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Treatment and prevention of acute rheumatic fever Authors Allan Gibofsky, MD, JD, FACP, FCLM John B Zabriskie, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2012. | This topic last updated: Jul 17, 2012. INTRODUCTION Acute rheumatic fever (ARF) is a nonsuppurative complication of pharyngeal infection with group A streptococcus. Signs and symptoms of ARF develop two to three weeks following pharyngitis and include arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum [1]. (See "Clinical manifestations and diagnosis of acute rheumatic fever".) In developing areas of the world, acute rheumatic fever and rheumatic heart disease are estimated to affect nearly 20 million people and are the leading causes of cardiovascular death during the first five decades of life [2]. In the United States and other developed countries, the incidence of ARF is much lower, likely due to improved hygienic standards and routine use of antibiotics for acute pharyngitis [3]. (See "Epidemiology and pathogenesis of acute rheumatic fever".) There is no therapy that slows progression of valvular damage in the setting of ARF. There are three major goals of treatment: Symptomatic relief of acute disease manifestations Eradication of the group A beta-hemolytic streptococcus (GAS) Prophylaxis against future GAS infection to prevent recurrent cardiac disease Issues related to treatment and secondary prevention of rheumatic fever will be reviewed here. Issues related to primary prevention (eg, treatment of streptococcal tonsillopharyngitis) and the epidemiology, pathogenesis, clinical manifestations and diagnosis of acute rheumatic fever are discussed in detail separately. (See "Treatment and prevention of streptococcal tonsillopharyngitis" and "Epidemiology and pathogenesis of acute rheumatic fever" and "Clinical manifestations and diagnosis of acute rheumatic fever".) TREATMENT Treatment of acute rheumatic fever consists of antibiotic therapy, heart failure management, and anti-inflammatory therapy. Antibiotic therapy Patients with acute rheumatic fever should be initiated on antibiotic therapy to eradicate GAS carriage. Treatment should proceed as delineated for management of streptococcal pharyngitis, whether or not pharyngitis is present at the time of diagnosis (table 1) [4]. In addition, household contacts should have throat cultures performed; those with positive results should also receive a full course of antibiotic therapy, even if asymptomatic. (See "Treatment and prevention of streptococcal tonsillopharyngitis".) Carditis Patients with severe carditis (significant cardiomegaly, congestive heart failure, and/or third-degree heart block) should be treated with conventional therapy for heart failure. (See "Clinical manifestations and diagnosis of acute rheumatic fever" and "Overview of the therapy of heart failure due to systolic dysfunction".) Valve surgery may be necessary when heart failure due to regurgitant lesions cannot be managed with medical therapy alone [5-7]. Surgical outcomes are generally better if valve surgery can be performed when carditis is quiescent [6]. Valve repair, if feasible, is preferred over valve replacement since repair avoids the need for longterm anticoagulation associated with mechanical valves and the long-term risk of deterioration of a bioprosthesis [5,7]. Section Editors Robert Sundel, MD Daniel J Sexton, MD Deputy Editor Elizabeth TePas, MD, MS

