Acute Rheumatic Fever

Definition
Acute rheumatic fever (ARF) is a postinfectious inflammatory syndrome following pharyngeal infections with group A streptococci. o Tends to be a recurrent illness, requiring prophylaxis against group A streptococcal infection The duration of therapy is discussed under Specific Treatments. Clinical features may include: o Common manifestations Carditis o May affect the myocardium, endocardium, or pericardium Migratory polyarthritis o Less common manifestations Sydenhams chorea: a neurologic disorder characterized by sudden and uncontrollable jerky movements and emotional lability Subcutaneous nodules Erythema marginatum: an evanescent, serpiginous rash

Epidemiology
Incidence o ~3% of persons with untreated group A streptococcal pharyngitis develop ARF. o Worldwide, ~500,000 cases occur annually with >200,000 deaths. In developing countries, it remains a significant public health problem. In industrialized countries, ARF is far less common than it was during the early and midtwentieth century. o Disease has become rare because of early treatment of streptococcal infections. Age o Most often occurs in children Peak age-related incidence is between 5 and 15 years. o Most initial attacks in adults occur at the end of the second and beginning of the third decades of life. o Recurrent attacks have been documented as late as the fifth decade.

Risk Factors

Lower standards of living, especially crowding

Etiology

o Poor access to medical care High prevalence of group A streptococci in the community Degree of host/herd immunity to the prevalent M-types in an affected community Possible predisposing genetic influence in some persons

ARF results from: o Abnormal or dysfunctional immune response to 1 as-yet-unidentified somatic or extracellular antigens produced by group A streptococci o Genetic susceptibility may play a role. HLA class ll allele associated with susceptibility o Key steps appear to be: Pharyngitis is caused by streptococcus A. o Other streptococcal infections are not associated with ARF. Antibodies are produced against streptococcal antigens. o The target antigens of these antibodies cross-react with host antigens (e.g., myosin shares epitopes with streptococcal M protein) These antibodies initiate an immunologic/inflammatory response that leads to tissue damage. T cell activation may also play a role. Specific serotypes of group A streptococcus are more often associated with development of ARF. o Serotypes 1, 3, 5, 6, 18 o Mucoid isolates o Despite the identification of "rheumatogenic strains," any streptococci capable of causing pharyngitis can cause ARF.

Symptoms & Signs

Latent period o ~3 weeks (15 weeks) between pharyngeal infection and appearance of clinical features The pharyngitis is not always symptomatic. o Exception: Chorea and indolent carditis may follow a prolonged latent period of up to 6 months. Onset is usually marked by: o Fever o Arthralgias Carditis: pancarditis involving the pericardium, myocardium, and endocardium

Present in 4060% of patients with ARF Valvular damage is the hallmark of rheumatic carditis. Mitral valve is almost always affected. o Early damage leads to regurgitation. o Later, scarring, fibrosis, and calcification can lead to stenosis. Aortic valve may be damaged as well, but less commonly. o Aortic valve disease never occurs alone, but always in concert with mitral valve disease. o Findings on clinical examination early in the disease may include: Murmur of mitral regurgitation, less often aortic insufficiency Sinus tachycardia S3 gallop Pericardial friction rub Cardiomegaly Migratory polyarthritis o Present in as many as 75% of cases o Most often affects the ankles, wrists, knees, and elbows over a period of days o Asymmetric o Arthritis is extremely painful and disabling prior to treatment. o Usually does not involve the small joints of the hands and feet; seldom involves hip joints Sydenhams chorea o Occurs in < 10% of patients with ARF o Latent period between initiating streptococcal infection and chorea may be as long as several months. o Characterized by rapid, purposeless, involuntary movements that affect primarily the face, feet, and hands, and disappear with sleep o Generalized or restricted to 1 side of the body (hemi-chorea) o Facial grimacing is common. o Emotional instability/lability may be present. o Examination shows no defect in muscle strength or sensory perception. Subcutaneous nodules o Usually present in < 5% of cases
o o

