The individual who has had an attack of rheumatic fever is at very high risk of developing recurrences after subsequent GAS pharyngitis and needs continuous antimicrobial prophylaxis to prevent such recurrences (secondary prevention). The duration of prophylaxis depends on the number of previous attacks, the time lapsed since the last attack, the risk of exposure to streptococcal infections, the age of the patient, and the presence or absence of cardiac involvement. Penicillin is again the agent of choice for secondary prophylaxis, but sulfadiazine or erythromycin are acceptable alternatives in penicillin-allergic individuals.

This report is an update of a 1988 statement by this committee. It expands on the previous statement, includes more recent therapeutic modalities, and makes more specific recommendations for the duration of secondary prophylaxis.(Pediatrics 1995;96:758-764)

ABBREVIATIONS. GAS, group A -hemolytic Streptococcus; ASO, antistreptolysin O; anti-DNase B, antideoxyribonuclease B; PSRA; poststreptococcal reactive arthritis.

This report is an update of a 1988 statement by this committee on prevention of rheumatic fever.¹ Prevention of both initial and recurrent attacks of rheumatic fever depends on the control of group A -hemolytic streptococcal (GAS) tonsillopharyngitis (strep throat). Prevention of first attacks (primary prevention) is accomplished by proper identification and adequate antibiotic treatment of this streptococcal infection. The individual who has had an attack of rheumatic fever is at high risk of developing recurrences after subsequent GAS pharyngitis and needs continuous antimicrobial prophylaxis to prevent such recurrences (secondary prevention).^2-6

The incidence of rheumatic fever remains very low in most areas of the United States.⁷ In certain areas of the country, sharp increases in incidence of rheumatic fever were noted in the mid-1980s.^8-20 Reappearance of acute rheumatic fever in several areas serves as a reminder of the importance of continued attention to prevention of rheumatic fever in the United States and in other developed countries. In developing countries, the incidence of the disease continues to be high.

GAS infections of the pharynx are the precipitating cause of rheumatic fever. During epidemics, as many as 3% of untreated acute streptococcal sore throats may be followed by rheumatic fever; in endemic infections, the incidence of rheumatic fever is substantially less.²¹ Appropriate antibiotic treatment of streptococcal pharyngitis prevents acute rheumatic fever in most cases.²² Unfortunately, at least one third of episodes of acute rheumatic fever result from inapparent streptococcal infections.⁸ In addition, some symptomatic patients do not seek medical care. Therefore, in these instances rheumatic fever is not preventable.

Prevention of initial episodes of acute rheumatic fever requires accurate recognition and proper antibiotic treatment of GAS pharyngitis. Streptococcal skin infections (impetigo or pyoderma) do not lead to acute rheumatic fever and are not discussed here. Symptoms common in individuals with streptococcal pharyngitis or tonsillitis ( Table 1) include sore throat (generally of sudden onset), pain on swallowing, and fever of varying degree (usually from 101^o to 104^oF). Headache, abdominal pain, nausea, and vomiting may occur, especially in children. Clinical signs suggesting streptococcal infection are primarily tonsillopharyngeal erythema with or without exudate and anterior cervical lymphadenitis. Other findings include soft palate petechiae, beefy red swollen uvula, excoriated nares (especially in infants), and a scarlatiniform rash. However, none of these manifestations is specific, and they can occur with other respiratory tract infections. Signs and symptoms usually not associated with streptococcal infection are coryza, hoarseness, cough, diarrhea, conjunctivitis, anterior stomatitis, and discrete ulcerative lesions.

Symptoms of acute pharyngitis are caused more often by viruses than by GAS. Differentiation of GAS pharyngitis from viral pharyngitis based on history and clinical findings is difficult. Even experienced clinicians are unable to differentiate streptococcal pharyngitis from pharyngitis caused by other pathogens with acceptable sensitivity and specificity based on history and clinical findings. Viruses that commonly cause pharyngitis include adenoviruses, enteroviruses, herpesviruses, and influenza viruses. Other causes of acute pharyngitis include groups C and G streptococci, Neisseria gonorrhoeae, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Arcanobacterium haemolyticum. GAS is not a common cause of pharyngitis in preschool children, but outbreaks in child care settings have been reported.^23,24 Although rheumatic fever is rare in this age group in the United States, it is more common in developing countries. Initial attacks of rheumatic fever are also rare in older adults, but recurrences are well documented.

