Park's Pediatric Cardiology for Practitioners, 6th Ed.

Acute Rheumatic Fever

Prevalence

Acute rheumatic fever is relatively uncommon in the United States but is a common cause of heart disease in less developed countries. However, in the past few decades, new outbreaks have occurred, and new sporadic cases are being reported in the United States.

Cause

1. Acute rheumatic fever is believed to be an immunologic response that occurs as a delayed sequela of group A streptococcal infection of the pharynx but not of the skin. The attack rate of acute rheumatic fever after streptococcal infection varies with the severity of the infection, ranging from 0.3% to 3%.

2. Important predisposing factors include family history of rheumatic fever, low socioeconomic status (poverty, poor hygiene, medical deprivation), and age between 6 and 15 years (with a peak incidence at 8 years of age).

Pathology

1. The inflammatory lesion is found in many parts of the body, most notably in the heart, brain, joints, and skin.

2. Rheumatic carditis was considered to be pancarditis, with myocarditis being the most important element. It is now recognized that the valvular component may be as important as or much more important than myocardial and pericardial involvement. In rheumatic myocarditis, myocardial contractility is rarely impaired, and the serum level of troponin is not elevated. It is not only the valve leaflets that are heavily involved with fibrinous vegetations on the coapting surfaces, but the entire mitral valve apparatus is also involved (with annular dilatation and stretching of chordae tendineae).

3. Valvular damage most frequently and most severely involves the mitral, less commonly the aortic, and rarely the tricuspid and pulmonary valves.

4. Aschoff bodies in the atrial myocardium are believed to be characteristic of rheumatic fever. These consist of inflammatory lesions associated with swelling, fragmentation of collagen fibers, and alterations in the staining characteristics of connective tissue, now believed to be necrotic myocardial cells.

Clinical Manifestations

Acute rheumatic fever is diagnosed by the use of revised Jones criteria (updated in 1993; see Box 20-1). The criteria are three groups of important clinical and laboratory findings: (1) five major manifestations, (2) four minor manifestations, and (3) supporting evidence of an antecedent group A streptococcal infection. These and other important clinical findings are presented here.

History

1. History of streptococcal pharyngitis, 1 to 5 weeks (average, 3 weeks) before the onset of symptoms, is common. The latent period may be as long as 2 to 6 months (average, 4 months) in cases of isolated chorea.

BOX 20-1 Guidelines for the Diagnosis of Initial Attack of Rheumatic Fever

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Supporting Evidence of Antecedent Group A Streptococcal Infection

Positive throat culture or rapid streptococcal antigen test result

Elevated or rising streptococcal antibody titer

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.


 If supported by evidence of preceding group A streptococcal infection, the presence of two major manifestations or of one major and two minor manifestations indicates a high probability of acute rheumatic fever.

From Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki’s Disease of the Council of Cardiovascular Disease in the Young, American Heart Association: Circulation 87:302-307, 1993.

2. Pallor, malaise; easy fatigability; and other history, such as epistaxis (5%–10%) and abdominal pain, may be present.

Major Manifestations

Five major criteria of acute rheumatic fever are discussed below.

Arthritis

Arthritis, the most common manifestation of acute rheumatic fever (70% of cases), usually involves large joints (e.g., knees, ankles, elbows, wrists). Often more than one joint is involved, either simultaneously or in succession, with a characteristic migratory nature of the arthritis. Swelling, heat, redness, severe pain, tenderness, and limitation of motion are common. If the patient was given salicylate-containing analgesics, these signs of inflammation may be mild. The arthritis responds dramatically to salicylate therapy; if patients treated with salicylates (with documented therapeutic levels) do not improve in 48 hours, the diagnosis of acute rheumatic fever probably is incorrect.

Carditis

Carditis occurs in 50% of patients. Signs of carditis include some or all of the following.

1. Tachycardia (out of proportion to the degree of fever) is common; its absence makes the diagnosis of myocarditis unlikely.

2. A heart murmur of mitral regurgitation (MR) or aortic regurgitation (AR) (or both) is almost always present. Although the American Heart Association’s Jones criteria recommend not to make the diagnosis of acute rheumatic carditis without audible murmurs of MR or AR, this is debatable. Significant echocardiographic abnormalities may be present in the absence of heart murmur.

