Acute Rheumatic Fever (ARF)

1. Introduction and Definition

Acute Rheumatic Fever (ARF) is a nonsuppurative, immune-mediated, systemic inflammatory sequela of untreated group A Streptococcus (GAS) pharyngitis,. It is characterized by inflammatory lesions involving the heart, joints, subcutaneous tissues, and the central nervous system.

While the arthritis and chorea associated with ARF are self-limiting, the cardiac involvement (rheumatic carditis) can lead to permanent valvular damage, known as Rheumatic Heart Disease (RHD). RHD remains the most common form of acquired heart disease in children and young adults in developing nations.

2. Epidemiology

2.1. Incidence and Prevalence

• Global Burden: The incidence of ARF varies significantly based on geography and socioeconomic status. In developing countries and among indigenous populations in developed nations (e.g., Maoris in New Zealand, Australian Aborigines), the annual incidence can exceed 50 per 100,000 children.
• Developed Nations: In the United States and Western Europe, the incidence has declined dramatically to approximately 0.5 per 100,000 population. This decline is attributed to improved living conditions (less overcrowding), widespread use of antibiotics for pharyngitis, and a shift in the prevalence of rheumatogenic GAS strains,.
• Age Distribution: ARF is a disease of school-age children, with a peak incidence between 5 and 15 years, paralleling the peak age for GAS pharyngitis. It is rare in children younger than 3 years.

2.2. Risk Factors

• Host Factors: There is a genetic predisposition to ARF. Concordance rates are higher in monozygotic twins compared to dizygotic twins. Certain HLA class II alleles are associated with susceptibility.
• Environmental Factors: Overcrowding and poverty are the most significant environmental risk factors as they facilitate the rapid transmission of GAS.

3. Etiology and Pathogenesis

3.1. The Agent: Group A Streptococcus

ARF results exclusively from infection of the upper respiratory tract with Group A Streptococcus (GAS). Skin infections (impetigo) with GAS are associated with post-streptococcal glomerulonephritis but have not been definitively proven to cause ARF, although this remains a topic of debate in some endemic regions.

Rheumatogenicity: Not all GAS strains cause ARF. "Rheumatogenic" strains (e.g., M types 1, 3, 5, 6, 18, and 29) are heavily encapsulated (mucoid) and rich in M protein, which resists phagocytosis,.

3.2. Mechanism: Molecular Mimicry

The most widely accepted theory of pathogenesis is molecular mimicry.

• Latent Period: There is a latent period of 10–21 days between the pharyngitis and the onset of ARF, suggesting an immune-mediated process rather than direct bacterial toxicity.
• Cross-Reactivity: The GAS bacterium shares antigenic determinants (epitopes) with human host tissues. Antibodies and T-cells directed against GAS M protein, N-acetyl-beta-D-glucosamine (cell wall carbohydrate), and capsular hyaluronate cross-react with host proteins such as cardiac myosin (heart valve), laminin (valvular endothelium), synovium (joints), and basal ganglia (brain).
• Valve Damage: This autoimmune reaction leads to inflammation and subsequent scarring of the heart valves.

4. Clinical Manifestations

The clinical presentation of ARF is defined by the Revised Jones Criteria (2015). The major manifestations are carditis, arthritis, chorea, erythema marginatum, and subcutaneous nodules.

4.1. Migratory Polyarthritis

• Frequency: Occurs in approximately 75% of patients.
• Characteristics:
  • Involves large joints (knees, ankles, wrists, elbows).
  • Classically migratory: inflammation moves from one joint to another; one joint heals as another becomes inflamed.
  • Joints are hot, red, swollen, and exquisitely tender. The pain is often disproportionate to the objective signs.
• Course: It is self-limiting (weeks) and does not result in permanent deformity.
• Response to Therapy: There is a dramatic therapeutic response to salicylates (aspirin). Lack of improvement after 48 hours of salicylate therapy should prompt consideration of an alternative diagnosis.

4.2. Carditis

Carditis is the most serious manifestation, occurring in 50–60% of cases. It is a pancarditis involving the endocardium, myocardium, and pericardium.

