ETIOPATHOGENESIS, Clinical features, INVESTIGATION and MANAGEMENT of ACUTE RHEUMATIC FEVER. University Exam Final Year MBBS ( LAQ ). Harrison reference
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ACUTE RHEUMATIC FEVER (ARF)
Final Year MBBS - Long Answer Question | Harrison's Principles of Internal Medicine 22E (2025)
DEFINITION
Acute Rheumatic Fever (ARF) is a multisystem inflammatory disease resulting from an autoimmune reaction to infection with Group A Streptococcus (GAS) (Streptococcus pyogenes). Almost all manifestations resolve completely except for cardiac valvular damage (Rheumatic Heart Disease - RHD), which may persist after other features resolve.
- Harrison's 22E, Chapter 371
EPIDEMIOLOGY
- Primarily affects children aged 5-14 years; rare after age 30
- Initial episodes rare in adults; recurrent episodes remain common in adolescents and young adults
- RHD prevalence peaks at 25-40 years of age
- No clear gender association for ARF; RHD is more common in females (up to 2x)
- Global burden: >40 million with RHD, >300,000 deaths annually; 95% in low- and middle-income countries (LMICs)
- Highest burden in: sub-Saharan Africa, Pacific nations, South/Central Asia, Australasia
ETIOPATHOGENESIS
1. Organism Factors (Group A Streptococcus)
- Classically caused by GAS pharyngitis (upper respiratory tract infection)
- Certain M-protein serotypes (types 1, 3, 5, 6, 14, 18, 19, 24, 27, 29) are classically "rheumatogenic" - but many more serotypes are now known to be rheumatogenic
- Recent evidence also implicates skin infection in ARF pathogenesis
- The 2-3 week latent period between infection and ARF onset reflects the time needed to mount an immune response
- Skin streptococcal infections are never associated with ARF (unlike post-streptococcal glomerulonephritis, which can follow either throat or skin infection)
2. Host Factors (Genetic Susceptibility)
- Only 3-6% of any population are susceptible to ARF, suggesting strong genetic predisposition
- This proportion does not vary dramatically between populations
- HLA class II antigens (HLA-DR7, HLA-DR4) are associated with susceptibility
- Familial clustering supports a genetic basis
3. Pathogenetic Mechanism - Molecular Mimicry
The central mechanism is molecular mimicry (Type II and Type IV hypersensitivity):
- GAS M protein contains epitopes structurally similar to human cardiac proteins (myosin, tropomyosin, laminin, vimentin)
- Antibodies directed against streptococcal M proteins cross-react with cardiac antigens (pericardial, myocardial, valvular)
- CD4+ T cells directed against M protein also recognize cardiac antigens
- Antibody binding activates complement and recruits Fc-receptor-bearing cells (neutrophils, macrophages)
- Cytokines produced by stimulated T cells lead to macrophage activation (forming Aschoff bodies in myocardium)
- Combined antibody- and T cell-mediated reactions damage heart tissue
- Chorea results from antibody binding to basal ganglia
- Arthritis is caused by immune complex deposition in joints
- Skin manifestations result from delayed hypersensitivity reactions
Key point: Streptococci are completely absent from the lesions - confirming the immunological (not infective) basis of tissue damage.
4. Pathology - Aschoff Bodies (Pathognomonic)
The Aschoff body is the pathognomonic lesion of ARF:
- Focal inflammatory lesions found in cardiac tissues
- Composed of: T lymphocytes, plasma cells, and plump activated macrophages called Anitschkow cells (also called "caterpillar cells" due to central wavy ribbon of chromatin)
- Aschoff bodies may be found in all three cardiac layers (pancarditis)
Gross/Microscopic pathology:
- Acute valvulitis: Fibrinoid necrosis within cusps/tendinous cords; small (1-2 mm) verrucae (vegetations) along lines of closure
- MacCallum plaques: Subendocardial irregular thickenings in left atrium due to regurgitant jets
- Chronic RHD: Leaflet thickening, commissural fusion, shortening and fusion of tendinous cords (leading to mitral stenosis)
- Mitral valve involved virtually always; isolated in ~2/3; with aortic valve in ~25%
(Robbins Pathologic Basis of Disease, Chapter 12)
Fig. 12.22 - Robbins Pathologic Basis of Disease: Acute and chronic rheumatic heart disease
CLINICAL FEATURES
ARF typically develops 2-3 weeks after GAS pharyngitis. Manifestations are remembered by the mnemonic JONES (Jones Criteria):
Major Criteria (JONES)
| Feature | Frequency | Key Details |
|---|---|---|
| J - Joints (Arthritis) | 75% | Migratory polyarthritis of large joints (knees, ankles, elbows, wrists); exquisitely painful; fleeting |
| O - cOre (Carditis) | >50% | Pancarditis - pericarditis, myocarditis, endocarditis; murmurs (mitral regurgitation most common) |