Echocardiographic examination can determine the severity of cardiac enlargement, the presence and degree of MR and AR, and the presence of pericardial effusion more objectively than auscultation can. Inclusion of echocardiographic abnormalities may enhance the correct diagnosis of acute rheumatic carditis (Vijayalakshmi et al, 2005). However, a hemodynamically insignificant echocardiographic finding of MR alone is considered insufficient to diagnose myocarditis. Gross prolapse of the mitral valve or the presence of posterolateral (not central) MR jet by color-flow mapping may be significant. (With chronic rheumatic MR, fusion of the leaflets and cordae and contracture of these structures occur, and the regurgitation jets tends to become more central.) Other abnormal echocardiographic findings may include pericardial effusion, increased left ventricular (LV) dimension, or impaired LV function.

3. Pericarditis (with friction rub, pericardial effusion, chest pain, and electrocardiographic [ECG] changes) may be present. Pericarditis does not occur without mitral valve involvement in rheumatic fever. Pericardial effusion is usually of small amount and almost never causes cardiac tamponade.

4. Cardiomegaly on chest radiograph is indicative of severity of rheumatic carditis (or valvulitis) or congestive heart failure (CHF).

5. Signs of CHF (gallop rhythm, distant heart sounds, cardiomegaly) are indications of severe cardiac dysfunction.

Erythema Marginatum

Erythema marginatum occurs in fewer than 10% of patients with acute rheumatic fever. The characteristic nonpruritic serpiginous or annular erythematous rashes are most prominent on the trunk and the inner proximal portions of the extremities; they are never seen on the face. The rashes are evanescent, disappearing on exposure to cold and reappearing after a hot shower or when the patient is covered with a warm blanket. They seldom are detected in air-conditioned rooms.

Subcutaneous Nodules

Subcutaneous nodules are found in 2% to 10% of patients, particularly in cases with recurrences; it is almost never present as a sole manifestation of rheumatic fever. They are hard, painless, nonpruritic, freely movable, swelling, and 0.2 to 2 cm in diameter. They usually are found symmetrically, singly or in clusters, on the extensor surfaces of both large and small joints, over the scalp, or along the spine. They are not transient, lasting for weeks, and have a significant association with carditis. Subcutaneous nodules are not exclusive to rheumatic fever. They occur in 10% of children with rheumatoid arthritis, and benign subcutaneous nodules have been described in children and adults. In adults, they occur with rheumatoid arthritis, systemic lupus erythematosus (SLE), and other diseases.

Sydenham’s Chorea

Sydenham’s chorea (St. Vitus’ dance) is found in 15% of patients with acute rheumatic fever. It occurs more often in prepubertal girls (8–12 years) than in boys. It is a neuropsychiatric disorder consisting of both neurologic signs (choreic movement and hypotonia) and psychiatric signs (e.g., emotional lability, hyperactivity, separation anxiety, obsessions, and compulsions). It begins with emotional lability and personality changes. These are soon replaced (in 1–4 weeks) by the characteristic spontaneous, purposeless movement of chorea (which lasts 4–18 months), followed by motor weakness. The distractability and inattentiveness outlast the choreic movements. The adventitious movements, weakness, and hypotonia continue for an average of 7 months (up to 17 months) before slowly waning in severity. Recently, elevated titers of “antineuronal antibodies” recognizing basal ganglion tissues have been found in more than 90% of patients. The levels of the antineuronal antibody titer are positively related to the severity of choreic movements. These findings suggest that chorea may be related to dysfunction of basal ganglia and cortical neuronal components.

Minor Manifestations

The following are four minor criteria for the diagnosis of acute rheumatic fever.

1. Arthralgia refers to joint pain without the objective changes of arthritis. It must not be considered a minor manifestation when arthritis is used as a major manifestation in making the diagnosis of rheumatic fever.

2. Fever (usually with a temperature of at least 102°F [38.8°C]) is present early in the course of untreated rheumatic fever.

3. In laboratory findings, elevated acute-phase reactants (elevated C-reactive protein [CRP] levels and elevated erythrocyte sedimentation rate [ESR]) are objective evidence of an inflammatory process.

