal infection is unlikely.

The treatment of patients with acute rheumatic fever depends, to some degree, on the specific manifestations of the rheumatic fever. All patients, regardless of their manifestations, shoul
have a therapeutic course of antibiotics tailored to eradicate any streptococcal infection. This should be initiated after a throat culture has been obtained to determine whether streptococci are present, but the antibiotics should be administered even in the absence of a positive throat culture. One intramuscular injection of benzathine penicillin G (600,000 to 1,200,000 U) or a 10-day course of penicillin G (200,000 to 250,000 U four times a day) is recommended. Patients who are allergic to penicillin should receive another appropriate antibiotic for 10 days.

As early as 1876 aspirin was recommended for the treatment of acute rheumatic fever. Although salicylates reduce fever and arthritis, there is no evidence that they prevent carditis or permanent damage to the heart. Hench et al., who discovered cortisone, were the first to use steroids in the treatment of patients with acute rheumatic fever. There have been several studies in which the incidence of cardiac disease seemed to be reduced with the use of steroids. However, there were methodologic problems with these studies, and the results probably are inconclusive. In 1955, the results of a combined UK and US study indicated no significant differences among patients treated with aspirin, cortisone, or adrenocorticotropic hormone (ACTH) and the incidence of rheumatic heart disease. The incidence of residual heart disease was related directly to the initial severity of the cardiac disease. Therefore,
although aspirin and steroids remain the mainstay of the treatment of patients with acute rheumatic fever, there has been no consistent demonstration that cardiac damage is prevented or minimized by either salicylates or steroids.

Aspirin is the only anti-inflammatory agent that is recommended for the treatment of acute rheumatic fever characterized by arthritis alone or associated with minimal carditis. Minimal carditis includes the presence of minimal cardiomegaly or prolonged PR interval on the electrocardiogram alone or a grade 1/6 to 2/6 apical systolic murmur. The dosage of aspirin is 90 to 120 mg/kg/day or enough to maintain a serum salicylate level of 15 to 25 mg per dL. One to 2 weeks of aspirin treatment is recommended when arthritis alone is present, and 2 to 4 weeks of treatment is recommended when minimal carditis is present in addition to arthritis.

If carditis is severe or moderately severe, the patient should be treated with prednisone (2 mg/kg/day, not to exceed 60 mg per day) for 1 to 4 weeks. Shortly after or simultaneous with stopping steroid therapy, aspirin (90 to 120 mg/kg/day) should be begun and continued for 1.5 to 6 months. Aspirin probably should be continued until active inflammation subsides (until the erythrocyte sedimentation rate is normal). Congestive heart failure may be treated with a digitalis preparation and diuretic drugs. If congestive heart failure is severe, oxygen inhalation may be helpful. Occasionally, operative repair or replacement of a severely compromised cardiac valve may be necessary during acute rheumatic fever if signs and symptoms of severe congestive heart failure are unresponsive to medical therapy.

The importance of bed rest in the treatment of acute rheumatic fever is based on clinical observation and a little scientific investigation. In general, patients with chorea will prefer bed rest because of ataxia and those with arthritis will prefer bed rest because of joint pain. Bed rest for patients with carditis should be tempered by the severity of the carditis, congestive heart failure, and arrhythmia.

Rheumatic chorea is treated by maintaining the patient in a quiet environment. If choreiform movements are severe, the patient’s bed rails may have to be cushioned to prevent inadvertent injury. Pharmacologic therapy to control the chorea until it resolves may be helpful.

The only serious sequela of acute rheumatic fever is cardiac damage, particularly cardiac valve damage. The mitral and aortic valves are affected most frequently. In general, the severity of chronic rheumatic cardiac disease is proportional to the severity of the initial carditis during an episode of acute rheumatic fever. The clinical features of chronic rheumatic valvular disease depend on the valve affected and the severity of the valvular dysfunction. Also, specific treatment for chronic rheumatic valvular disease is dependent on the severity of the valve dysfunction. Although valvular heart disease is the most common cardiac manifestation of acute rheumatic fever, certain forms of congestive cardiomyopathy may be a late sequela of acute rheumatic fever.