| N - Nodules (subcutaneous) | <10% | 0.5-2 cm; painless; over bony prominences or extensor tendons |
| E - Erythema marginatum | <10% | Pink, non-pruritic, blanching macules/papules; serpiginous pattern on trunk and proximal limbs; spares face |
| S - Sydenham's Chorea | 30% | Involuntary, non-rhythmic, purposeless movements; worse unilaterally; stops during sleep; "St. Vitus' dance" |
Carditis (most important, detailed):
- Pancarditis affects all layers - endocardium, myocardium, pericardium
- Endocarditis/Valvulitis: Most significant - mitral valve most affected (mitral regurgitation = apical pansystolic murmur); aortic valve second
- Myocarditis: Tachycardia, cardiac enlargement, heart failure
- Pericarditis: Pericardial friction rub, chest pain
- ECG changes: Prolonged PR interval (1st degree AV block) is most common
- Rapid sleeping pulse and tachycardia out of proportion to fever
- Subclinical (echocardiographic) carditis exists without clinical signs
Arthritis (most common, detailed):
- Migratory polyarthritis of large joints
- Each joint affected for hours to a few days, then moves on
- Exquisitely painful, out of proportion to clinical signs
- Responds rapidly and dramatically to NSAIDs (diagnostic clue - absence of NSAID response should prompt reconsideration)
- Synovial fluid: sterile with lymphocyte predominance
- Leaves no permanent joint damage
Sydenham's Chorea:
- May appear late (up to 6 months after infection) - can occur in isolation without other ARF features
- Involuntary, non-rhythmic, purposeless movements
- Usually more pronounced on one side (hemichorea)
- Stops completely during sleep (distinguishes from other movement disorders)
- Associated with emotional lability
Minor Criteria
| Minor Criterion | Low-Risk Populations | Moderate/High-Risk Populations |
|---|---|---|
| Arthralgia | Polyarthralgia | Monoarthralgia |
| Fever | ≥38.5°C | ≥38.5°C |
| ESR | ≥60 mm/hr | ≥30 mm/hr |
| CRP | ≥3.0 mg/dL | ≥3.0 mg/dL |
| ECG | Prolonged PR interval | Prolonged PR interval |
(Note: Arthralgia cannot be used as a minor criterion if arthritis is being used as a major criterion; prolonged PR cannot be minor if carditis is major)
INVESTIGATIONS
Always Request (Harrison's Table 371-3):
| Investigation | Purpose |
|---|---|
| ECG | Prolonged PR interval (1st-degree AV block); pericarditis changes |
| Echocardiogram | Detect subclinical valvulitis; assess severity of carditis (MANDATORY in all suspected ARF) |
| Complete Blood Count (CBC) | Normochromic normocytic anemia; leukocytosis |
| C-Reactive Protein (CRP) | Elevated in active inflammation (≥3.0 mg/dL) |
| ESR | Elevated; ≥60 mm/hr (low-risk), ≥30 mm/hr (high-risk) |
| Streptococcal serology | Antistreptolysin O (ASO) titer: elevated >200 Todd units; Anti-DNase B (more sensitive for skin infections) |
In Relevant Situations:
- Throat swab / skin sore swab: GAS culture (may be negative by time ARF presents)
- Blood cultures: To exclude infective endocarditis
- Synovial fluid aspirate: Cell count, microscopy, culture, gonococcal PCR
- Pregnancy test (if applicable)
- Creatinine (UEC): Baseline before NSAID use
To Exclude Alternative Diagnoses:
- Autoantibodies, dsDNA, anti-CCP antibodies (to exclude lupus/JIA/reactive arthritis)
- Urine for Neisseria gonorrhoeae, Chlamydia trachomatis molecular tests
- Viral serology: hepatitis, CMV, parvovirus B19, respiratory viruses
Evidence of Preceding Streptococcal Infection (mandatory for diagnosis):
- ASO titer (rises 3-6 weeks after pharyngeal infection)
- Anti-DNase B (better for skin infections, stays elevated longer)
- Throat culture (often negative by time ARF diagnosed)
- Note: Both tests together have >95% sensitivity
DIAGNOSIS - REVISED JONES CRITERIA (AHA 2015)
Evidence of preceding GAS infection is mandatory plus:
| ARF Episode | Criteria Required |
|---|---|
| Initial ARF | 2 major OR 1 major + 2 minor criteria |
| Recurrent ARF | 2 major OR 1 major + 2 minor OR 3 minor criteria |
Risk population stratification (important update in 2015 revision):
- Low-risk populations: ARF incidence <2/100,000 school-aged children/year; focus on high specificity - monoarthritis not counted as major criterion
- Moderate/High-risk populations: Higher incidence settings; focus on high sensitivity - monoarthritis is a major criterion; monoarthralgia is a minor criterion
Special circumstances (diagnosis made without full Jones criteria):
- Pure Sydenham's chorea (may occur in isolation)
- Indolent carditis (slowly progressive valvular disease discovered late)
- Recurrent ARF in patient with established RHD
(Goldman-Cecil Medicine, Table 269-3; Harrison's 22E, Chapter 371)
MANAGEMENT
A. Hospitalization
All patients with ARF should be hospitalized for monitoring and initiation of treatment.
