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Acute Rheumatic Fever¶

Chapter 371 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 371

Key Clinical Points¶

Acute rheumatic fever (ARF) is a multisystem autoimmune disease resulting from an infection with group A Streptococcus (GAS).
Valvular damage (rheumatic heart disease [RHD]) is the hallmark of rheumatic carditis; the mitral valve is almost always affected.
Diagnosis requires evidence of preceding GAS infection plus 2 major or 1 major + 2 minor Jones criteria manifestations.
Secondary prophylaxis with benzathine penicillin G (1.2 million units IM every 4 weeks) is the mainstay of preventing recurrence.
RHD is the most common cause of acquired heart disease in children in low- and middle-income countries (LMICs).
Pathogenesis involves 'molecular mimicry' where immune responses to streptococcal antigens (M protein) cross-react with human tissues.
Chorea (Sydenham's) may occur alone or with other features, often following a long latent period of up to 6 months.
Echocardiography is essential for diagnosing subclinical carditis and staging RHD (Stages A–D).
Low-risk populations (ARF incidence ≤ 2 per 100,000) have different Jones criteria thresholds compared to moderate/high-risk populations.
Primary prevention focuses on timely treatment of GAS pharyngitis; secondary prevention focuses on long-term antibiotic prophylaxis.

DEFINITION & OVERVIEW¶

• Definition (Harrison's 22e): ◦ Acute rheumatic fever (ARF) is a multisystem disease resulting from an autoimmune reaction to infection with group A Streptococcus. • Clinical Course: ◦ Most manifestations resolve completely. ◦ Exception: Cardiac valvular damage (rheumatic heart disease [RHD]) may persist after other features disappear. • Global Impact: ◦ RHD is the most common cause of acquired heart disease in children in LMICs. ◦ >40 million people worldwide affected by RHD; >300,000 deaths annually. ◦ 95% of ARF cases and RHD deaths occur in developing countries (sub-Saharan Africa, Pacific nations, Australasia, China, South/Central Asia).

EPIDEMIOLOGY¶

• Age Distribution: ◦ ARF: Primarily children aged 5–14 years. ◦ RHD: Peaks between 25 and 40 years. • Gender/Risk Factors: ◦ No clear gender association for ARF. ◦ RHD more commonly affects females (up to twice as frequently). ◦ ~3–6% of any population may be susceptible to ARF. • Risk Factors: ◦ Exposure to Group A streptococcal upper respiratory tract infection. ◦ Overcrowded living conditions, rural/urban slum residence, and poverty. ◦ Poor access to health care or failure to seek treatment. ◦ Female gender (specifically for chorea). ◦ Inadequate diagnosis/treatment of streptococcal pharyngitis.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Pathogen: ◦ Primarily group A streptococci. ◦ Many M-serotypes are rheumatogenic (e.g., 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29). • Pathogenesis Theory: ◦ Molecular Mimicry: Immune response to streptococcal antigens (M protein) cross-reacts with human tissues. ◦ Mechanism: Antigen processing cells → T cell activation → activation of humoral/cellular immunity → cross-reactive antibodies bind to heart valve endothelial cells → activation of VCAM-1 → recruitment of lymphocytes and cell lysis via complement → release of peptides (laminin, keratin, tropomyosin) → further activation of cross-reactive T cells leading to tissue damage and epitope spreading. • Host Factors: ◦ Susceptibility is an inherited characteristic (44% concordance in monozygotic twins vs. 12% in dizygotic; heritability ~60%). ◦ Genetic associations: HLA class II alleles, polymorphisms in TNF and mannose binding lectin, IGH locus (IGHV4-61*02), and complement factor H.

CLINICAL FEATURES¶

• General Presentation: ◦ Latent period: ~3 weeks (1–5 weeks) between infection and ARF symptoms. ◦ Exceptions: Chorea and indolent carditis may have latent periods up to 6 months. ◦ Common features: Polyarthritis (60–75%) and carditis (50–75%). ◦ Fever: Usually high-grade (≥39°C), but lower grades occur. • Heart Involvement: ◦ Up to 75% of ARF patients progress to RHD. ◦ Mitral valve is almost always affected; isolated aortic involvement is rare. ◦ Early damage leads to regurgitation; long-term results in leaflet thickening, scarring, calcification, and stenosis. ◦ Myocardial inflammation may cause P-R interval prolongation (1st-degree AV block) and muffled S1. • Joint Involvement: ◦ Polyarthritis: Most common form; typically migratory, asymmetric, involving large joints (knees, ankles, hips, elbows). ◦ Symptoms: Severe pain, swelling, redness; highly responsive to salicylates/NSAIDs. ◦ Aseptic monoarthritis may occur if anti-inflammatories are started early. • Chorea: ◦ Sydenham's chorea: Often occurs without other features; primarily in females. ◦ Symptoms: Darting movements of the tongue, head, and upper limbs; emotional lability/obsessive-compulsive traits. ◦ Duration: Movements usually resolve within 6 weeks (up to 6 months); associated symptoms may last longer. • Skin Manifestations: ◦ Erythema marginatum: Pink macules with serpiginous edges; evanescent; trunk/limbs, not face. ◦ Subcutaneous nodules: Painless, small (0.5–2 cm) lumps over bony prominences; appear 2–3 weeks after onset; associated with carditis.