Aspirin (80 to 100 mg/kg per day in children and 4 to 8 g/day in adults) is the major anti-inflammatory agent for relief of symptoms due to acute rheumatic fever [8]. The efficacy of other anti-inflammatory drugs in the setting of active rheumatic carditis is uncertain [9-13]. A meta-analysis of eight randomized trials including 996 patients with acute rheumatic fever found no significant difference in the risk of cardiac disease at one year between the corticosteroid-treated and aspirin-treated groups [13]. No reduction in the risk of heart valve lesions was observed with corticosteroids or intravenous immunoglobulin [13]. Arthritis and rash Anti-inflammatory agents are the mainstay of symptomatic management due to acute rheumatic fever [8]. Aspirin (80 to 100 mg/kg per day in children and 4 to 8 g/day in adults) is helpful for reducing discomfort related to arthritis and fever. Anti-inflammatory therapy should be continued until all symptoms have resolved. Normalization of inflammatory markers (erythrocyte sedimentation rate and C-reactive protein concentration) may be used as indicator of resolution. The rash associated with ARF is temporary and does not require specific treatment, although antihistamines may help to alleviate pruritus. (See "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases".) PREVENTION Prevention of initial and recurrent attacks of rheumatic fever depends on control of group A streptococcal tonsillopharyngitis [14,15]. Primary prevention Prevention of initial attack of rheumatic fever (primary prevention) is accomplished by prompt diagnosis and antibiotic treatment of group A streptococcal tonsillopharyngitis. These issues are discussed in detail separately. (See "Evaluation of acute pharyngitis in adults" and "Approach to diagnosis of acute infectious pharyngitis in children and adolescents" and "Treatment and prevention of streptococcal tonsillopharyngitis".) Appropriate antibiotic treatment of streptococcal pharyngitis prevents acute rheumatic fever in most cases [16]. However, at least one third of acute rheumatic fever episodes occur in the setting of inapparent streptococcal infection [17]. In addition, rheumatic fever is not preventable in symptomatic patients who do not seek medical care. Streptococcal skin infections (such as impetigo or pyoderma) have not been proven to lead to acute rheumatic fever. (See "Impetigo".) Secondary prevention Patients who have had an attack of rheumatic fever and develop subsequent GAS pharyngitis are at high risk for a recurrent attack of rheumatic fever, with progression in severity of rheumatic heart disease from the initial episode. The most effective method to limit progression of rheumatic heart disease severity is prevention of recurrent GAS pharyngitis, especially since GAS infection need not be symptomatic to trigger a recurrent attack of rheumatic fever. For these reasons, prevention of recurrent rheumatic fever (secondary prevention) requires continuous antimicrobial prophylaxis, rather than recognition and treatment of acute GAS pharyngitis episodes. Continuous prophylaxis is warranted for patients with well-documented history of rheumatic fever (including cases with Syndenham chorea as the sole manifestation) and those with definite evidence of rheumatic heart disease. (See "Clinical manifestations and diagnosis of acute rheumatic fever".) Prior to initiation of prophylaxis, a full therapeutic course of antibiotic therapy should be given to patients with acute rheumatic fever to eradicate residual GAS, even if a throat culture is negative (table 1). (See 'Primary prevention' above.) Prophylactic antibiotics should be initiated immediately at the end of the therapeutic antibiotic course. During the course of prophylaxis, patients and their household contacts who develop acute episodes of group A streptococcal pharyngitis should be evaluated and treated promptly as outlined separately. (See "Treatment and prevention of streptococcal tonsillopharyngitis".) Duration Secondary prevention for prevention of recurrent rheumatic fever consists of years of prophylactic antibiotic administration. The total duration depends risk of recurrent rheumatic fever and severity of disease. The risk of recurrent rheumatic fever depends on several factors [4,10]:

The number of previous attacks Time since the last attack Risk of exposure to streptococcal infections Patient age Presence or absence of cardiac involvement Risk is increased among individuals with ongoing exposure to streptococcal infections including children, those in close contact with children (parents, healthcare workers) and those living in crowded situations (college students, military personnel) [18]. Risk increases with number of previous attacks but decreases as the interval lengthens since the most recent attack. The optimal duration of antibiotic prophylaxis following acute rheumatic fever is uncertain. Patients who have had rheumatic carditis (with or without valvular disease) are at relatively high risk for recurrent carditis and are likely to sustain increasingly severe cardiac involvement with each recurrence [19,20]. Therefore, in general, prophylaxis in the setting of carditis should continue until the patient is a young adult (21 years of age), which is usually 10 years from an acute attack with no recurrence (table 2) [4,21,22]. This approach was evaluated in a Chilean study of 59 patients with history of ARF judged to be at relatively low risk for recurrence of acute rheumatic fever [22]. Among patients with history of ARF without carditis, prophylaxis was discontinued after 5 years or at age 18 (whichever was longer). During 3349 patient-months of followup, only two acute rheumatic fever recurrences were observed (0.7 per 100 patient-years). These data suggest that acute rheumatic fever prophylaxis can likely be discontinued safely in young adults judged to be at low risk for recurrence who are maintained under careful prospective surveillance. The duration of prophylaxis following acute rheumatic fever is outlined by severity category in the Table (table 2) [4,23]. Antibiotic prophylaxis should continue even after valve surgery, including prosthetic valve replacement. Upon reaching the end of a planned course for secondary prophylaxis, the risk for GAS exposure and severity of valvular disease should be reviewed. A decision regarding cessation or continuation of antibiotic prophylaxis should be made based on individual clinical risks and benefits. Antibiotic selection The preferred antibiotic approach for secondary prevention of recurrent rheumatic fever is administration of long acting benzathine penicillin G (Bicillin L-A) intramuscularly every four weeks (table 3) [4,24]. Since the early descriptions of benzathine penicillin use in the 1940s and 1950s, there are data suggesting that some benzathine penicillin preparations may have a shorter duration of protection [25]; further study is needed. A shorter dosing interval (eg, administration every two to three weeks) is appropriate for populations in which the incidence of rheumatic fever is particularly high. This approach is also warranted for individuals in low-incidence regions who have had recurrent acute rheumatic fever despite adherence to a regimen administered every four weeks. The long-term benefits of intramuscular benzathine penicillin G prophylaxis outweigh the risk of allergic reaction, as life-threatening allergic reactions are rare [26]. However, the advantages of this approach must be weighed against the inconvenience and pain associated with injection. Options for oral prophylaxis include penicillin V, sulfadiazine and macrolides. Success with oral prophylaxis depends on patient adherence, so clear communication regarding the importance of prophylaxis and how antibiotics should be taken is critical. Even with optimal adherence, the risk of recurrence is higher in individuals receiving oral prophylaxis than those receiving intramuscular benzathine penicillin G [27]. This was illustrated in a controlled trial of 405 children and adolescents with rheumatic fever assigned to receive four weeks of intramuscular benzathine penicillin G, oral potassium penicillin G or oral sulfadiazine. In the first two years of the study, streptococcal infections recurred in 7, 20 and 24 percent of patients, respectively; rheumatic fever recurred in 0, 4.8, and 2.7 percent of the patients, respectively. Therefore, parenteral prophylaxis is preferred for patients at high risk for rheumatic fever recurrence; oral agents are appropriate for patients at lower risk for rheumatic fever recurrence. Accordingly, switching from intramuscular to oral prophylaxis once patients have reached young adulthood and have remained free of rheumatic attacks is appropriate.

