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Rheumatic
fever is a nonsuppurative, acute inflammatory complication of group
A streptococcal infection, causing combinations of arthritis, carditis,
subcutaneous nodules, erythema marginatum, and chorea. Diagnosis is
based on applying the Jones criteria to information from history,
examination, and laboratory testing. Treatment includes aspirin
or other NSAIDs, corticosteroids during severe carditis, and antimicrobials
to eradicate residual streptococcal infection and prevent reinfection.
A first episode of acute rheumatic fever (ARF) occurs most often between 5 and 15 yr and is uncommon before 3 and after 21 yr. Testing for group A streptococcal (GAS) infection for primary prevention of rheumatic fever is therefore usually not necessary in patients younger than 3 yr with pharyngitis. In the US, incidence is < 1/100,000. The attack rate (percentage of patients with untreated GAS pharyngitis who develop ARF) varies from 0.4 to 3.0%. Higher attack rates occur with certain streptococcal M protein serotypes and a stronger host immune response. In patients with a prior episode of ARF, the attack rate in untreated GAS pharyngitis approaches 50%, underscoring the importance of long-term antistreptococcal prophylaxis. Incidence has declined in most developed countries but remains high in the underdeveloped world. However, more recent local outbreaks of ARF suggest that more virulent (rheumatogenic) strains of streptococci may have returned to the US. The prevalence of chronic rheumatic heart disease is uncertain because criteria are not standardized and autopsy is not performed routinely.
Etiology
and Pathophysiology
GAS infection is the etiologic precursor of ARF, but host and environmental factors are important. GAS M proteins share epitopes (antigenic-determinant sites that are recognized by antibodies) with proteins found in synovium, heart muscle, and heart valve, suggesting that molecular mimicry contributes to the arthritis, carditis, and valvular damage. Genetic host risk factors include the D8/17 B-cell antigen and certain class II histocompatibility antigens. Malnutrition, overcrowding, and lower socioeconomic status predispose to streptococcal infections and subsequent episodes of rheumatic fever.
The joints, heart, skin, and CNS are most often affected. Pathology varies by site.
Joints:
Joint involvement manifests as nonspecific inflammation in a synovial biopsy specimen, sometimes with small foci resembling Aschoff bodies (granulomatous collections of leukocytes, myocytes, and interstitial collagen).
Heart:
Cardiac involvement manifests as carditis, which can involve myocardium, endocardium, and pericardium, and is sometimes followed years later by chronic rheumatic heart disease (eg, primarily valvular stenosis, but can also include regurgitation, arrhythmias, and ventricular dysfunction). Aschoff bodies often develop in the myocardium and other parts of the heart. Fibrinous nonspecific pericarditis, sometimes with effusion, occurs only in patients with endocardial inflammation and usually subsides without permanent damage. Characteristic and potentially dangerous valve changes may occur. Acute interstitial valvulitis may cause valvular edema. Left untreated, valve thickening, fusion, and retraction or other destruction of leaflets and cusps may result, leading to stenosis or insufficiency. Similarly, chordae tendineae can shorten, thicken, or fuse, adding to regurgitation of damaged valves or producing regurgitation of an otherwise unaffected valve. Dilation of valve rings may also cause regurgitation. The mitral, aortic, tricuspid, and pulmonic valves are affected, in order of decreasing frequency. Regurgitation and stenosis are the usual effects on the mitral and tricuspid valves; the aortic valve generally becomes regurgitant initially and stenotic much later.
Skin:
Subcutaneous nodules are indistinguishable from those of RA but on biopsy show features resembling Aschoff bodies. Erythema marginatum differs histologically from other skin lesions with similar macroscopic appearance, eg, the rash of systemic-onset juvenile rheumatoid arthritis (JRA), Henoch-Schönlein purpura, erythema chronicum migrans, and erythema multiforme. Perivascular neutrophilic and mononuclear infiltrates of the dermis occur.
CNS:
Sydenham chorea, the form of chorea that occurs with ARF, manifests in the CNS as hyperperfusion and increased metabolism in the basal ganglia. Increased levels of antineuronal antibodies have also been demonstrated.
Symptoms and Signs
An initial episode of symptoms occurs typically about 2 to 4 wk after the streptococcal infection. The 5 major manifestations of ARF (see Table 1: Rheumatic Fever: Modified Jones Criteria for a First Episode* ), occurring alone or in combination, produce many clinical patterns.