Throat cultures are the conventional method for establishing the diagnosis of streptococcal infection. In an untreated patient with streptococcal pharyngitis, a properly obtained (vigorously swabbing both tonsils and posterior pharynx) throat culture is almost always positive. Unfortunately, the culture does not reliably distinguish between acute streptococcal infections and streptococcal carriers with concomitant viral infections. Streptococcal pharyngeal carriage is a common finding, particularly in school-age children. Quantitation of GAS from the throat swab culture cannot be used to differentiate carriage from infection, because sparse growth may be associated with true infection. A negative throat culture permits the physician to withhold antibiotic therapy in the majority of patients with sore throats. A throat culture should be read at 24 hours and, if negative, should be incubated an additional 24 hours to achieve optimal sensitivity for detecting GAS.

Many GAS antigen detection tests are available commercially. These tests vary in method. Most of these tests have a high degree of specificity, but their sensitivity in clinical practice is unacceptably low. Therefore, treatment is indicated for the patient with acute pharyngitis who has a positive rapid streptococcal antigen test. A negative test does not exclude the presence of GAS, and a throat culture should be obtained. As with the throat culture, a positive antigen detection test may reflect chronic colonization by GAS, and the acute illness may be caused by another agent. Newer tests are being developed that may have increased sensitivity (optical immunoassay and a gene probe test), but further evaluations are needed before recommendations can be made for clinical use.

Streptococcal antibody tests are of no immediate value in the diagnosis or treatment of acute streptococcal pharyngitis. Elevated or rising antistreptococcal antibody titers provide reliable confirmation of a recent GAS infection. Antibody tests may be of value in identifying a preceding GAS infection in a patient suspected of having rheumatic fever. Serologic tests should not be used to differentiate carriage from infection. The most commonly used antibody assays are antistreptolysin O (ASO) and antideoxyribonuclease B (anti-DNase B). These tests are valuable in patients who have possible nonsuppurative complications of streptococcal infections (acute rheumatic fever or acute glomerulonephritis). The ASO test is usually obtained first, and if not elevated, an anti-DNase B test may be done. Elevated titers for both tests may persist for several weeks to a few months. ASO titers rise and fall more rapidly than anti-DNase B. Anti-DNase B titers may remain elevated for several months after even uncomplicated GAS infection. A commercially available slide agglutination test for the detection of antibodies to several streptococcal antigens is the Streptozyme test (Wampole Laboratories, Stamford, CT). It is simpler to perform than traditional streptococcal antibody tests, is rapid, and is widely available. However, the test is less well standardized and less reproducible than other antibody tests, and in the committee's judgment, it should not be used as a definitive test for evidence of a preceding GAS infection.

Prevention of rheumatic fever requires eradication of GAS from the throat. In selecting a regimen for the treatment of GAS pharyngitis, physicians should consider various factors, including bacteriologic and clinical efficacy, ease of adherence to the recommended regimen (frequency of daily administration, duration of therapy, and palatability), cost, spectrum of activity of the selected agent, and potential side effects. No single regimen eradicates GAS from the pharynx in 100% of treated patients.

Penicillin is the antimicrobial agent of choice for the treatment of GAS, except in individuals with histories of penicillin allergy ( Table 2). Penicillin has a narrow spectrum of activity and a long-standing proven efficacy and is the least expensive regimen. GAS resistant to penicillin have not been documented. Penicillin may be administered intramuscularly or orally depending on the physician's assessment of the patient's likely adherence to an oral regimen and the risks of rheumatic fever in a particular population. Penicillin, even when started as long as 9 days after the onset of acute illness, effectively prevents primary attacks of rheumatic fever.²⁵ Therefore, a brief delay for processing the throat culture (24 to 48 hours) before antibiotic therapy is started does not increase the risk of rheumatic fever. However, early diagnosis and therapy may reduce the period of infectivity and morbidity, allowing the patient to return to normal activity sooner. Patients are considered noncontagious 24 hours after the initiation of therapy.²⁶

The oral antibiotic of choice if penicillin V (phenoxymethyl penicillin) ( Table 2). Many recent comparative clinical trials used dosages of 40 mg/kg per 24 hours given three times daily, not to exceed 750 mg. Generally, 250 mg two or three times daily is recommended for most children.^27,28 Little information is available about comparable doses in adults; therefore, a dose of 500 mg two to three times daily is recommended for adolescents and adults. All patients should continue to take penicillin regularly for an entire 10-day period, even though they will likely be asymptomatic after the first few days. Penicillin V is preferred to penicillin G because it is more resistant to gastric acid. Although the broader-spectrum penicillins, ampicillin and amoxicillin, are often used for treatment of GAS pharyngitis, they offer no microbiologic advantage over the less expensive penicillin.