The preferred oral agent is penicillin V (table 3). Sulfadiazine or sulfisoxazole is appropriate for patients allergic to penicillin; this antibiotic class is effective for preventing GAS infection although it cannot be used to achieve eradication. An oral macrolide such as azithromycin is acceptable for patients allergic to both penicillin and sulfa drugs. Prior to initiation of prophylaxis, a full therapeutic course of antibiotic therapy should be given to patients with acute rheumatic fever to eradicate residual GAS, even if a throat culture is negative (table 1). Prophylactic antibiotics should be initiated immediately at the end of the therapeutic antibiotic course. During the course of prophylaxis, patients and their household contacts who develop acute episodes of group A streptococcal pharyngitis should be evaluated and treated promptly. (See "Treatment and prevention of streptococcal tonsillopharyngitis".) Poststreptococcal reactive arthritis Poststreptococcal reactive arthritis (PSRA) is a reactive arthritis that occurs after a symptom-free interval following GAS pharyngitis. It differs from the arthritis associated with ARF, as outlined separately. (See "Clinical manifestations and diagnosis of acute rheumatic fever", section on 'Differential diagnosis'.) PSRA can be difficult to distinguish from arthritis associated with ARF on clinical grounds, and a small proportion of patients with PSRA have been observed to develop valvular heart disease [28,29]. For this reason, some favor administering secondary prophylaxis in the setting of suspected PSRA for up to one year after the onset of symptoms, although the efficacy of this approach is not well established [4]. Evidence of valvular disease after one year should prompt continued prophylaxis as outlined in the preceding sections, and it may be presumed that the presenting symptoms were manifestations of acute rheumatic fever. In the absence of valvular disease after one year, antibiotic prophylaxis may be discontinued. SUMMARY AND RECOMMENDATIONS We recommend that patients with acute rheumatic fever be initiated on antibiotic therapy as delineated for eradication of streptococcal pharyngitis, whether or not pharyngitis is present at the time of diagnosis (table 1) (Grade 1C). (See 'Treatment' above.) Patients with severe carditis should be treated with conventional therapy for heart failure. Valve surgery may be necessary when heart failure due to regurgitant lesions cannot be managed with medical therapy alone. Aspirin is the mainstay of symptomatic management due to acute rheumatic fever. (See 'Carditis' above and 'Arthritis and rash' above.) Prevention of initial attack of rheumatic fever (primary prevention) is accomplished by prompt diagnosis and antibiotic treatment of group A streptococcal tonsillopharyngitis. (See "Treatment and prevention of streptococcal tonsillopharyngitis".) Prevention of recurrent rheumatic fever (secondary prevention) requires prevention of recurrent GAS pharyngitis. We recommend continuous antimicrobial prophylaxis, rather than recognition and treatment of acute GAS pharyngitis episodes (Grade 1B). (See 'Secondary prevention' above.) In general, prophylaxis for in the setting of carditis should continue until the patient is a young adult (18 years of age), which is usually 10 years from an acute attack with no recurrence (table 2). At the end of a planned course for secondary prophylaxis, the risk for GAS exposure and severity of valvular disease should be reviewed. (See 'Duration' above.) We suggest long-acting benzathine penicillin G for secondary prevention of recurrent rheumatic fever (table 3) (Grade 2B). Switching from intramuscular to oral prophylaxis once patients have reached young adulthood and have remained free of rheumatic attacks is appropriate. (See 'Antibiotic selection' above.) We suggest administering secondary prophylaxis in the setting of suspected poststreptococcal reactive arthritis for up to one year after the onset of symptoms (Grade 2C). Evidence of valvular disease after one year should prompt continued prophylaxis; otherwise, antibiotic prophylaxis may be discontinued.

