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Rheumatic Fever
Jonathan Schimmel, MD
Achyut B. Kamat, MD
image BASICS
  • Acute rheumatic fever (ARF) is a delayed inflammatory sequela of group A Streptococcus (GAS) tonsillopharyngitis that affects multiple organ systems.
  • Can lead to rheumatic heart disease (RHD)
  • Recurrence in adults and children is common if antibiotic prophylaxis is withheld.
  • Systems affected: cardiovascular, nervous, hematologic/lymphatic/immunologic, skin/exocrine, musculoskeletal
Pediatric Considerations
Can affect any age but most common ages 5 to 15 years
  • ARF and RHD are now largely restricted to developing countries and some poor populations of wealthy countries.
  • Male = female, but females more likely to develop chorea.
  • Can occur as an epidemic
  • Worldwide, incidence (new cases) has been declining for decades, attributed to increasing antibiotic use and improved living conditions. Most new cases are in developing countries.
  • In early studies, ARF developed in 3% of children with untreated GAS pharyngitis.
  • Incidence of ARF in the United States in the 1960s was 13.3/100,000 and is currently <1/100,000.
  • 95% of cases currently occur in developing countries.
Worldwide, more than 15 million people have RHD, and prevalence has been rising due to improved medical care and longer survival (despite decreasing incidence of ARF).
  • Preceded by tonsillopharyngitis of GAS, also known as Streptococcus pyogenes, a gram-positive organism
  • Molecular mimicry: Antibodies against M protein on GAS cross-reacts with cardiac and vessel endothelial proteins, leading to an inflammatory cascade.
  • Susceptibility is associated with certain genetic polymorphisms, including toll-like receptors, cytokines, and human leukocyte antigen genes. Not fully understood
  • Increased susceptibility in certain populations, including Australian aborigines, New Zealand Maori, and Pacific Islanders
Genetic susceptibility and possible increased risk with iron deficiency or low serum albumin.
  • Primary prevention: Antibiotics are effective at reducing incidence of ARF after known or suspected GAS pharyngitis. Number needed to treat is 100 (1)
  • Secondary prevention: long-term antibiotic prophylaxis to prevent recurrence
  • Requires laboratory evidence of preceding GAS infection (see “Initial Tests (lab, imaging)”).
  • Revised Jones criteria
  • Initial ARF: 2 major OR 1 major + 2 minor
  • Recurrent ARF: 2 major OR 1 major + 2 minor OR 3 minor

    Major Criteria

    Minor Criteria

    • Carditis/valvulitis

    • Low-risk: fever ≥38.5°C

    • Mod-high risk: fever ≥38°C

    • Low-risk: polyarthritis

    • Mod-high risk: mono/polyarthritis

    • Low-risk: polyarthralgia

    • Mod-high risk: monoarthralgia

    • Sydenham chorea

    • Erythema marginatum

    • ↑PR interval

    • CRP ≥3 mg/dL, and/or

    • Low-risk: ESR ≥60 mm/hr

    • Mod-high risk: ESR ≥30 mm/hr

    • Subcutaneous nodules

  • The revised criteria distinguish between patients with low-risk versus moderate-high risk of having ARF. Patients can be considered low-risk if they are from and among a low incidence group (2)[C].
  • Neuro: Sydenham chorea: Involuntary movements may be general or unilateral and may involve the face. “Milkmaid grip” is intermittent hypotonia appreciated on test of grip strength.
  • Cardiac: pericardial friction rub, blowing holosystolic murmur, rarely diastolic, or new or changing murmur; rarely evidence of heart failure
  • Skin
    • Subcutaneous nodules (<10%): firm, painless, up to 2 cm, over bony surfaces or tendons, usually extensor surfaces. More common in severe ARF, persists up to several weeks
    • Erythema marginatum (5-13%): nonpruritic, blanching, evanescent, pale pink macular transitions to central clearing, found on trunk and occasionally limbs, accentuated by warming the skin
  • Systemic lupus erythematosus
  • Poststreptococcal reactive arthritis
  • Juvenile rheumatoid arthritis
  • Infectious arthritis
  • Viral myocarditis
  • Innocent cardiac murmur
  • Tourette syndrome
  • Kawasaki syndrome
  • Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)
Initial Tests (lab, imaging)
  • Bacteriologic/serologic evidence of GAS infection (2)[B]:
    • Rapid streptococcal antigen test with high pretest probability
    • Throat culture (sensitivity 25% by time of ARF)
    • Elevated or rising antistreptolysin O (ASO) titer; peaks ˜1 month postinfection.
  • If ASO negative, check anti-DNAse B (peaks ˜2.5 months, remains elevated up to 9 months), streptokinase, and antihyaluronidase (3).
  • Bacteriologic/serologic evidence may be negative in chorea or chronic indolent rheumatic carditis.
  • ESR and CRP are acute-phase reactants that almost always increase in ARF.
  • CBC with differential: leukocytosis, possible normocytic anemia
  • Complement levels normal (do not need to check)
  • ECG: PR prolongation, AV block, signs of pericarditis
  • Arthrocentesis of affected joints shows sterile inflammatory fluid with 10 to 100,000 WBC/mm3.
  • Chest x-ray: may have cardiomegaly from myocarditis
  • Echocardiogram: Assess chamber size and function, pericardial effusion, and valve disease.
  • All cases of confirmed or suspected ARF should have an echocardiogram (2)[B], due to the 18% prevalence of subclinical carditis.
  • Antimyosin scintigraphy can detect carditis (nonspecific).