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Table 1
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Modified Jones
Criteria for a First Episode*
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Major manifestations
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Carditis
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Chorea
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Erythema marginatum
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Polyarthritis
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Subcutaneous nodules
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Minor manifestations
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Arthralgia
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Elevated ESR or C-reactive protein
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Fever
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Prolonged PR interval (on ECG)
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*Diagnosis of acute rheumatic fever requires either 2 major or 1 major and 2 minor manifestations, and evidence of group A streptococcal infection (elevated or rising antistreptococcal antibody titer [eg, antistreptolysin-O, anti-DNase B], positive throat culture, or positive rapid antigen test).
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Adapted from Guidelines for the diagnosis of rheumatic fever. Jones criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. JAMA 268(15):2069–2073, 1992.
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Joints:
Migratory polyarthritis is the most common manifestation, occurring in about 70% of children; it is often accompanied by fever. Occasionally monarthritis occurs. Joints become extremely painful and tender and may also be red, hot, and swollen. Ankles, knees, elbows, and wrists are usually involved. Shoulders, hips, and small joints of the hands and feet also may be involved, but almost never alone. If vertebral joints are affected, other disease should be suspected.
Arthralgia-like symptoms may be due to nonspecific myalgia or tenodynia in the periarticular zone; tenosynovitis may develop at the site of muscle insertions. Joint pain and fever usually subside within 2 wk and seldom last > 1 mo.
Heart:
Carditis can occur alone or in combination with pericardial rub, murmurs, cardiac enlargement, or heart failure. In the 1st episode of ARF, carditis occurs in about 50%. A patient may seek medical attention for high fever, chest pain, or if heart failure produces respiratory, peripheral, or abdominal manifestations. In about 50% of cases, cardiac damage (ie, valve dysfunction) occurs much later.
Murmurs are common and usually evident early. The soft diastolic blow of aortic regurgitation and the presystolic murmur of mitral stenosis may be difficult to detect. Murmurs often persist indefinitely. If no worsening occurs during the next 2 to 3 wk, new manifestations of carditis seldom follow. ARF typically does not produce chronic, smoldering carditis. Scars left by acute valvular damage may contract and change, and secondary hemodynamic difficulties may develop in the myocardium without persistence of acute inflammation.
Heart failure from the combination of carditis and valvular dysfunction may produce dyspnea without rales, nausea and vomiting, a right upper quadrant or epigastric ache, and a hacking, nonproductive cough.
Skin:
Cutaneous and subcutaneous features are uncommon and almost never occur alone, usually developing in a patient who already has carditis, arthritis, or chorea. Fever and other systemic manifestations such as anorexia and malaise can be prominent but are not specific. Subcutaneous nodules, which occur most frequently on the extensor surfaces of large joints, usually coexist with arthritis and carditis. About 2% of children with ARF have nodules. Ordinarily, the nodules are painless, transitory, and responsive to the treatment of joint or heart inflammation.
Erythema marginatum is a serpiginous, flat or slightly raised, nonscarring, and painless rash. About 2% of children have this rash. It sometimes lasts < 1 day. Its appearance is often delayed after the inciting streptococcal infection; it may appear with or after the other manifestations of rheumatic inflammation.
CNS:
Sydenham's chorea occurs in about 10% of children. It may develop along with other manifestations but frequently arises after the other manifestations have subsided. Onset of chorea is typically insidious and may be preceded by inappropriate laughing or crying. Chorea consists of rapid and irregular jerking movements that may begin in the hands but often becomes generalized, involving the feet and face. Associated motor symptoms include loss of fine motor control, weakness, and hypotonia. Obsessive-compulsive behavior develops in many patients.
Other:
Lethargy, malaise, and fatigue often occur and may be caused by heart failure. Other manifestations may include abdominal pain and anorexia, either because of the hepatic mechanism described for heart failure or from concomitant mesenteric adenitis. Because of the fever, elevated WBC count, and abdominal guarding, the situation may resemble acute appendicitis, particularly when other rheumatic manifestations are absent. Epistaxis occurs in about 4% of children with an initial episode and 9% of those with a recurrence.
Prolonged episodes of ARF (> 8 mo) occur in about 5% of patients, with spontaneous recurrences of inflammation (clinical and laboratory manifestations) unrelated to intervening streptococcal infection or to cessation of anti-inflammatory therapy. Recurrences usually mimic the initial episode.
Diagnosis
Diagnosis of a first episode of ARF is based on the modified Jones criteria (see Table 1: Rheumatic Fever: Modified Jones Criteria for a First Episode*); 2 major criteria or 1 major and 2 minor criteria are required, along with evidence of preceding GAS infection. The Jones criteria should not be used to establish a recurrence.