B. Eradication of GAS (Antibiotics)
Drug of choice: Penicillin
| Route | Regimen |
|---|---|
| Benzathine Penicillin G (IM, preferred) | 1.2 million units single dose IM (600,000 units for children ≤27 kg) |
| Phenoxymethyl penicillin (oral) | 500 mg twice daily (250 mg for children ≤27 kg) × 10 days |
| Amoxicillin (oral) | 50 mg/kg/day (max 1 g) × 10 days |
| Penicillin allergy: Azithromycin | 250 mg daily (oral macrolide) |
C. Treatment of Arthritis
- First-line: Aspirin (Salicylates) - 80-100 mg/kg/day in divided doses (max 4-8 g/day)
- Alternative: Naproxen - 10-20 mg/kg/day divided twice-daily
- Duration: 1-2 weeks after all symptoms resolve (not just joint symptoms)
- Dramatic NSAID response within 24-48 hours is itself diagnostically helpful
- Monitor renal function (check creatinine before starting NSAIDs)
D. Treatment of Carditis
- Mild/Moderate carditis: Bed rest, NSAIDs, close monitoring
- Severe carditis with heart failure:
- Treat with goal-directed heart failure therapy: diuretics, angiotensin receptor blockers (ACEi/ARBs)
- Fluid restriction
- Bed rest
- Corticosteroids (prednisolone): Some experts recommend in severe cases despite limited high-quality evidence
- Valve surgery: Rarely needed acutely; can be considered for acute valve leaflet rupture
- Echocardiography should be performed on all cases
E. Treatment of Chorea
- Usually does not require specific treatment - resolves spontaneously within weeks to months
- Supportive care: reduce stress, avoid stimulants
- For severe/disabling cases: Carbamazepine or valproic acid (preferred over haloperidol)
- Steroids occasionally used in severe chorea
F. Secondary Prophylaxis (Most Important Long-Term Measure)
Prevents recurrent GAS infections and subsequent ARF episodes that worsen cardiac damage.
| Patient Category | Duration |
|---|---|
| ARF without carditis | 5 years or until age 21 (whichever is longer) |
| ARF with carditis, no residual RHD | 10 years or until age 21 |
| ARF with carditis and residual RHD | At least 10 years or until age 40 (sometimes lifelong) |
| Severe RHD or post-valve surgery | Lifelong |
Drug of choice: Benzathine Penicillin G
- 1.2 million units IM every 4 weeks (3-weekly in high-risk patients)
- Alternative (less effective): Oral Penicillin V 250 mg twice daily
- Penicillin allergy: Erythromycin/Azithromycin
G. Bed Rest Protocol
| Severity | Activity Restriction |
|---|---|
| ARF without carditis | Bed rest until ESR/acute phase reactants normalize (~2 weeks) |
| ARF with mild carditis | Bed rest for 3-4 weeks |
| ARF with severe carditis | Strict bed rest for 2-3 months |
PROGNOSIS
- Arthritis, chorea, skin manifestations resolve completely with no permanent sequelae
- Carditis determines prognosis: 35-70% of patients with ARF develop chronic clinical RHD
- Resolution of carditis is most likely in the first year after acute episode
- Risk factors for RHD progression: severe initial carditis, recurrent ARF episodes, mitral valve involvement
- Secondary prophylaxis is the most effective intervention to prevent progression to severe RHD
SUMMARY TABLE
| Feature | Details |
|---|---|
| Causative organism | Group A Streptococcus (S. pyogenes) |
| Mechanism | Molecular mimicry - Type II + IV hypersensitivity |
| Latent period | 2-3 weeks after GAS pharyngitis |
| Age group | 5-14 years |
| Most common feature | Arthritis (75%) |
| Most important feature | Carditis (determines prognosis) |
| Pathognomonic lesion | Aschoff body (Anitschkow/caterpillar cells) |
| Diagnosis | Revised Jones Criteria (AHA 2015) |
| Most specific investigation | Echocardiography (subclinical carditis) |
| Antibiotic of choice | Benzathine Penicillin G |
| Secondary prophylaxis | Benzathine Penicillin G 1.2M units IM 4-weekly |
Sources:
- Harrison's Principles of Internal Medicine, 22nd Edition (2025), Chapter 371 - Acute Rheumatic Fever
- Goldman-Cecil Medicine International Edition, Chapter 269
- Robbins & Cotran Pathologic Basis of Disease, Chapter 12
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