Benzathine penicillin G is preferred particularly for patients who are unlikely to complete a 10-day course of oral therapy and patients with personal or family histories of rheumatic fever or rheumatic heart disease or other environmental factors (such as crowded living conditions or low socioeconomic status) that place them at substantial risk for the development of rheumatic fever.^17,29-31 Benzathine penicillin should be given as a single injection in a large muscle mass. This formulation is painful; injections that contain procaine penicillin in addition to benzathine penicillin G are less painful. Less discomfort is associated with intramuscular benzathine penicillin G if the medication is warmed to room temperature before administration.

The recommended dosage of benzathine penicillin G is 600 000 U intramuscularly for patients weighing 27 kg (60 lb) or less, and 1 200 000 U for patients weighing more than 27 kg. The combination of 900 000 U of benzathine penicillin G and 300 000 U of procaine penicillin G is satisfactory therapy for most children.³² The efficacy of this combination for heavier patients such as teenagers or adults requires further study.

Allergic reactions to penicillin are more common in adults than in children. Reactions occur in only a small percentage of patients, are more frequent after injection, and include urticaria and angioneurotic edema. A serum sickness-like reaction characterized by fever and joint pains may be mistaken for acute rheumatic fever. Anaphylaxis is rare but serious. A careful history for allergic reactions to penicillin should be obtained.

Oral erythromycin is acceptable for patients allergic to penicillin. Treatment also should be prescribed for 10 days. Erythromycin estolate (20 to 40 mg/kg per day in two to four divided doses) or erythromycin ethyl succinate (40 mg/kg per day in two to four divided doses) is effective in treating streptococcal pharyngitis;³³ however, the efficacy of a twice-daily regimen in adults requires further study. The maximum dose of erythromycin is 1 g/d. Although strains of GAS resistant to erythromycin are prevalent in some areas of the world and have resulted in treatment failures,³⁴ they are uncommon in most parts of the United States.³⁵

The new macrolide azithromycin has a similar susceptibility pattern to that of erythromycin against GAS but may cause less frequent gastrointestinal side effects. Azithromycin can be administered once daily and produces high tonsillar tissue concentrations.^36-38 A 5-day course of azithromycin is approved by the Food and Drug Administration as a second-line therapy for the treatment of individuals 16 years of age or older with GAS pharyngitis. The recommended dosage is 500 mg as a single dose on the first day, followed by 250 mg once daily for 4 days.³⁶

A 10-day course of an oral cephalosporin is an acceptable alternative, particularly for penicillin-allergic individuals. Narrower-spectrum cephalosporins such as cefadroxil or cephalexin are probably preferable to the broader-spectrum cephalosporins such as cefaclor, cefuroxime, cefixime, and cefpodoxime. Some penicillin-allergic persons (less than 20%) are also allergic to cephalosporins, and these agents should not be used in patients with immediate (anaphylactic-type) hypersensitivity to penicillin.(39,40)

Several reports indicate that a 10-day course with an oral cephalosporin is superior to 10 days of oral penicillin in eradicating GAS from the pharynx.^41-44 Recent reports suggest that a 5-day course with selected oral cephalosporins is comparable to a 10-day course of oral penicillin in eradicating GAS from the pharynx.^38,45-47 Such regimens are not currently approved by the Food and Drug Administration, and further studies are warranted to expand and confirm these observations.

Azithromycin and oral cephalosporins are considerably more expensive than penicillin.

Other Considerations

Some studies suggest that -lactamase-producing upper respiratory tract flora may interfere with penicillin in the treatment of GAS pharyngitis. Initial antibiotic therapy directed against these organisms remains controversial and is usually not necessary in patients with acute pharyngitis.

Certain antimicrobials are not recommended for treatment of streptococcal upper respiratory tract infections. Tetracyclines should not be used because of the high prevalence of resistant strains. Sulfonamides and trimethoprim-sulfamethoxazole will not eradicate GAS in patients with pharyngitis and should not be used to treat active infections.⁴⁸ Chloramphenicol is not recommended because of unpredictable efficacy and potential serious toxicity.

Follow-Up Throat Cultures

The majority of patients with GAS pharyngitis respond clinically to antimicrobial therapy, and GAS are eradicated from the pharynx.^{27,28,32,36,38,41-47} Post-treatment throat cultures 2 to 7 days after completion of therapy are indicated only in patients who remain symptomatic, who develop recurring symptoms, or who have had rheumatic fever and are at unusually high risk for recurrence.