A preceding streptococcal infection is suggested by a recent history of pharyngitis and confirmed by a positive throat culture, an increase in the antistreptolysin O titer, or a positive rapid GAS antigen test. Recent scarlet fever is highly suggestive. Throat cultures and rapid antigen tests are often negative by the time ARF manifests, whereas titers of antistreptolysin O and other antibodies typically are peaking. Only 80% of children with a prior infection have a significantly elevated antistreptolysin O titer; anti-DNase B antibody level should be obtained in such cases.
Joint aspiration may be needed to exclude other causes, such as infection. The fluid is usually cloudy and yellow, with an elevated WBC count composed primarily of neutrophils; culture is negative. Complement levels are usually normal or slightly decreased, compared with decreased levels in other inflammatory arthritides.
Baseline ECG and echocardiogram are performed at the time of diagnosis. Normal cardiac troponin I levels in children exclude prominent myocardial damage. ECG abnormalities such as PR prolongation do not correlate with other evidence of carditis. Only 35% of children with ARF have a prolonged PR interval. Other ECG abnormalities may be due to pericarditis, enlargement of ventricles or atria, or arrhythmias. Echocardiography can detect evidence of carditis in many patients. Chest x-rays are not routinely performed but can detect cardiomegaly, a common manifestation of carditis in ARF. Biopsy of a subcutaneous nodule can aid in early diagnosis, especially when other major clinical manifestations are absent. Rheumatic carditis must be distinguished from congenital heart disease and endocardial fibroelastosis; echocardiography or coronary angiography can be used to verify difficult diagnoses.
ESR and serum C-reactive protein (CRP) are sensitive but not specific. The ESR is often > 120 mm/h. CRP is often > 2 mg/dL; because it rises and falls faster than ESR, a normal CRP may confirm the absence of inflammation in a patient with prolonged ESR elevation after acute symptoms have subsided. In the absence of carditis, ESR usually returns to normal within 3 mo. Evidence of acute inflammation, including ESR, usually subsides within 5 mo in uncomplicated carditis. The WBC count reaches 12,000 to 20,000/μL and may go higher with corticosteroid therapy.
The differential diagnosis includes JRA (especially systemic-onset JRA and, less so, polyarticular JRA), Lyme disease, reactive arthritis, arthropathy of sickle cell disease, leukemia or other malignancy, SLE, embolic bacterial endocarditis, serum sickness, Kawasaki disease, drug reactions, and gonococcal arthritis. These are frequently distinguished by history or specific laboratory tests. The absence of an antecedent GAS infection, the diurnal variation of the fever, evanescent skin rash, and prolonged symptomatic joint inflammation usually distinguish systemic-onset JRA from ARF.
Prognosis
Prognosis depends mostly on the severity of the initial carditis. Patients with severe carditis during the first episode may have residual heart disease that is often worsened by the rheumatic fever recurrences to which they are particularly susceptible. Murmurs eventually disappear in about ½ of patients whose acute episodes were manifested by mild carditis without major cardiac enlargement or decompensation. Risk of recurrent inflammation is intermediate, between the low risk of those without carditis and the high risk of those with a history of severe carditis, but recurrences may cause or worsen permanent cardiac damage. Patients who did not have carditis are less likely to have recurrences and are unlikely to develop carditis if ARF recurs. Sydenham chorea usually lasts several months and resolves completely in most patients, but about 1⁄3 of patients have recurrences. All other manifestations subside without residual effects.
Treatment
The primary goals are suppression of inflammation and relief of acute symptoms, eradication of GAS infection, and prophylaxis against future infection to prevent recurrent heart disease.
Patients should generally limit their activities if symptomatic with arthritis, chorea, or heart failure. In the absence of carditis, no physical restrictions are needed after the initial episode subsides. In asymptomatic patients with carditis, strict bed rest has no proven value.
Aspirin controls fever and pain from arthritis and carditis. The dose is titrated upward until clinical effectiveness is attained or toxicity supervenes. The starting dose for children and adolescents is 15 mg/kg po qid. If not effective overnight, the dosage is increased to 22.5 mg/kg qid the next day and 30 mg/kg qid on the next. Salicylate toxicity is manifested by tinnitus, headache, or hyperpnea and may not appear until after ≥ 1 wk. Salicylate levels are measured only to manage toxicity. Enteric-coated, buffered, or complex salicylate molecules provide no advantage. Other NSAIDs can be used. For example, naproxen , 7.5 to 10 mg/kg po bid, is as effective as aspirin . If a therapeutic effect has not occurred after the 4th day, which is sometimes the case if carditis or arthritis is severe, NSAIDs should be abandoned in favor of a corticosteroid.