DIFFERENTIAL DIAGNOSIS¶

• Carditis Mimics: Congenital heart disease, cardiomyopathies, pericardial effusion, infective endocarditis, mitral valve prolapse. • Arthritis Mimics: Juvenile idiopathic arthritis, systemic lupus erythematosus (SLE), reactive arthritis, septic arthritis. • Chorea Mimics: Tourette syndrome, drug-induced movement disorders, Wilson disease, Huntington disease.

INVESTIGATIONS & DIAGNOSIS¶

Evidence of Infection: ◦ Required for all cases (except chorea/low-grade carditis). ◦ Methods: Throat swab, skin sore swab, serology (ASO and anti-DNase B titers).
Clinical Assessment: ◦ Evaluate for major manifestations: Carditis, Polyarthritis, Chorea, Erythrema Marginatum, Subcutaneous Nodules.
Laboratory Monitoring (Table 371-3): ◦ Always: ECG, Echocardiogram, CBC, CRP, Streptococcal serology (ASO/ADB), Creatinine. ◦ Situational: Throat swab, skin sore swab, blood cultures, synovial fluid, pregnancy test.
Jones Criteria Application: ◦ Initial ARF: 2 major OR 1 major + 2 minor. ◦ Recurrent ARF: 2 major OR 1 major + 2 minor OR 3 minor. ◦ Major Criteria: Carditis, Polyarthritis, Chorea, Erythema marginatum, Subcutaneous nodules. ◦ Minor Criteria (Low-risk): Polyarthralgia, Fever (≥38.5°C), ESR ≥60 mm/h and/or CRP ≥3.0 mg/dL, Prolonged PR interval. ◦ Minor Criteria (Mod/High-risk): Monoarthralgia, Fever (≥38°C), ESR ≥30 mm/h and/or CRP ≥3.0 mg/dL, Prolonged PR interval.
Echocardiographic Staging (Table 371-1): ◦ Stage A (Minimal): Mild MR or AR without morphologic features; only for age ≤20. ◦ Stage B (Mild): Mild regurgitation + ≥1 morphologic feature (if age ≤20) OR ≥2 morphologic features (if age >20) OR mild MR and AR. ◦ Stage C (Advanced): Moderate/severe MR or AR, any MS or AS, pulmonary hypertension, or decreased LV systolic function. ◦ Stage D (Advanced with complications): Stage C criteria + clinical complications (heart failure, arrhythmia, stroke, infective endocarditis).
Exclusion of Alternatives: ◦ Tests: Autoantibodies (dsDNA, anti-CCP), Urine for N. gonorrhoeae/C. trachomatis, Viral panels (Hepatitis, CMV, Parvovirus, etc.).

MANAGEMENT & TREATMENT¶

Initial Management: ◦ Perform echocardiography on all cases to establish baseline carditis severity. ◦ Monitor for heart failure and initiate secondary prophylaxis.
Antibiotic Therapy: ◦ Penicillin (Oral): 500 mg (250 mg if ≤27 kg) BID; OR Amoxicillin 50 mg/kg (max 1g) daily for 10 days. ◦ Penicillin (IM): 1.2 million units (600,000 units if ≤27 kg) every 4 weeks. ◦ Erythromycin: 250 mg BID (for penicillin-allergic patients).
Symptomatic Treatment: ◦ Salicylates/NSAIDs: Aspirin (50–60 mg/kg/day, max 80–100 mg/kg/day) OR Naproxen (10–20 mg/kg/day). ◦ Glucocorticoids: Prednisone 1–2 mg/kg/day (max 80 mg), tapered over 3 weeks.
Secondary Prophylaxis (Table 371-4): ◦ No carditis: → 5 years after last attack or age 21 (whichever is longer). ◦ Carditis, no valvular disease: → 10 years after last attack or age 21 (whichever is longer). ◦ Persistent valvular disease: → 10 years after last attack or age 40 (whichever is longer); sometimes lifelong.
Follow-up: ◦ Enroll in local ARF registry; provide education on adherence to prophylaxis.