• Endocarditis (Valvulitis): This is the universal and essential lesion of rheumatic carditis.
  • Mitral Valve: Affected in nearly all cases. Acute inflammation causes mitral regurgitation, characterized by a high-pitched apical holosystolic murmur radiating to the axilla.
  • Aortic Valve: Less commonly involved alone; usually affected in combination with the mitral valve. Causes aortic regurgitation (high-pitched decrescendo diastolic murmur).
• Myocarditis: May cause tachycardia disproportionate to fever and, in severe cases, congestive heart failure.
• Pericarditis: Manifests as a friction rub, chest pain, or effusion. It rarely occurs without evidence of valvulitis.
• Subclinical Carditis: The 2015 criteria now recognize "subclinical carditis," defined as echocardiographic evidence of valvulitis in the absence of an auscultatory murmur.

4.3. Sydenham Chorea (St. Vitus Dance)

• Frequency: Occurs in 10–15% of cases.
• Latent Period: Long latent period (months) after the streptococcal infection; antibody titers may have normalized by the time chorea appears.
• Features:
  • Purposeless, involuntary, rapid movements of the trunk and extremities.
  • Emotional lability and personality changes.
  • Muscle weakness and incoordination.
• Clinical Signs:
  • Milkmaid’s Grip: Irregular contractions while squeezing the examiner's fingers.
  • Spooning: Extension of wrists and fingers when arms are extended.
  • Darting Tongue: Inability to sustain tongue protrusion.
• Prognosis: Self-limiting, rarely leaving neurologic sequelae, though symptoms can last for months.

4.4. Erythema Marginatum

• Frequency: Rare (<1%).
• Appearance: An evanescent, non-pruritic, pink, macular rash with a serpiginous (snake-like) border and pale center.
• Distribution: Found on the trunk and proximal extremities; spares the face.
• Nature: It is accentuated by heat and is transient.

4.5. Subcutaneous Nodules

• Frequency: Rare (<1%), usually associated with severe carditis.
• Appearance: Firm, painless, pea-sized nodules (0.5–1 cm) located over extensor surfaces of joints (knees, elbows) and the spine.

5. Diagnosis: The Revised Jones Criteria (2015)

The 2015 revision by the American Heart Association (AHA) stratifies populations into Low Risk and Moderate/High Risk to improve sensitivity in endemic areas.

Risk Stratification:

• Low Risk: ARF incidence <2 per 100,000 or RHD prevalence ≤1 per 1,000.
• Moderate/High Risk: All populations not meeting low-risk criteria.

5.1. Criteria Requirements

• Initial Attack: 2 Major Criteria OR 1 Major + 2 Minor Criteria.
• Recurrent Attack: 2 Major OR 1 Major + 2 Minor OR 3 Minor Criteria (Moderate/High risk only).
• Essential Requirement: All diagnoses (except chorea and indolent carditis) require evidence of antecedent GAS infection.

5.2. Major and Minor Manifestations by Risk Group

5.3. Evidence of Antecedent GAS Infection

Evidence is mandatory and can be provided by:

1. Positive Throat Culture for Group A Strep.
2. Positive Rapid Antigen Detection Test (Rapid Strep).
3. Elevated or Rising Streptococcal Antibody Titers:
   • Anti-Streptolysin O (ASO): Elevated in 80–85% of cases.
   • Anti-DNase B: Useful if ASO is normal.
   • Using both tests detects 95–100% of recent infections.

Exceptions: Evidence of antecedent GAS is not required for:

• Isolated Chorea.
• Indolent carditis presenting months after onset.