Prednisone 0.25 to 1 mg/kg po bid (or 0.125 to 0.5 mg po qid) up to 60 mg/day is recommended. If inflammation is not suppressed after 2 days, a corticosteroid pulse of methylprednisolone succinate (30 mg/kg IV once/day, maximum 1 g/day, for 3 successive days) may be given. Oral corticosteroids are given until ESR has remained normal for ≥ 1 wk and then are tapered at the rate of 5 mg q 2 days. To prevent worsening of inflammation during the corticosteroid taper, NSAIDs are begun simultaneously and continued until 2 wk after the corticosteroid has been stopped. Laboratory tests are used to monitor disease activity and response to treatment. Inflammatory markers such as ESR and CRP are the best indicators of therapeutic response.
Recurrences of cardiac inflammation (indicated by fever or chest pain) may subside spontaneously, but NSAIDs or corticosteroids should be resumed for heart failure uncontrolled by cardiotonic drugs. In patients with prolonged, recurrent episodes of carditis, immunosuppressive drugs may also be effective. Although useful in the acute episode, NSAIDs and corticosteroids do not prevent or reduce long-term valve damage.
Although poststreptococcal inflammation is well developed by the time ARF is detected, antibiotics are used to eradicate any lingering organisms and to prevent reinfection. Appropriate regimens for the treatment of acute infection are discussed in Gram-Positive Cocci: Streptococcal and Enterococcal Infections.
Antistreptococcal prophylaxis should be maintained continuously after the initial episode of ARF to prevent recurrences (see Table 2: Rheumatic Fever: Recommended Prophylaxis Against Recurrent Group A Streptococcal Infection). Antibiotics taken orally are just as effective as those given by injection, and the oral route is usually recommended because the injections are painful and require clinic visits and observation for postinjection reactions. The optimal duration of antistreptococcal prophylaxis is uncertain. Children without carditis should receive prophylaxis for 5 yr or up to age 21 (if the patient turns 21 before 5 yr of prophylaxis is completed). The American Academy of Pediatrics recommends that those with carditis without evidence of residual heart damage receive prophylaxis for 10 yr. Children with carditis and evidence of residual heart damage should receive prophylaxis for >
10 yr; many experts recommend that such patients continue prophylaxis indefinitely. Some experts believe prophylaxis should be life long in all patients with chorea and should continue in all patients who have close contact with young children, owing to their high rate of GAS carriage.
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Table 2
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Recommended Prophylaxis
Against Recurrent Group A Streptococcal Infection
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Patient Parameter
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Drug
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Dose
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Standard
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Penicillin G benzathine
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1.2 million units IM q 3–4 wk*
≤ 27 kg: 600,000 units IM q 3–4 wk*
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Alternatives
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Penicillin V or
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250 mg po bid
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Sulfadiazine
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≤ 27 kg: 500 mg po once/day
> 27 kg: 1 g po once/day
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Allergic to penicillin and sulfadiazine
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Erythromycin
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250 mg po bid
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*In developing countries, IM prophylaxis q 3 wk is superior to q 4 wk.
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In patients with known or suspected rheumatic valvular disease who have not remained on prophylactic antibiotics, short-term prophylaxis against bacterial endocarditis should be instituted for dental or oral surgical procedures likely to cause gingival bleeding, upper respiratory tract surgery, and surgery or instrumentation of the GU and lower GI tracts (see Table 3: Endocarditis: Procedures Requiring Antimicrobial Endocarditis Prophylaxis, see Table 4: Endocarditis: Recommended Endocarditis Prophylaxis During Oral-Dental, Respiratory Tract, or Esophageal Procedures*, see Table 5: Endocarditis: Recommended Endocarditis Prophylaxis During GI or GU Procedures).
Poststreptococcal
Reactive Arthritis
Poststreptococcal
reactive arthritis is development of arthritis after group A streptococcal infection
in patients who do not meet the criteria for acute rheumatic fever.
Poststreptococcal reactive arthritis may represent an attenuated variant of ARF. Compared with the arthritis of ARF, poststreptococcal reactive arthritis typically involves fewer joints, is less migratory but more protracted, and responds less to aspirin . It can be treated with other NSAIDs (eg, ibuprofen , naproxen , tolmetin ). Although clinical practice for secondary prevention of cardiac involvement varies greatly, it is reasonable to give antistreptococcal prophylaxis for 1 yr and then to repeat the echocardiogram. If cardiac lesions are detected by echocardiogram, long-term prophylaxis is indicated.
Last full review/revision November 2005
Content last modified November 2005
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