Acute rheumatic fever (ARF) is a systemic, immune-mediated disease that is triggered by pharyngeal infection with group A streptococci (GAS). Fever, migratory polyarthritis, and carditis are the most common clinical manifestations. ARF is most frequent among 5–15 year olds with a declining incidence in adults. It is extremely rare in children under age 3, prompting speculation that more than one GAS infection is needed before ARF can develop. ARF is not considered a sequela of cutaneous GAS infection.
The pathogenesis of ARF is not clearly understood but appears to involve an immune response to group A streptococcal antigens that then cross-reacts with human tissue through molecular mimicry. Strains of GAS differ in their ability to trigger ARF, and changes in the prevalence of rheumatogenic strains can affect the incidence of ARF. Recent evidence supports the conclusion that ARF has declined in the United States over the past decades largely because of a decline in rheumatogenic types of GAS causing pharyngitis.
The reported attack rate of ARF among patients with untreated GAS pharyngitis is 0.4–3% in epidemic circumstances, with a much lower rate endemically. Genetic factors appear to influence the person’s susceptibility to ARF. Observational studies in the 19th century recognized familial tendencies to develop ARF, and in the early 1940s, studies showed familial clustering of the disease, with greatest risk occurring in children if both parents had rheumatic heart disease. Genetic susceptibility to develop ARF has been characterized as autosomal recessive or autosomal dominant with variable penetrance and has been linked with HLA types. Significant increases in the frequency of DRB1*0701, DR6, and DQB1*0201 confer susceptibility to rheumatic fever in several international studies. Monozygotic twins, however, are not usually concordant for ARF, indicating that there are also important environmental factors involved in the pathogenesis of the disease.
In 1944, Dr. T. Duckett Jones developed diagnostic criteria for ARF—the “Jones criteria”—based on his observations of hundreds of patients. The Jones criteria have been revised several times, most recently in 1992 (Table 52–1), and continue to form the basis for the clinical diagnosis of ARF. Exceptions to these criteria include patients who present with chorea or indolent carditis; these patients often do not fulfill the requirement for evidence of antecedent GAS infection because their antistreptococcal antibody levels usually have returned to normal at the time of presentation.
Table 52–1. Modified Jones Criteria for Diagnosis of Acute Rheumatic Fever.a ||Download (.pdf)
Table 52–1. Modified Jones Criteria for Diagnosis of Acute Rheumatic Fever.a
- Major criteria
- Erythema marginatum
- Subcutaneous nodules
- Minor criteria
- Elevated acute phase reactant (C-reactive protein or erythrocyte sedimentation rate)
- Prolonged PR interval on electrocardiogram
- Supporting evidence of antecedent group A streptococcal infection
- Positive throat culture or rapid antigen test
- Elevated or rising streptococcal antibody titer
Arthritis occurs in approximately 75% of patients with ARF. The arthritis is migratory, which is in contrast to poststreptococcal reactive arthritis, and polyarticular. The arthritis usually affects the larger joints, especially knees, ankles, wrists and elbows, and less commonly involves the smaller joints of the hands and feet. The axial skeleton is rarely affected. Inflamed joints are often red, hot, swollen, and exquisitely tender—to the point that even minimal contact with the affected joint can cause exquisite pain. Left untreated, inflammation of an individual joint resolves spontaneously over days, but the polyarthritis persists for 1–4 weeks. The arthritis of ARF responds dramatically to salicylates. This response is so characteristic that the lack of response to salicylate therapy within 48 hours should prompt the clinician to doubt the diagnosis of ARF and to consider other possibilities.
Carditis occurs in approximately 50–60% of ARF cases and accounts for significant morbidity and even mortality. When ARF affects the heart, it usually involves the endocardium, myocardium, and pericardium to varying degrees. Endocarditis leading to mitral or aortic valvulitis (or both) is most characteristic and occurs most frequently; the tricuspid and pulmonary valves are rarely affected. The revised Jones criteria for ARF require auscultation of a new valvular murmur in order to meet the criterion of “carditis”; echocardiography findings of valvular regurgitation without a murmur do not fulfill either major or minor criteria. When chronic rheumatic heart disease results, valvular regurgitation can be replaced by valvular stenosis. Myocarditis manifests as tachycardia that is disproportionate to the degree of fever and is persistent even in sleep. Pericarditis is the least common finding in rheumatic carditis. It usually manifests as a pericardial effusion or friction rub. The presence of myocarditis or pericarditis in the absence of valvular involvement is unlikely to be due to ARF, and other diagnoses should be explored in this circumstance.
Sydenham chorea (St. Vitus dance), which occurs in 10–15% of patients, is usually a later manifestation of ARF. The characteristic features of chorea are purposeless involuntary movements, incoordination, facial grimacing, and emotional lability. Chorea is a self-limited illness, and full recovery takes several months. Rarely, symptoms can occur over years and are exacerbated by stress, pregnancy, oral contraceptives, and intercurrent illnesses. Chorea is thought to be due to antibodies that cross-react with basal ganglia neurons.
Erythema marginatum occurs in less than 2% of patients. It is an erythematous, flat, serpiginous macular rash with pale central clearing. The rash usually occurs on the trunk and extremities and characteristically spares the face. The rash waxes and wanes and may be transient.
Subcutaneous nodules develop in less than 1% of cases of ARF, most often in those with severe carditis. The nodules are firm, nontender, and usually less than 2 cm in diameter. They are typically located over bony prominences or tendon sheaths. Nodules usually resolve spontaneously without permanent sequelae.