4. A prolonged PR interval on the ECG is neither specific for acute rheumatic fever nor an indication of active carditis.

Evidence of Antecedent Group A Streptococcal Infection

1. A history of sore throat or of scarlet fever unsubstantiated by laboratory data is not adequate evidence of recent group A streptococcal infection.

2. Positive throat cultures or rapid streptococcal antigen tests for group A streptococci are less reliable than antibody tests because they do not distinguish between recent infection and chronic pharyngeal carriage.

3. Streptococcal antibody tests are the most reliable laboratory evidence of antecedent streptococcal infection capable of producing acute rheumatic fever. The onset of the clinical manifestations of acute rheumatic fever coincides with the peak of the streptococcal antibody response.

a. Antistreptolysin 0 (ASO) titer is well standardized and therefore is the most widely used test. It is elevated in 80% of patients with acute rheumatic fever and in 20% of normal individuals. Only 67% of patients with isolated chorea have an elevated ASO titer. ASO titers of at least 333 Todd units in children and 250 Todd units in adults are considered elevated. A single low ASO titer does not exclude acute rheumatic fever. If three antistreptococcal antibody tests (antistreptolysin O, antideoxyribonuclease B, and antihyaluronidase tests) are obtained, a titer for at least one antibody test is elevated in more than 95% of patients.

b. The antideoxyribonuclease B titers of 240 Todd units or greater in children and 120 Todd units or greater in adults are considered elevated.

c. A slide agglutination test (Streptozyme test, Wampole Laboratories, Cranbury, NJ) that detects antibodies, is a relatively simple slide agglutination test, but it is less standardized and less reproducible than the other antibody tests. It should not be used as a diagnostic test for evidence of antecedent group A streptococcal infection.

Other Clinical Features

1. Abdominal pain, a rapid sleeping heart rate, tachycardia out of proportion to fever, malaise, anemia, epistaxis, and precordial pain are relatively common but not specific.

2. A positive family history of rheumatic fever also may heighten the suspicion.

Diagnosis

1. The revised Jones criteria are used for the diagnosis of acute rheumatic fever (see Box 20-1). A diagnosis of acute rheumatic fever is highly probable when either two major manifestations or one major and two minor manifestations, plus evidence of antecedent streptococcal infection, are present. The absence of supporting evidence of a previous group A streptococcal infection makes the diagnosis doubtful (see later discussion for exceptions).

2. The following tips help in applying the Jones criteria:

a. Two major manifestations are always stronger than one major plus two minor manifestations.

b. Arthralgia or a prolonged PR interval cannot be used as a minor manifestation when using arthritis and carditis, respectively, as major manifestations.

c. The absence of evidence of an antecedent group A streptococcal infection is a warning that acute rheumatic fever is unlikely (except when chorea is present).

d. The vibratory innocent (Still’s) murmur is often misinterpreted as a murmur of MR and thereby is a frequent cause of misdiagnosis (or overdiagnosis) of acute rheumatic fever. The murmur of MR is a regurgitant-type systolic murmur (starting with the S1) caused by MR, but the innocent murmur is low pitched and an ejection type. A cardiology consultation during the acute phase minimizes the frequency of misdiagnosis.

e. The possibility of the early suppression of full clinical manifestations should be sought during the history taking. Subtherapeutic doses of aspirin or salicylate-containing analgesics (e.g., Bufferin, Anacin) may suppress full manifestations.

3. Exceptions to the Jones criteria include the following three specific situations:

a. Chorea may occur as the only manifestation of rheumatic fever.

b. Indolent carditis may be the only manifestation in patients who come to medical attention months after the onset of rheumatic fever.

c. Occasionally, patients with rheumatic fever recurrences may not fulfill the Jones criteria.

Differential Diagnosis

1. Juvenile rheumatoid arthritis is often misdiagnosed as acute rheumatic fever. The following findings suggest juvenile rheumatoid arthritis rather than acute rheumatic fever: involvement of peripheral small joints, symmetrical involvement of large joints without migratory arthritis, pallor of the involved joints, a more indolent course, no evidence of preceding streptococcal infection, and the absence of prompt response to salicylate therapy within 24 to 48 hours.