Painless, small (0.52 cm), mobile lumps beneath the skin overlying bony prominences, particularly: Hands Feet Elbows Occiput Vertebrae (occasionally) o Found over extensor surfaces of joints o Appear 23 weeks after onset of disease o Last from a few days up to 3 weeks o Commonly associated with carditis o Extremely rare in patients experiencing an initial attack o Seen most often in patients with longstanding rheumatic heart disease Erythema marginatum o Usually present in < 5% of cases o Uncommon manifestation o Evanescent macular eruption with rounded borders concentrated on the trunk Sometimes on limbs Almost never on face
o

Differential Diagnosis

Rheumatoid arthritis (juvenile or adult) Gonococcal arthritis Lyme disease Systemic lupus erythematosus Sarcoidosis Bacterial endocarditis Viral myocarditis Poststreptococcal reactive arthritis (PSRA) o It has been proposed that not all arthritis occurring after streptococcal pharyngitis represents true ARF. o This is controversial, and still under debate. o Discussion has centered on whether this truly is a distinct entity that does not require lifelong antibiotic prophylaxis. o Current guidelines state that: If the Jones criteria are fulfilled (see Diagnostic Approach), treat the patient as though ARF is present. If, as may rarely occur, the Jones criteria are not fulfilled, and other causes of arthritis (e.g., rheumatoid disease) are ruled out, the patient may be said to have PSRA.

These patients may not need antibiotic prophylaxis, but this issue has not been definitively addressed.
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Diagnostic Approach
Diagnosis is based on clinical symptoms but requires supporting evidence from microbiology and immunology laboratories. The Jones Criteria for rheumatic fever, updated in 1992: o Major criteria Carditis: pancarditis involving the pericardium, myocardium, and endocardium Migratory polyarthritis o To qualify as a major criterion, must be objective evidence of inflammation (i.e., not just arthralgias without clinical findings) Sydenhams chorea Subcutaneous nodules Erythema marginatum o Minor criteria Clinical o Fever o Arthralgias Laboratory o Elevated acute phase reactants Electrocardiogram o Prolonged PR interval o To fulfill the Jones Criteria Either 2 major criteria or 1 major criterion and 2 minor criteria plus o Evidence of an antecedent streptococcal infection Supporting evidence of a recent group A streptococcal infection o Positive throat culture or rapid antigen detection test and/or o Elevated or rising anti-streptolysin O or other streptococcal antibody test o A 2002 review of the Jones criteria left them intact, but added certain caveats: In areas of high prevalence, the Jones criteria may underdiagnose ARF. Use of echocardiography in patients without cardiac findings is unsupported, since mitral or aortic regurgitation can be found in many persons without ARF or other overt cardiac disease.

Laboratory Tests

No one specific laboratory test can establish a diagnosis of ARF. o Recommended tests Acute phase reactants o C-reactive protein Erythrocyte sedimentation rate Peripheral leukocyte count Blood cultures (if febrile) Clinical microbiology and clinical immunology tests are needed to confirm the diagnosis. o Rapid streptococcal antigen detection test If negative, a confirmatory throat culture must be performed. o Throat culture for group A streptococci (obtain 2 or 3 cultures) Group A streptococci can be recovered from the upper respiratory tract of only 2540% of patients at the time the diagnosis is made. o Anti-streptolysin O titer At least 80% of patients with ARF have an elevated anti-streptolysin O titer at presentation. An initially elevated titer is convincing. o Demonstrating an increase in titer from the acute to the convalescent phase is more reliable. o With 2 additional streptococcal antibody tests, the percentage of patients who show evidence of a preceding group A streptococcal infection will increase to > 95%. Anti-DNAse B Anti-hyaluronidase test o Repeat anti-streptolysin O and anti-DNAse B titers 1014 days later if test not confirmatory.

Imaging
Echocardiography may reveal: o Mitral regurgitation o Cardiomegaly o Echocardiographic demonstration of valvular regurgitation cannot be used as a major diagnostic criterion in patients without cardiac findings on examination, since this is a common finding in normal individuals. Chest x-ray o If clinical or echocardiographic evidence of carditis

Diagnostic Procedures

Electrocardiography may show:

o o

Sinus tachycardia Prolonged PR interval (first-degree heart block) Second- and third-degree heart block can also occur.