Treatment Failures

Failure to eradicate GAS from the throat occurs more frequently after the administration of oral penicillin than the after administration of intramuscular benzathine penicillin G.⁴⁹ Repeated courses of antibiotic therapy are usually not indicated in asymptomatic patients who continue to harbor GAS after appropriate therapy. Many patients in whom treatment fails are chronic carriers who have prolonged periods of GAS colonization.⁵⁰ A second course of therapy in asymptomatic individuals should be considered only for those with previous rheumatic fever or members of their families. In symptomatic individuals who continue to harbor GAS in the pharynx after completion of a course of therapy, a second course, preferably with another regimen, is recommended. Agents such as amoxicillin-clavulanate, cephalosporins, clindamycin, and the combination of penicillin with rifampin may be beneficial in the treatment of patients with GAS pharyngitis in whom penicillin treatment has failed.

Carriers

Chronic streptococcal carriers (defined as individuals with positive throat cultures for GAS without illness or immunologic response to GAS antigens) usually do not need to be identified or treated with antibiotics. However, a difficult diagnostic problem arises when symptomatic upper respiratory tract viral infections develop in carriers. Because it is impossible to distinguish carriers from infected individuals, a single course of appropriate antibiotic therapy should be administered to any patient with pharyngitis and evidence of GAS by a throat swab culture or an antigen detection test. Streptococcal carriers seem to be at little risk for developing rheumatic fever. In general, chronic carriers are thought not to be important in the spread of GAS to individuals who live and work around them.

An individual with a previous attack of rheumatic fever in whom streptococcal pharyngitis develops is at high risk for a recurrent attack of rheumatic fever. A GAS infection need not be symptomatic to trigger a recurrence. Furthermore, rheumatic fever recurrence can occur even when a symptomatic infection is optimally treated. For these reasons, prevention of recurrent rheumatic fever requires continuous antimicrobial prophylaxis rather than recognition and treatment of acute episodes of streptococcal pharyngitis. Continuous prophylaxis is recommended for patients with well-documented histories of rheumatic fever (including cases manifested solely by Sydenham chorea) and those with definite evidence of rheumatic heart disease. Such prophylaxis should be initiated as soon as acute rheumatic fever or rheumatic heart disease is diagnosed. A full therapeutic course of penicillin (as outlined in Table 2) first should be given to patients with acute rheumatic fever to eradicate residual GAS, even if a throat culture is negative at that time. Streptococcal infections occurring in family members of patients with current or previous rheumatic fever should be treated promptly.

Duration of Prophylaxis

Continuous antimicrobial prophylaxis provides the most effective protection from rheumatic fever recurrences. Risk of recurrence depends on several factors. Risk increases with multiple previous attacks, whereas the risk decreases as the interval since the most recent attack lengthens.^4,6,51 In addition, the likelihood of acquiring a streptococcal upper respiratory tract infection is an important consideration. Individuals with increased exposure to streptococcal infections include children and adolescents, parents of young children, teachers, physicians, nurses and allied health personnel in contact with children, military recruits, and others living in crowded situations. A higher risk of recurrences in economically disadvantaged populations has been demonstrated.^17,52

Physicians must consider each individual situation when determining the appropriate duration of prophylaxis. The committee's recommendations are given in Table 3. Patients who have had rheumatic carditis, with or without valvar disease, are at a relatively high risk for recurrences of carditis and are likely to sustain increasingly severe cardiac involvement with each recurrence.^5,6,53 Therefore, patients who have had rheumatic carditis should receive long-term antibiotic prophylaxis well into adulthood and perhaps for life. The duration of prophylaxis depends on whether residual heart damage (valvar disease) is present or absent. For patients with persistent valvar disease, the committee recommends prophylaxis for at least 10 years after the last episode of acute rheumatic fever and at least until 40 years of age. Prophylaxis should continue even after valve surgery, including prosthetic valve replacement. For patients without persistent valvar disease, prophylaxis should continue for 10 years or well into adulthood, whichever is longer.

In contrast, patients who have had rheumatic fever without rheumatic carditis are at considerably less risk of cardiac involvement with a recurrence. Therefore, a physician may consider discontinuing prophylaxis in these individuals after several years.⁵⁴ In general, prophylaxis should continue until the patient reaches age 21 and 5 years have elapsed since the last rheumatic fever attack, whichever is longer.

In all situations, the decision to discontinue prophylaxis or reinstate it should be made after discussion with the patient of potential risks and benefits and careful consideration of the epidemiologic risk factors enumerated above.