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GRAPHICS
Treatment of pharyngitis due to group A streptococcus
Adults and adolescents (>27 kg)
Oral penicillin V* (phenoxymethyl penicillin) 500 mg two to three times daily for 10 days Intramuscular penicillin, single dose Penicillin G benzathine and penicillin G procaine (Bicillin C-R) 2.4 million units or penicillin G benzathine (Bicillin L-A) 1.2 million units Amoxicillin 875 mg orally twice daily or 500 mg three times daily for 10 days Cephalexin 500 mg orally twice daily for 10 days 25-50 mg/kg per day orally in two equally divided doses (maximum 1000 mg per day) for 10 days 50 mg/kg per day orally (maximum 1000 mg per day). May be administered once daily or in two or three equally divided doses; duration is 10 days Penicillin G benzathine and penicillin G procaine (Bicillin C-R 900/300) 1.2 million units. Consists of benzathine penicillin G 900,000 units mixed with procaine penicillin G 300,000 units. 250 mg two to three times daily for 10 days

Children (27 kg)

For patients with potential severe hypersensitivity to beta-lactam antibiotics (eg, penicillin, cephalosporins): Azithromycin 500 mg orally on day one followed by 250 mg daily on days two through five Clindamycin 28 to 70 kg: 20 mg/kg/day orally in three equally divided doses for 10 days >70 kg: 450 to 600 mg orally three times daily for 10 days * Oral penicillin V is the drug of choice for GAS pharyngitis. Penicillin G benzathine and penicillin G procaine (Bicillin C-R 900/300) requires further study before routine use in adults or large adolescents is acceptable. Bicillin L-A (benzathine penicillin G 600,000 units IM) is an acceptable alternative regimen for patients <27 kg. Although single dose amoxicillin is recommended by the 2009 AHA guidelines, its superiority over the doses listed has not been proven definitively, and it is not approved for children younger than 12. Dose alteration needed for severe renal insufficiency. Other cephalosporins also acceptable (cefadroxil, cefprozil, cefaclor, cefuroxime, loracarbef, cefdinir, cefpodoxime, cefixime and ceftibuten). Cefpodoxime and cefdinir are US FDA approved for five days of therapy; all other cephalosporins require 10 days of therapy. Erythromycin or clarithromycin also acceptable (10 days of therapy). Modified with permission from: Gerber, MA, Baltimore, RS, Eaton, CB, et al. Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis: A Scientific Statement From the American Heart 20 mg/kg per day orally in three equally divided doses for 10 days 12 mg/kg orally once daily for five days

Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation 2009; 119(11):1541-51. Copyright 2009 Lippincott Williams & Wilkins. Additional data from: American Academy of Pediatrics. Group A Streptococcal infections. In: Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed, Pickering, LK (Ed), American Academy of Pediatrics, Elk Grove Village, IL 2006. p.610.

Secondary prophylaxis for rheumatic fever - Duration of therapy

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

Duration after last attack

10 years or until 40 years of age (whichever is longer); sometimes lifelong prophylaxis (see text)

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

10 years or until 21 years of age (whichever is longer)

5 years or until 21 years of age (whichever is longer)

* Clinical or echocardiographic evidence. Modified with permission from: Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis: A Scientific Statement From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation 2009; 119(11):1541-51. Copyright 2009 Lippincott Williams & Wilkins.

Secondary prophylaxis for rheumatic fever - Selection of therapy

Continuous regimen
Adults >27 kg Penicillin G benzathine intramuscular (Bicillin LA) Penicillin V oral Sulfadiazine Allergy to penicillin and sulfadiazine:
Azithromycin 250 mg orally once daily 5 mg/kg orally once daily (up to 250 mg)

Children 27 kg 600,000 units every 4 weeks* 250 mg orally twice daily 500 mg orally once daily

1.2 million units every 4 weeks* 250 mg orally twice daily 1000 mg orally once daily

* In high-risk situations, administration every three weeks is justified and recommended. For small children and infants: 25,000 units per kg intramuscularly every 4 weeks or 3 weeks (high-risk). Macrolide susceptibility testing should be pursued prior to use of this drug class. Erythromycin is an acceptable alternative to azithromycin, although the latter has fewer adverse effects and permits once daily dosing. Erythromycin dosing for adults: 250 mg orally twice daily. Dosing for children: 20 mg/kg/day divided twice daily (maximum 500 mg per day). Modified with permission from: Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis: A Scientific Statement From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation 2009; 119(11):1541-51. Copyright 2009 Lippincott Williams & Wilkins.

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