Treatment Approach
At the time of diagnosis, all patients must be treated as if they have a group A streptococcal infection, whether or not the organism is recovered by culture. Two subsequent therapeutic interventions are necessary for all patients with ARF: o Prophylactic anti-streptococcal antibiotic therapy for at least 5 years

In many patients, lifelong prophylaxis is recommended. Acute therapy for clinical manifestations

Specific Treatments
Conventional antibiotic treatment Start immediately. Complete a 10-day course in adults. o Oral penicillin V (500 mg bid) o Intramuscular benzathine penicillin G (a single intramuscular injection of 1.2 million U) Some choose as initial treatment of the presumed streptococcal infection Also serves as the first dose of secondary prophylaxis for prevention of recolonization of the upper respiratory tract Can result in a transient elevation of the erythrocyte sedimentation rate, which can prove confusing in the acute phase of the disease o Amoxicillin (50 mg/kg daily, maximum 1 g) Patients with penicillin allergy [1] o Erythromycin (250 mg bid for 10 days) or o Clindamycin (20 mg/kg tid, maximum 1.8 g/d for 10 days) or o Azithromycin (12 mg/kg daily, maximum 500 mg for 5 days) or o Clarithromycin (15 mg/kg bid, maximum 250 mg bid for 10 days) or o Narrow-spectrum cephalosporin (i.e., cephalexin, cefadroxil) Avoid in patients with immediate (type l) hypersensitivity to penicillin.

Secondary prophylaxis To prevent subsequent infection of upper respiratory tract with group A streptococci o Recommendations of the American Heart Association (AHA) and of the World Health Organization (WHO) are for: Benzathine penicillin G (IM injection of 1.2 million U every 4 weeks)or Oral penicillin V (250 mg bid) or Oral sulfadiazine (1.0 g/d) o Patients with penicillin allergies Erythromycin (250 mg bid) or Azalides o In patients who are at high risk for recurrence of ARF: Benzathine penicillin G IM given every 3 weeks is more effective in reducing the risk of recurrence. o Risk of recurrence of ARF is highest during the first 5 years after the attack; secondary prophylaxis is always given for at least this period. Risk of recurrence increases with multiple previous attacks. o After 5 years, the duration of prophylaxis is often individualized for specific patients weighing risks and benefits. The decision to continue or discontinue secondary prophylaxis depends on: o Whether the patient has documented rheumatic heart disease o Whether patients are at high risk of exposure, e.g., students, school teachers, medical or military personnel o Many believe that those with documented recurrences and/or documented rheumatic valvular heart disease should receive secondary prophylaxis for life. o Suggested duration of secondary prophylaxis Patients without proven carditis o 5 years after last attack or 21 years of age (whichever is longer) Patients with carditis (mild mitral regurgitation or healed carditis) o 10 years after last attack or 25 years of age (whichever is longer)

More severe valvular disease Lifelong Valvular surgery o Lifelong

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Treatment of clinical manifestations Medical therapy depends on the clinical status of the patient. Adult patients with arthritis, arthralgias, fever o Salicylate in doses escalating to 2 g qid o Aspirin is drug of choice. 48 g/d in adults divided in 45 doses up to 2 weeks Reduce dose to 6070 mg/kg daily for next 24 weeks. o May be given for 46 weeks and gradually tapered to prevent a rebound Erythrocyte sedimentation rate is 1 method for determining rate of taper for salicylates (usually at least 2 weeks). o Naproxen 1020 mg/kg daily Good symptomatic response Less studied o Hold salicylates and NSAIDs until diagnosis confirmed. If given prior to diagnosis, it may be difficult to confirm the diagnosis of ARF. o No indication for use of steroids solely for arthritis Carditis o Corticosteroids play a role in patients with severe carditis accompanied by congestive heart failure. In adults, prednisone or prednisolone can be started at dosages as high as 30 mg PO qid in especially severe cases. Recommended at doses of 12 mg/kg daily (maximum 80 mg) Potential benefits weighed against adverse effects (i.e., GI bleed, fluid retention) With improvement, salicylates can be added during steroid dose tapering (46 weeks). Chorea o In mild cases Generally no treatment recommended o In severe cases Carbamazepine or sodium valproate Use for 12 weeks after symptoms resolve.