Intramuscular Benzathine Penicillin G

An injection of 1 2000 000 U of this long-acting penicillin preparation every 4 weeks is the recommended regimen for secondary prevention in most circumstances in the United States (Table 4). In countries where the incidence of rheumatic fever is particularly high, in special circumstances, or in certain high-risk individuals, such as patients with residual rheumatic carditis, the administration of benzathine penicillin G every 3 weeks is justified and recommended.^55,56 Long-acting penicillin is of particular value in patients with high risk of rheumatic fever recurrence, especially those with rheumatic heart disease in whom recurrence is very serious. The advantages of benzathine penicillin G must be weighed against the inconvenience to the patient and pain of injection, which causes some individuals to discontinue prophylaxis.

Oral Agents

Successful oral prophylaxis depends primarily on patient adherence to prescribed regimens (compliance). Patients need careful and repeated instructions about the importance of continuing prophylaxis. Most failures of prophylaxis occur in nonadherent patients. Even with optimal patient adherence, the risk of recurrence is higher in individuals receiving oral prophylaxis than in those receiving intramuscular benzathine penicillin G.⁴⁹ Oral agents are more appropriate for patients at lower risk for rheumatic fever recurrence. Accordingly, some physicians elect to switch patients to oral prophylaxis when they have reached late adolescence or young adulthood and have remained free of rheumatic attacks for at least 5 years.

Penicillin V

The dosage for children and adults is 250 mg twice daily (Table 4). There are no published data about the use of other penicillins, macrolides, or cephalosporins for the secondary prevention of rheumatic fever.

Sulfadiazine

Whereas sulfonamides are not effective in the eradication of GAS, they do prevent infection. The recommended dose of sulfadiazine is 0.5 g once a day for patients weighing 27 kg (60 lb) or less and 1.0 g once a day for patients weighing more than 27 kg. Sulfadiazine and sulfisoxazole seem to be equivalent; therefore, the use of sulfisoxazole is acceptable based on extrapolation from data demonstrating that sulfadiazine has proven effectiveness in secondary prophylaxis. The recommended dose of sulfisoxazole is the same as that for sulfadiazine. Sulfonamide prophylaxis is contraindicated in late pregnancy because of transplacental passage of the drugs and potential competition with bilirubin for albumin-binding sites.

Erythromycin

For the patient who is allergic to penicillin and sulfisoxazole, erythromycin is recommended. The dose for children and adults is 250 mg twice daily.

Patients with rheumatic valvar heart disease also require additional short-term antibiotic prophylaxis before certain surgical and dental procedures to prevent the possible development of bacterial endocarditis. Patients with prosthetic valves or previous endocarditis are at particularly high risk. Antibiotic regimens used to prevent recurrences of acute rheumatic fever are inadequate for prevention of bacterial endocarditis. The current recommendations of the American Heart Association concerning prevention of bacterial endocarditis should be followed.⁵⁷ Because -hemolytic streptococci in the oropharynx may have developed resistance to oral penicillin being used for secondary prevention of rheumatic fever, the agent selected to prevent endocarditis should be other than a penicillin. Patients who have had rheumatic fever but do not have evidence of rheumatic heart disease do not need endocarditis prophylaxis.

Multisystem manifestations that do not fulfill the Jones criteria for the diagnosis of acute rheumatic fever may develop in children and adults after acute streptococcal pharyngitis. This syndrome has been referred to as poststreptococcal reactive arthritis (PSRA). Characteristically, the arthritis of PSRA does not respond dramatically to antiinflammatory agents. Because recent reports suggest that patients with PSRA may have silent or delayed-onset carditis,⁵⁸ these patients should be carefully observed for several months for the subsequent development of carditis. Some physicians administer secondary prophylaxis to these patients for a period of up to 1 year. If carditis is not observed, prophylaxis can be discontinued. If carditis is detected, the patient should be classified as having had rheumatic fever and should continue to receive secondary prophylaxis.

COMMITTEE MEMBERSHIP

Adnan Dajani, MD, Chairperson
Arnold Bayer, MD
Ann Bolger, MD
Patricia Ferrieri, MD
Michael Gewitz, MD
Cecelia Hutto, MD
Jane Newburger, MD
Soraya Nouri, MD
Stanford Shulman, MD
Kathryn Taubert, PhD
Walter Wilson, MD

LIAISON REPRESENTATIVES

Tommy Gage, DDS, PhD
American Dental Association
Matthew Levison, MD
Infectious Diseases Society of America
Georges Peter, MD
American Academy of Pediatrics Committee on Infectious Diseases

The committee appreciates the input from various members of the Committee on Infectious Diseases of the American Academy of Pediatrics and the critical review by Dr. Floyd W. Denny. Debi Riley and Jeanette Allison rendered excellent secretarial assistance.

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The recommendations in this statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate.