Acute Rheumatic Fever

• Molecular mimicry mechanism: GAS M protein (specifically M1 and M3 serotypes) shares epitopes with cardiac myosin, tropomyosin, and other sarcomeric proteins. Following streptococcal pharyngitis, cross-reactive antibodies and T cells generated against streptococcal antigens attack cardiac tissue. This explains the latency period (2-3 weeks) required for antibody generation and disease manifestation.

• Cardiac inflammation: The inflammatory infiltrate consists of activated T lymphocytes (CD4+ and CD8+) and macrophages that infiltrate all three cardiac layers. In the myocardium, this produces Aschoff bodies (pathognomonic lesions comprising central fibrinoid necrosis surrounded by Anitschkow cells and occasional multinucleated Aschoff giant cells). Endocardial involvement causes verrucous valve vegetations along the line of valve closure, particularly affecting the mitral valve (75% of cases). Pericarditis produces fibrinous inflammation and pericardial effusion.

• Chronic RHD progression: Recurrent ARF episodes lead to progressive valve fibrosis, calcification, and stenosis/regurgitation. The mitral valve is most commonly affected, followed by aortic, tricuspid, and rarely pulmonary valves. Valve damage becomes irreversible, predisposing to atrial fibrillation, heart failure, and thromboembolism.

• Group A Streptococcus pharyngitis: The sole confirmed antecedent; rheumatic strains (M types 1, 3, 5, 6, 19, 24) are most commonly associated. Skin infections (impetigo) do NOT typically precipitate ARF, as nephritogenic strains differ from rheumatogenic strains.

• Epidemiologic risk factors: Young age (peak 5-15 years), low socioeconomic status, crowded living conditions, poor nutritional status, and genetic predisposition (HLA-B5, HLA-DR2, HLA-DR3). Recurrence risk after first ARF episode is 30-50% if streptococcal reinfection occurs.

• Carditis (50% of initial ARF): Varies from subclinical myocarditis (detectable only by echo) to life-threatening heart failure. New or changing cardiac murmurs are cardinal signs: Carey-Coombs murmur (mid-diastolic apical murmur from endocarditis), Osler nodes, Janeway lesions, and splinter hemorrhages indicate severe endocarditis.

• Polyarthritis/Arthralgia (75%): Migratory polyarthritis affecting large joints (knees, ankles, shoulders, elbows) is characteristic. In low-risk populations, true polyarthritis is required for diagnosis; in high-risk populations, polyarthralgia alone suffices. Arthritis is evanescent, resolving without residual joint damage.

• Chorea (Sydenham chorea) (30%): Involuntary, purposeless movements with muscle weakness and emotional lability. Typically late manifestation (4-8 months after streptococcal infection), may occur in isolation ("pure chorea"), and may be first presentation. Completely reversible.

• Erythema marginatum (10%): Distinctive non-pruritic, pink macules with pale centers and clear margins, typically on trunk and proximal extremities, sparing face.

• Subcutaneous nodules (2-3%): Firm, painless nodules over bony prominences (elbows, knees, knuckles), shins; indicate severe disease.

• Constitutional symptoms: Low-grade fever, malaise, weight loss; high fever should prompt evaluation for other diagnoses.

• 2015 Jones Criteria (revised): Requires evidence of preceding GAS infection PLUS diagnosis differs by risk stratification:
• Initial ARF in low-risk populations: 2 major OR 1 major + 2 minor criteria
• Initial ARF in high-risk populations: 2 major OR 1 major (carditis) + 2 minor + evidence of preceding GAS
• Recurrent ARF in patients with established RHD: 2 major OR 1 major + 2 minor criteria
• Major criteria: Carditis (clinical and/or subclinical on echo), polyarthritis (high-risk) or monoarthritis/polyarthralgia (low-risk), chorea, erythema marginatum, subcutaneous nodules
• Minor criteria: Polyarthralgia, fever (≥38.5°C), ESR ≥60 mm/hr or CRP ≥3.0 mg/dL, and leucocytosis ≥11,000/μL

• Evidence of preceding GAS infection (required):
• Throat culture positive for GAS (low sensitivity ~30%, but highly specific if positive)
• Rapid strep antigen test
• Elevated or rising streptococcal antibody titers: ASO (antistreptolysin O) titer >1:320 or rising titer, or positive anti-DNase B. Note: ASO titers may already be declining at ARF presentation, so negative titers do NOT exclude diagnosis.

• Laboratory findings:
• Acute phase reactants: Elevated ESR (often >60) and CRP indicate inflammation; normal values make ARF less likely
• CBC: Leukocytosis common; anemia may develop
• Echocardiography (essential): Establishes carditis diagnosis and detects subclinical disease. Findings include mitral regurgitation (most sensitive for carditis), anterior mitral leaflet thickening, chamber dilatation, and reduced ventricular function. Echocardiography defines carditis as: (1) clinical carditis (auscultatory findings) OR (2) subclinical carditis (echo findings without clinical signs, allowing diagnosis with 1 major + 2 minor criteria alone in low-risk populations).

• Chest X-ray: May show cardiomegaly, pulmonary congestion if heart failure present

• ECG: Non-specific findings; may show first-degree AV block, higher-degree blocks, or arrhythmias

• Eradication of acute GAS infection (must precede anti-inflammatory therapy):
• Penicillin V 250 mg PO QID × 10 days (first-line for mild-moderate pharyngitis) OR
• Amoxicillin 50 mg/kg/day PO × 10 days (preferred in children due to taste)
• Cephalexin 500 mg PO QID × 10 days (penicillin-allergic without anaphylaxis)
• Azithromycin 500 mg loading dose, then 250 mg daily × 4 days (penicillin-allergic or non-compliant)
• IM benzathine penicillin G 1.2 million units (preferred in high-risk populations or poor compliance predicted)

• Anti-inflammatory therapy (initiated after GAS eradication):
• Aspirin: High-dose (80-100 mg/kg/day divided QID, maximum 6 g/day) × 1-2 weeks until acute phase reactants normalize, then taper over 2-6 weeks. Monitor for toxicity (tinnitus, altered mental status). Aspirin has both anti-inflammatory and analgesic properties; effective for arthritis and mild carditis.
• Corticosteroids (reserved for moderate-to-severe carditis): Prednisone 40-60 mg daily × 2-3 weeks tapered over 3-12 weeks. Superior to aspirin alone for carditis with severe inflammation or heart failure risk. Often combined with aspirin during taper to prevent rebound inflammation. No evidence that corticosteroids prevent permanent RHD.
• NSAIDs: Alternative to aspirin for arthralgia/arthritis in patients unable to tolerate aspirin, though less evidence base

• Management of specific manifestations:
• Heart failure: Standard therapy (diuretics, ACE inhibitors, beta-blockers); avoid NSAIDs
• Atrial fibrillation (if develops): Rate control and anticoagulation
• Chorea: Supportive care; mild cases often resolve spontaneously. Haloperidol (0.5-2 mg daily), carbamazepine, or valproic acid for severe/disruptive chorea
• Severe pancarditis with tamponade: Pericardiocentesis

• Secondary prophylaxis (CRITICAL to prevent recurrence and RHD progression):
• Duration depends on carditis presence and recurrence risk:
• No carditis, no RHD: Prophylaxis × 5 years or until age 21 (whichever is longer)
• Carditis without RHD: Prophylaxis × 10 years or until age 40
• RHD (any severity): Lifelong prophylaxis
• Agents (ranked by efficacy):
• IM benzathine penicillin G 1.2 million units monthly (most effective, preferred)
• Penicillin V 250 mg PO BID
• Sulfadiazine 1 g QID (penicillin-allergic)
• Azithromycin 250 mg daily (increasingly used but less data on long-term efficacy)
• Avoid erythromycin (GI side effects, resistance emerging)

• Monitoring during acute phase: Bed rest during acute inflammation (especially if carditis); gradual return to activity as inflammation subsides. Repeat echocardiography 3-6 months after initial episode to assess residual cardiac damage.