KEY PEARLS & CLINICAL TRAPS¶

• Clinical Rule: No treatment for ARF has been proven to alter the likelihood of developing or the severity of RHD. • Diagnostic Key: Echocardiography is mandatory for all suspected cases to stage RHD and assess carditis. • Prophylaxis Logic: Duration of secondary prophylaxis is strictly determined by the presence/severity of valvular disease (Table 371-4). • Early Intervention: Treatment of GAS pharyngitis within 9 days of sore throat onset prevents almost all cases of ARF.

Reference Tables¶

TABLE 371-1 Staging of Rheumatic Heart Disease Detected by Echocardiography a,b Stage A: Minimal Echocardiographic…¶

Harrison's 22e, p.2856

Stage A: Minimal Echocardiographic Criteria for RHD
Applies only to individuals aged ≤20 years old
• Clinical risk: might be at risk of valvular heart disease progression
• Echocardiographic features: the presence of mildc MR or AR without
morphologic features
Stage B: Mild RHD
Can apply to any age
• Clinical risk: at moderate or high risk of progression and at risk of developing
symptoms of valvular heart disease
• Echocardiographic features: evidence of mildc valvular regurgitation plus at
least one morphologic feature in individuals aged ≤20 years and at least two
morphologic features in individuals aged >20 yearsd; or mild regurgitation in
both mitral and aortic valves
Stage C: Advanced RHD at Risk of Clinical Complications
Can apply to any age
• Clinical risk: at high risk of developing clinical complications that require
medical or surgical intervention
• Echocardiographic features: moderate or severe MR, moderate or severe AR,
any MS or ASe, pulmonary hypertension, and decreased LV systolic function
Stage D: Advanced RHD with Clinical Complications
Can apply to any age
• Clinical risk: established clinical complications include cardiac surgery, heart
failure, arrhythmia, stroke, and infective endocarditis
• Echocardiographic features: moderate or severe MR, moderate or severe AR,
any MS or ASe, pulmonary hypertension, and decreased LV systolic function

TABLE 371-2 Jones Criteria A. For All Patient Populations with Evidence of Preceding Group A Streptococcal Infection…¶

Harrison's 22e, p.2857

A. For All Patient Populations with Evidence of Preceding Group A Streptococcal Infection
Diagnosis: initial ARF	2 major manifestations or 1 major plus 2 minor manifestations
Diagnosis: recurrent ARF	2 major or 1 major and 2 minor or 3 minor
B. Major Criteria

TABLE 371-3 Testing and Monitoring of ARF in the Acute Setting

Investigations
Always request: • Electrocardiogram (ECG) • Echocardiogram • Complete blood count (CBC) • C-reactive protein (CRP) • Streptococcal serology (antistreptolysin and anti-DNase B) In relevant situations: • Throat swab • Skin sore swab • Blood cultures • Synovial fluid aspirate • Ensure sample does not clot by using correct tubes that have been well mixed and transported promptly to the laboratory • Include request for cell count, microscopy, culture, and gonococcal polymerase chain reaction (PCR) • Pregnancy test • Creatinine test (UEC [urea, electrolytes, creatinine]) since nonsteroidal anti-inflammatory drugs can affect renal function Tests to exclude alternative diagnoses, depending on clinical presentation and locally endemic infections: • Autoantibodies, double-stranded DNA, anti–cyclic citrullinated peptide (anti-CCP) antibodies • Urine for Neisseria gonorrhoeae molecular test • Urine for Chlamydia trachomatis molecular test • Serologic or other testing for viral hepatitis, Yersinia spp., cytomegalovirus (CMV), parvovirus B19, respiratory viruses, Ross River virus, Barmah Forest virus
C. Minor Criteria
Low-risk populationsa	Moderate- and high-risk populations
Polyarthralgia	Monoarthralgia
Fever (≥38.5°C)	Fever (≥38°C)
ESR ≥60 mm in the first hour and/or CRP ≥3.0 mg/dLd	ESR ≥30 mm/h and/or CRP ≥3.0 mg/dLd
Prolonged PR intervale, after accounting for age variability (unless carditis is a major criterion)	Prolonged PR intervale, after accounting for age variability (unless carditis is a major criterion)

TABLE 371-4 American Heart Association Recommendations for Duration of Secondary Prophylaxis a¶

Harrison's 22e, p.2858

CATEGORY OF PATIENT	DURATION OF PROPHYLAXIS
Rheumatic fever without carditis	For 5 years after the last attack or 21 years of age (whichever is longer)
Rheumatic fever with persistent valvular disease, evident clinically or on echocardiography	For 10 years after the last attack, or 40 years of age (whichever is longer); sometimes lifelong prophylaxis