6. Differential Diagnosis

• Juvenile Idiopathic Arthritis (JIA): JIA typically presents with non-migratory arthritis, longer duration (>6 weeks), morning stiffness, and less dramatic response to aspirin compared to ARF. Systemic onset JIA has spiking fevers and rash but is distinct from erythema marginatum.
• Poststreptococcal Reactive Arthritis (PSRA): Arthritis following GAS pharyngitis that does not fulfill Jones criteria. Often involves small joints, is non-migratory, has a shorter latent period (<10 days), and responds poorly to aspirin.
• Infective Endocarditis: Distinguished by positive blood cultures, vegetations on echo, and embolic phenomena.
• Systemic Lupus Erythematosus (SLE): Distinguished by presence of ANA and other autoantibodies.
• Viral Myocarditis: May present with heart failure but lacks the characteristic valvulitis/murmurs of rheumatic carditis.
• Lyme Disease: History of tick bite, erythema migrans, monoarticular arthritis (knee).

7. Management

7.1. Antibiotic Therapy (Eradication of GAS)

Even if throat cultures are negative at presentation, all patients must be treated to eradicate any remaining GAS to prevent spread and further antigenic stimulation.

• Regimen:
  • Benzathine Penicillin G: Single intramuscular injection (1.2 million units for >27 kg; 600,000 units for <27 kg).
  • Oral Penicillin V: For 10 days.
  • Penicillin Allergy: Erythromycin, Azithromycin (5 days), or Clindamycin.

7.2. Anti-inflammatory Therapy

Therapy is aimed at suppressing inflammation causing arthritis and carditis.

• Arthritis:
  • Aspirin (Salicylates): This is the drug of choice.
  • Dosage: 50–70 mg/kg/day in 4 divided doses for 3–5 days, followed by 50 mg/kg/day for 2–3 weeks, then tapering.
  • Monitoring: Serum salicylate levels are typically not needed unless toxicity (tinnitus, hyperventilation) is suspected.
• Carditis:
  • Mild to moderate carditis is managed with salicylates similar to arthritis.
  • Severe Carditis (with CHF): Although not explicitly detailed in the treatment section of the provided text beyond salicylates, standard practice often involves corticosteroids (e.g., Prednisone) for severe carditis with cardiomegaly or heart failure, followed by a salicylate taper to prevent rebound. Note: The source text mentions withholding anti-inflammatory agents initially if the diagnosis is unclear (arthralgia only) to observe for migratory patterns.

7.3. Management of Sydenham Chorea

• Usually requires supportive care and a quiet environment.
• For severe chorea interfering with function, sedatives or anticonvulsants (e.g., valproic acid, carbamazepine) may be used (Note: specific drugs for chorea management are not detailed in the source text provided, but supportive care is emphasized).

7.4. Bed Rest

Bed rest is recommended during the acute febrile phase and while resting pulse rates are elevated. It is essential for patients with active carditis to reduce cardiac workload.

8. Prognosis and Complications

• Joints/Chorea: Arthritis and chorea heal completely without permanent sequelae.
• Heart: The long-term prognosis is determined entirely by the severity of the carditis.
  • Patients with no carditis during the initial attack have a low risk of developing it later.
  • Patients with severe carditis are at high risk for residual Rheumatic Heart Disease (RHD).
  • RHD Sequelae: Mitral stenosis (most common long-term lesion), aortic stenosis/regurgitation. These may require valve replacement surgery later in life.
• Recurrence: Patients with a history of ARF are at very high risk of recurrence with subsequent GAS infections. Recurrences worsen cardiac damage.

9. Prevention

Prevention is the most critical aspect of management to reduce the burden of RHD.

9.1. Primary Prevention

Primary prevention involves the accurate diagnosis and adequate antibiotic treatment of GAS pharyngitis to prevent the initial attack of ARF. Treatment within 9 days of symptom onset effectively prevents ARF.

9.2. Secondary Prevention (Prophylaxis)

Secondary prevention is the continuous administration of antibiotics to patients with a history of ARF to prevent GAS colonization and subsequent recurrences of ARF.

Preferred Regimen:

• Benzathine Penicillin G: 1.2 million units IM every 4 weeks (every 3 weeks in high-risk populations).
• Oral Alternatives: Penicillin V 250 mg BID or Sulfadiazine (less effective than IM penicillin due to compliance issues).
• Allergic Patients: Macrolides (Erythromycin).

Duration of Secondary Prophylaxis: The duration depends on the presence and severity of carditis.