• Rheumatic heart disease (most common long-term complication): Develops in 30-50% of those with carditis. Progressive fibrosis and calcification lead to:
• Mitral stenosis (most common hemodynamically significant lesion): Predisposes to atrial fibrillation and thromboembolism
• Aortic regurgitation/stenosis
• Chronic regurgitation → ventricular hypertrophy and eventual systolic dysfunction

• Acute heart failure: From severe carditis with myocardial inflammation; requires aggressive anti-inflammatory therapy and supportive care

• Atrial fibrillation: Develops in ~10% with carditis, particularly if mitral disease; requires anticoagulation and rate control

• Thromboembolic events: Stroke from cardioemboli (especially with AF and RHD); managed with anticoagulation

• Recurrent ARF: 30-50% risk with reinfection if secondary prophylaxis inadequate; each episode increases RHD severity

• Infective endocarditis: Late complication in RHD patients; requires antibiotic prophylaxis for procedures

• Sudden cardiac death: Rare but documented, particularly with severe myocarditis or underlying cardiomyopathy

Long-term outcomes

• 50% of patients with carditis develop permanent RHD; risk increases with severity of initial carditis and number of recurrent ARF episodes
• Recurrent episodes dramatically worsen prognosis: Each recurrence increases likelihood of permanent cardiac damage. After one ARF with carditis, risk of RHD is ~30%; after two recurrences, risk exceeds 60%
• Chorea alone: Excellent prognosis; no permanent sequelae
• RHD progression: Highly variable; some patients remain stable for decades, while others progress to severe valvular disease requiring surgical intervention within 5-10 years
• Survival in RHD: Dependent on valve involvement, severity, and access to cardiac surgery; mitral stenosis confers worse prognosis than isolated regurgitation

• Most important fact: ARF is entirely preventable—prompt treatment of streptococcal pharyngitis with antibiotics prevents ARF in virtually 100% of cases; secondary prophylaxis (especially IM benzathine penicillin G monthly) prevents recurrent ARF and halts RHD progression.

• Classic board buzzword: "Migratory polyarthritis" affecting large joints (not small joints like RA) + fever + elevated acute phase reactants + recent strep throat = ARF until proven otherwise

• Common clinical trap #1: ARF diagnosis does NOT require positive culture at time of presentation—rising streptococcal antibody titers (ASO, anti-DNase B) suffice for evidence of preceding GAS; culture sensitivity is only ~30% by ARF onset

• Common clinical trap #2: Skin infections/impetigo do NOT cause ARF; only pharyngitis causes ARF (rheumatogenic vs. nephritogenic strains)

• Common clinical trap #3: Normal ESR/CRP makes ARF diagnosis unlikely in a patient with suspected ARF; always obtain these to support diagnosis. Chorea may occur as sole manifestation weeks-months after streptococcal infection when acute phase reactants have normalized, allowing diagnosis with clinical finding alone ("pure chorea").

• Common clinical trap #4: Subclinical carditis detected only by echocardiography in a patient meeting other Jones criteria allows diagnosis even without murmurs; this is critical in high-risk populations where echo is now required

• Common clinical trap #5: Aspirin is contraindicated in severe carditis—use corticosteroids instead for moderate-severe disease with heart failure risk. Aspirin's anti-inflammatory dose (high-dose) is different from antiplatelet dose.

• Mnemonic for major Jones criteria: JONES
• Joint involvement (polyarthritis/arthralgia)
• Other findings (chorea, erythema marginatum, subcutaneous nodules)
• New cardiac murmurs/carditis
• Erythema marginatum
• Subcutaneous nodules

• Board pattern recognition: Teenager with recent strep throat → fever + migratory knee/ankle arthritis + new systolic murmur at apex (MR) + elevated ESR = Diagnose ARF immediately; obtain echo to grade carditis severity and initiate penicillin + high-dose aspirin (± prednisone if severe carditis)

• Lifetime management principle: Any patient with history of ARF and RHD requires:

1. 1.Lifelong penicillin prophylaxis (monthly IM benzathine penicillin G preferred)
2. 2.Antibiotic prophylaxis before dental procedures
3. 3.Anticoagulation if atrial fibrillation develops
4. 4.Echocardiographic monitoring every 1-3 years for RHD progression