Follow-Up Tests & Special Considerations
  • ESR and CRP are useful to monitor rebound inflammation.
  • Repeat echocardiograms to monitor evolution of carditis, even if not initially present (2)[C].
  • Household contacts should be screened with throat culture even if asymptomatic and treated with antibiotics if positive.
Test Interpretation
Prior treatment with aspirin or steroids may lead to falsely normal lab results.
  • Antibiotic
  • Anti-inflammatory agent (aspirin or naproxen)
  • Manage cardiac manifestations as needed in addition to standard ARF treatment (e.g. dysrhythmia, pericarditis, myocarditis, valvular disease, or heart failure).
First Line
  • Eradication: Treat initially as if active GAS infection, then begin prophylaxis.
  • If no penicillin allergy
    • Penicillin VK PO BID for 10 days, or benzathine penicillin G IM for 1, or amoxicillin PO for 10 days (preferred in children) (4)[A]
  • If penicillin allergy
    • Cephalosporin 1st generation PO for 10 days (4)[A], azithromycin PO for 5 days, or clindamycin PO for 10 days, or clarithromycin PO for 10 days (4)[B]
  • If there is heart failure, AV block third degree, or other severe manifestations of carditis, appropriate traditional management should be initiated.
  • Aspirin high-dose is effective for treatment of arthritis and fever (5)[B], but has not been shown to reduce or improve cardiac manifestations (6)[B]. High-dose aspirin for prolonged periods risks salicylate toxicity and if used, consider following salicylate levels.
  • If severe carditis is present, consider prednisone, although not shown to prevent or reduce cardiac manifestations (6)[B].
  • Chorea generally self-resolves and does not require treatment, but if symptoms are severe, can use valproic acid, carbamazepine, or an antipsychotic if still resistant (3)[B]. If symptoms persist, consider prednisone, which unlike cardiac disease has been shown effective for Sydenham chorea (3)[B].
Second Line
  • If penicillin allergy is present, erythromycin is preferred by the New Zealand guidelines, but not by the Infectious Diseases Society of America.
  • Naproxen is a reasonable alternative to aspirin (see “Pediatric Considerations”).
A cardiologist should be involved in management of ARF.
Valve stenosis is a late sequela that can result from fibrosis and calcification; it may require surgical correction (valve repair preferred over replacement) (7).
Admission Criteria/Initial Stabilization
  • Initial hospitalization may be helpful for diagnosis and to ensure stability.
  • Heart failure requires prompt hospitalization.
IV Fluids
Only if signs of dehydration or to augment preload; use caution if heart failure present.
Consider bedrest if severe symptoms, with gradual return to ambulation as tolerated (8)[C].
  • ARF patients should be on a prophylactic antibiotic throughout childhood until age 21 years and possibly indefinitely depending on cardiac damage because recurrence can worsen prognosis (9)[C].
    • First-line prophylaxis is long-acting benzathine penicillin G monthly IM injections (9)[A].
    • Penicillin V PO 250 mg BID is an alternative but has risk of nonadherence (9)[B].
    • If penicillin allergy, treat with sulfadiazine (9)[B].
    • If penicillin and sulfa drug allergy, treat with azithromycin (9)[C].
  • If diagnostic uncertainty exists, consider 1 year of secondary antibiotic prophylaxis followed by reassessment and echocardiogram (2)[C].
  • Routine antibiotic prophylaxis for dental procedures is no longer recommended by the American Heart Association for patients with RHD (7).
  • Have low threshold to test and treat episodes of acute tonsillopharyngitis.
Patient Monitoring
Initially weekly, then every 6 months
Pediatric Considerations
  • Use aspirin with caution in children given the risk of Reye syndrome.
  • Naproxen (10 to 20 mg/kg/day) has been found noninferior to aspirin with fewer risks in ARF, in a small study (5)[B].
Pregnancy Considerations
May exacerbate valve disease, particularly mitral stenosis. Refer pregnant patients to a cardiologist.
Regular diet, or low-sodium if heart failure present.
American Heart Association: http://www.heart.org
Sequelae are generally limited to the heart and depend on the severity of carditis during an acute attack.
1. Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Cochrane Database Syst Rev. 2006;(4):CD000023.
2. Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131(20):1806-1818.
3. Oosterveer DM, Overweg-Plandsoen WC, Roos RA. Sydenham’s chorea: a practical overview of the current literature. Pediatr Neurol. 2010;43(1):1-6.
4. Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55(10):e86-e102.
5. Hashkes PJ, Tauber T, Somekh E, et al. Naproxen as an alternative to aspirin for the treatment of arthritis of rheumatic fever: a randomized trial. J Pediatr. 2003;143(3):399-401.
6. Cilliers AM, Manyemba J, Saloojee H. Anti-inflammatory treatment for carditis in acute rheumatic fever. Cochrane Database Syst Rev. 2003;(2):CD003176.
7. Webb RH, Grant C, Harnden A. Acute rheumatic fever. BMJ. 2015;351:h3443.
8. The Cardiac Society of Australia and New Zealand. New Zealand Guidelines for Rheumatic Fever: Diagnosis, Management and Secondary Prevention of Acute Rheumatic Fever and Rheumatic Heart Disease: 2014 Update. Auckland, New Zealand: Heart Foundation of New Zealand; 2014.
9. 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: endorsed by the American Academy of Pediatrics. Circulation. 2009;119(11):1541-1551.
  • I00 Rheumatic fever without heart involvement
  • I01.9 Acute rheumatic heart disease, unspecified
  • I01.0 Acute rheumatic pericarditis
Clinical Pearls
  • ARF is an inflammatory disease that affects multiple organ systems including the heart.
  • Modified Jones criteria for diagnosis include 2 major or 1 major + 2 minor manifestation in the context of a preceding documented GAS infection.
  • Treatment involves aspirin and antibiotic eradication followed immediately by long-term antibiotic prophylaxis.