Monitoring

In severe refractory cases only Intravenous immunoglobin (IVIG) Congestive heart failure o Conventional medical measures o See Chronic Heart Failure.
o

Monitor for disease progression and development of valvular disease. Erythrocyte sedimentation rate o Can be measured periodically to help in determining the rate of salicylate tapering o Patients should not resume full activity until the erythrocyte sedimentation rate normalizes. Echocardiography o Periodic follow-up to check for resolution or progression of heart disease Initially at 1 month to determine progression of carditis o Consider repeating after 1 month if initially negative. Electrocardiogram o Repeat in 2 weeks and at 2 months if prolonged PR interval or other heart block or rhythm abnormality.

Complications
Recurrence Cardiac complications o Valvular stenosis and/or regurgitation Most serious complication Mitral valve is involved most frequently, followed by the aortic valve. See Mitral Stenosis, Mitral Regurgitation, and Aortic Stenosis for details. o Infective endocarditis Minor degrees of rheumatic valvular involvement can increase susceptibility to infective endocarditis. See Infective Endocarditis for details. o Congestive heart failure o Cardiac arrhythmias o Pericarditis Sydenhams chorea o Varies in severity from mild to disabling o Eventually resolves completely, usually within 6 weeks

Prognosis

Prognosis depends on the severity of the initial carditis.

Those with severe carditis are prone to more severe rheumatic heart disease and are more susceptible to recurrence. o Those with mild carditis (no cardiomegaly or acute decompensation) are less prone to rheumatic heart disease and recurrence. o Those without carditis are least prone to recurrence and are unlikely to develop carditis if rheumatic fever recurs.
o

Prevention
Prompt and appropriate treatment of group A streptococcal infection o Strep throat o Scarlet fever See Infective Endocarditis: Prevention for endocarditis prophylaxis in patients with rheumatic heart disease.

ICD-9-CM
390 Rheumatic fever without mention of heart involvement [includes rheumatic fever (active) (acute)]

See Also

Aortic Regurgitation Aortic Stenosis Infective Endocarditis Mitral Regurgitation Mitral Stenosis Streptococcal Infections, Group A Tricuspid Valve Disease

Internet Sites
Professionals o Rheumatic Fever U.S. Centers for Disease Control and Prevention Patients o Rheumatic fever MedlinePlus: Medical Encyclopedia o Rheumatic Heart Disease/Rheumatic Fever American Heart Association

References
1. Gerber MA 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: endorsed by the American Academy

of Pediatrics.Circulation 119:1541, 2009 [PMID:19246689]

General Bibliography
Bisno AL et al: Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Infectious Diseases Society of America.Clin Infect Dis 35:113, 2002 [PMID:12087516] Carapetis JR, McDonald M, Wilson NJ: Acute rheumatic fever. Lancet366:155, 2005 Jul 9-15 [PMID:16005340] Ferrieri P, Jones Criteria Working Group: Proceedings of the Jones Criteria workshop. Circulation 106:2521, 2002 [PMID:12417554] Raju BS, Turi ZG: Rheumatic fever, in Braunwalds Heart Disease, 8th ed, P Libby et al (eds). Philadelphia, Saunders, 2008 This topic is based on Harrisons Principles of Internal Medicine, 17th edition, chapter 315, Acute Rheumatic Fever by JR Carapetis.

PEARLS
Patients with ARF should be treated with antibiotics in order to eliminate streptococci from the pharynx even if symptomatic pharyngitis is absent. Although less and less common in the developed world, rheumatic heart disease remains the major cause of acquired valvular disease in the world.