2. Other collagen vascular diseases (SLE, mixed connective tissue disease); reactive arthritis, including poststreptococcal arthritis; serum sickness; and infectious arthritis (such as gonococcal) occasionally require differentiation.

3. Virus-associated acute arthritis (rubella, parvovirus, hepatitis B virus, herpesviruses, enteroviruses) is much more common in adults.

4. Hematologic disorders, such as sicklemia and leukemia, should be considered in the differential diagnosis.

Clinical Course

1. Only carditis can cause permanent cardiac damage. Signs of mild carditis disappear rapidly in weeks, but those of severe carditis may last for 2 to 6 months.

2. Arthritis subsides within a few days to several weeks, even without treatment, and does not cause permanent damage.

3. Chorea gradually subsides in 6 to 7 months or longer and usually does not cause permanent neurologic sequelae.

Management

1. When acute rheumatic fever is suggested by history and physical examination, one should obtain the following laboratory studies: complete blood count, acute-phase reactants (ESR and CRP), throat culture, ASO titer (and a second antibody titer, particularly with chorea), chest radiographs, and ECG. Cardiology consultation is indicated to clarify whether there is cardiac involvement; two-dimensional echocardiographic and Doppler studies are usually performed at that time.

2. Benzathine penicillin G, 0.6 to 1.2 million units intramuscularly, is given to eradicate streptococci. This serves as the first dose of penicillin prophylaxis as well (see later discussion). In patients who are allergic to penicillin, erythromycin, 40 mg/kg per day in two to four doses for 10 days, may be substituted for penicillin.

3. Antiinflammatory or suppressive therapy with salicylates or steroids must not be started until a definite diagnosis is made. Early suppressive therapy may interfere with a definite diagnosis of acute rheumatic fever by suppressing full development of joint manifestations and suppressing acute-phase reactants.

4. When the diagnosis of acute rheumatic fever is confirmed, one must educate the patient and parents about the need to prevent subsequent streptococcal infection through continuous antibiotic prophylaxis.

5. Bed rest of varying duration is recommended. The duration depends on the type and severity of the manifestations and may range from 1 week (for isolated arthritis) to several weeks for severe carditis. Bed rest is followed by a period of indoor ambulation of varying duration before the child is allowed to return to school. The ESR is a helpful guide to the rheumatic activity and therefore to the duration of restriction of activities. Full activity is allowed when the ESR has returned to normal, except in children with significant cardiac involvement. Table 20-1 is a general guide to the period of bed rest and indoor ambulation.

TABLE 20-1

GENERAL GUIDELINES FOR BED REST AND INDOOR AMBULATION

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 Questionable cardiomegaly.

 Definite but mild cardiomegaly.

 Marked cardiomegaly or heart failure.

TABLE 20-2

RECOMMENDED ANTIINFLAMMATORY AGENTS

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Dosages: Prednisone: 2 mg/kg/day in four divided doses.

Aspirin: 100 mg/kg/day in four to six divided doses.

 The dose of prednisone should be tapered and aspirin started during the final week.

 Aspirin may be reduced to 60 mg/kg/day after 2 weeks of therapy.

6. Therapy with antiinflammatory agents should be started as soon as acute rheumatic fever has been diagnosed.

a. For mild to moderate carditis, aspirin alone is recommended in a dose of 90 to 100 mg/kg per day in four to six divided doses. An adequate blood level of salicylates is 20 to 25 mg/100 mL. This dose is continued for 4 to 8 weeks, depending on the clinical response. After improvement, the therapy is withdrawn gradually over 4 to 6 weeks while monitoring acute-phase reactants.

b. For arthritis, aspirin therapy is continued for 2 weeks and gradually withdrawn over the following 2 to 3 weeks. Rapid resolution of joint symptoms with aspirin within 24 to 36 hours is supportive evidence of the arthritis of acute rheumatic fever.

c. Prednisone (2 mg/kg per day in four divided doses for 2 to 6 weeks) is indicated only in cases of severe carditis (Table 20-2).