The fever in ARF is usually >39.0°C. It is commonly present at the onset of illness and resolves even without treatment over several weeks. In the absence of frank arthritis, arthralgia fulfill a minor criterion in the revised Jones criteria. Arthralgia may be migratory, and the pain may be severe, even without objective signs of arthritis.
Approximately one third of patients with ARF have no history of a recent symptomatic pharyngeal infection and, therefore, it is necessary to find laboratory evidence of a recent GAS infection. This can be done either by obtaining a throat culture or a rapid antigen test for GAS from a throat swab, or by documenting an elevated, or rising, serum antistreptococcal antibody titer. It is important to recognize that antistreptococcal antibody levels in the normal population vary by patient age, geographic location, and season of the year.
The antistreptolysin O (ASO) titer is the most commonly used streptococcal antibody test to establish a recent streptococcal infection. An ASO titer of 240 Todd units or higher in adults or 320 Todd units or higher in children is considered modestly elevated. ASO titers above 500 Todd units are uncommon in healthy individuals and therefore would serve as evidence of a recent streptococcal infection.
Because ASO titers can be normal in approximately 20% of ARF patients, other streptococcal antibody tests can be used to establish a recent GAS infection; these include anti-deoxyribonuclease B (anti-DNase B), antistreptokinase, and anti-hyaluronidase.
Aspiration of involved joints of ARF patients with polyarthritis reveals sterile inflammatory synovial fluid, typically with 10,000–100,000 white blood cells/mcL and a neutrophil predominance.
The nonclinical minor criteria of the revised Jones criteria include an increased PR interval on electrocardiogram and elevated acute phase reactants (C-reactive protein or erythrocyte sedimentation rate or both). Acute phase reactants are almost always elevated in patients with polyarthritis or acute carditis but are often normal in patients with chorea alone.
Like ARF, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), gonococcal arthritis, reactive arthritis, and serum sickness can cause fever and acute polyarticular arthritis in children. Choreiform movements can occur in SLE, neoplasms involving the basal ganglia, Wilson disease, and Huntington disease. Chorea can occasionally be encountered in pregnancy (“chorea gravidarum”).
Treatment of ARF requires prevention of future streptococcal infections, anti-inflammatory treatment, and symptomatic care (Table 52–2). Upon diagnosis and irrespective of the results of throat cultures for GAS, a dose of benzathine penicillin or 10 days of oral penicillin or erythromycin is recommended. Anti-inflammatory treatment includes oral salicylates (50–100 mg/kg/d) in four daily doses. This is continued for 2–4 weeks then is gradually tapered over 4–6 weeks. Glucocorticoid treatment should be reserved for those patients with congestive heart failure or at least moderate cardiomegaly on chest radiograph. Glucocorticoids are tapered slowly over several weeks; during taper of glucocorticoids, salicylates are added. For patients with Sydenham chorea, haloperidol or phenobarbital may be of some benefit.
Table 52–2. Treatment of Acute Rheumatic Fever. ||Download (.pdf)
Table 52–2. Treatment of Acute Rheumatic Fever.
|Mild or no carditis||Aspirin 50–100 mg/kg/d in four divided doses for 2–4 weeks, then taper over 4–6 weeks|
|Moderate or severe carditis||Prednisone 2 mg/kg/d in two doses for 2–4 weeks, then taper with addition of aspirin when prednisone is ≤0.5 mg/kg/d.|
|Primary antistreptococcal therapy||1.2 million units of benzathine penicillin G intramuscularly or penicillin or erythromycin orally for 10 days|
|Prophylaxis of GAS infection||1.2 million units benzathine penicillin G intramuscularly every 4 weeks or sulfadiazine 500 mg orally twice daily (≤27 kg) or 1 g orally twice daily (≥27 kg) or penicillin V 250 mg orally twice daily|
|Medications to control cardiac symptoms (if needed)||Diuretic, angiotensin-converting enzyme inhibitor, and/or cautious use of digoxin|
|Medications to control chorea (if needed)||Haloperidol or phenobarbitol|
|Bacterial endocarditis prophylaxis||As recommended by the American Heart Association|
Prevention of GAS infection is of utmost importance and prevents recurrent attacks of ARF that can be associated with increased severity of cardiac disease or with development of cardiac disease not previously present. All patients with ARF should receive antimicrobial prophylaxis with intramuscular benzathine penicillin G every 4 weeks or twice daily oral penicillin or sulfadiazine (erythromycin if allergic to penicillin and sulfa). The recommendations for the duration of secondary prophylaxis of streptococcal infection are based on likelihood of recurrence and the numbers of years since the last ARF episode (Table 52–3).
Table 52–3. Recommendations of Duration of Antimicrobial Prophylaxis in Patients with Acute Rheumatic Fever. ||Download (.pdf)
Table 52–3. Recommendations of Duration of Antimicrobial Prophylaxis in Patients with Acute Rheumatic Fever.
|Patients with rheumatic fever with carditis and residual heart disease||At least 10 years after last episode and at least until age 40, sometimes lifelong prophylaxis|
|Rheumatic fever with carditis but no residual heart disease (no valvular disease)||10 years or well into adulthood, whichever is longer|
|Rheumatic fever without carditis||5 years or until age 21 years, whichever is longer|
The long-term manifestation of ARF is rheumatic heart disease, and the prognosis of patients with ARF is generally attributable to the degree of cardiac involvement and the recurrence of GAS infection. Rheumatic heart disease may subsequently develop in patients with chorea or polyarthritis if they have recurrent ARF, thus emphasizing the importance of prophylactic antibiotics.