7. Treatment of CHF includes the following (also see Chapter 27):

a. Complete bed rest with orthopneic position and moist, cool oxygen

b. Prednisone for severe carditis of recent onset (see Table 20-2)

c. Digoxin is used with caution, beginning with half the usual recommended dose, because some patients with rheumatic carditis are supersensitive to digitalis) (see Table 27-5).

d. Furosemide, 1 mg/kg every 6 to 12 hours, if indicated

8. Management of Sydenham’s chorea:

a. Reduce physical and emotional stress and use protective measures as indicated to prevent physical injuries.

b. Give benzathine penicillin G, 1.2 million units, initially for eradication of streptococci and every 28 days for prevention of recurrence, just as in patients with other rheumatic manifestations. Without the prophylaxis, about 25% of patients with isolated chorea (without carditis) develop rheumatic valvular heart disease in 20-year follow-up.

c. Antiinflammatory agents are not needed in patients with isolated chorea.

d. For severe cases, any of the following drugs may be used: phenobarbital (15–30 mg every 6–8 hours), haloperidol (starting at 0.5 mg and increasing every 8 hours to 2 g), valproic acid, chlorpromazine (Thorazine), diazepam (Valium), or steroids.

TABLE 20-3

RECOMMENDED DURATION OF PROPHYLAXIS FOR RHEUMATIC FEVER

Category

Duration

Rheumatic fever without carditis

At least for 5 years or until age 21 years, whichever is longer

Rheumatic fever with carditis but without residual heart disease (no valvular disease)

At least for 10 years or well into adulthood, whichever is longer

Rheumatic fever with carditis and residual heart disease (persistent valvular disease)

At least 10 years since last episode and at least until age 40 years; sometimes lifelong prophylaxis

Modified from Dajani A, Taubert K, Ferrieri P, et al. Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: a statement for health professionals: Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, The American Heart Association. Pediatrics 96:758-764. 1995.

e. Results of plasma exchange (to remove antineuronal antibodies) and intravenous immune globulin therapy (to inactivate the effects of the antineuronal antibodies) are promising in decreasing the severity of chorea and they were better than prednisone (Garvey et al, 2005).

Prognosis

The presence or absence of permanent cardiac damage determines the prognosis. The development of residual heart disease is influenced by the following three factors.

1. Cardiac status at the start of treatment: The more severe the cardiac involvement at the time the patient is first seen, the greater the incidence of residual heart disease.

2. Recurrence of rheumatic fever: The severity of valvular involvement increases with each recurrence.

3. Regression of heart disease: Evidence of cardiac involvement at the first attack may disappear in 10% to 25% of patients 10 years after the initial attack. Valvular disease resolves more frequently when prophylaxis is followed.

Prevention

Primary Prevention

Primary prevention of rheumatic fever is possible with a 10-day course of penicillin therapy for streptococcal pharyngitis. However, primary prevention is not possible in all patients because about 30% of the patients develop subclinical pharyngitis and therefore do not seek medical treatment. Another 30% of patients develop acute rheumatic fever without symptoms of streptococcal pharyngitis (30%).

Secondary Prevention

1. Who should receive prophylaxis?

Patients with documented histories of rheumatic fever, including those with isolated chorea and those without evidence of rheumatic heart disease, must receive prophylaxis.

2. For how long?

Ideally, patients should receive prophylaxis indefinitely. For patients who had acute rheumatic fever without carditis, the prophylaxis should continue for at least 5 years or until the person is 21 years of age, whichever is longer. For patients who are in a high-risk occupation (e.g., schoolteachers, physicians, nurses), prophylaxis should be continued for a longer period of time. The chance of recurrence is highest in the first 5 years after acute rheumatic fever. If the patient had rheumatic carditis or residual valvular disease as a result of rheumatic fever, the duration of prophylaxis should be longer (Table 20-3).

3. Method of prophylaxis

The method of choice for secondary prevention is benzathine penicillin G, 1.2 million units given intramuscularly every 28 days (not once a month). Alternative methods, although not as effective, are the following:

a. Oral penicillin V, 250 mg, twice daily

b. Oral sulfadiazine 1 g or sulfisoxazole 0.5 g once daily

c. Oral erythromycin ethyl succinate, 250 mg, twice daily