Acute Rheumatic Fever (ARF)

Definition and Etiology

Acute rheumatic fever is an inflammatory, non-suppurative complication of pharyngeal infection with Group A Streptococcus (GAS) - Streptococcus pyogenes. It is NOT a direct infection of the heart or joints; rather, it is an autoimmune reaction triggered by molecular mimicry - similarities between streptococcal antigens and human tissue proteins cause cross-reactive antibodies and T cells to attack host tissues.

Skin manifestations result from delayed hypersensitivity
Carditis results from antibody binding + T-cell infiltration of the heart
Arthritis results from immune complex deposition in joints
Chorea results from antibody binding to basal ganglia

Epidemiology

Most common in children 5 to 15 years of age
Occurs equally in males and females; however, rheumatic heart disease (RHD) is more common in women
ARF develops in ~1.6-2.5% of patients with untreated streptococcal pharyngitis
~50% of preceding GAS pharyngeal infections can be asymptomatic
Rare before age 3; infrequent after age 15

Latency

Symptoms begin approximately 2-3 weeks (average 18.6 days) after GAS pharyngitis, except chorea, which typically appears 4-8 weeks after infection.

Clinical Manifestations

The classic manifestations are remembered with the Jones Criteria:

Major Criteria

Manifestation	Frequency	Key Features
Fever	>90%	Often the first sign
Arthritis	~75% (adults more than children)	Migratory, large-joint polyarthritis (knees 76%, ankles 50%); exquisitely tender; responds rapidly to NSAIDs; sterile synovial fluid
Carditis	15-91% (depending on echo use)	Pancarditis; mitral valve most commonly affected; Carey-Coombs murmur (middiastolic); most clinically significant complication
Chorea (Sydenham chorea / St. Vitus dance)	~30%	Involuntary, non-rhythmic, purposeless movements of body, limbs, face; more pronounced unilaterally; stops during sleep
Erythema marginatum	<10%	Pink, non-pruritic, blanching macules/papules spreading in a serpiginous pattern on trunk and proximal limbs
Subcutaneous nodules	<10%	0.5-2 cm, painless, over bony prominences or extensor tendons

Carditis - Details

The mitral valve is affected in almost all cases of carditis
Aortic valve involved in ~20-30% of cases
Tricuspid involved frequently but rarely in a meaningful manner
Classic murmurs:
- Mitral regurgitation: high-pitched, blowing, holosystolic, apical murmur
- Carey-Coombs murmur: low-pitched, apical, middiastolic flow murmur
- Aortic regurgitation: high-pitched, decrescendo diastolic murmur (aortic area)
Heart failure in 5-10% of first ARF episodes; more frequent with recurrences
Myocarditis without valvulitis should NOT be attributed to rheumatic fever

Diagnosis - Revised Jones Criteria (AHA 2015)

There is no definitive test. ARF is a clinical diagnosis of exclusion.

A. Definition:

Initial ARF: 2 major OR 1 major + 2 minor criteria
Recurrent ARF: 2 major, OR 1 major + 2 minor, OR 3 minor criteria

Plus: Evidence of preceding GAS infection (positive throat culture, rapid antigen test, or elevated/rising streptococcal antibody titers: ASO, anti-DNase B)

B. Major Criteria

	Low-Risk Populations	Moderate/High-Risk Populations
Carditis	Clinical and/or subclinical echocardiographic valvulitis	Same
Arthritis	Polyarticular only	Monoarticular or polyarticular
Chorea	Yes	Yes
Erythema marginatum	Yes	Yes
Subcutaneous nodules	Yes	Yes

C. Minor Criteria

	Low-Risk	Moderate/High-Risk
Arthralgia	Polyarthralgia	Monoarthralgia
Fever	≥38.5°C	≥38.5°C
ESR	≥60 mm	≥30 mm
CRP	≥3.0 mg/dL	≥3.0 mg/dL
ECG	Prolonged PR interval	Same

Low-risk = ARF incidence <2 per 100,000 school-aged children per year, or RHD prevalence ≤1 per 1000 population per year

Investigations

Throat culture / rapid antigen test for GAS
ASO titer, anti-DNase B - evidence of prior GAS infection
ESR, CRP - elevated
CBC - normochromic normocytic anemia + leukocytosis
ECG - prolonged PR interval (first-degree AV block)
Echocardiogram - can detect subclinical valvulitis; should be done in all suspected ARF

Treatment

1. Eradication of GAS

Benzathine penicillin G 1.2 million units IM (single dose) - preferred
Oral penicillin V or amoxicillin for 10 days
Macrolide (e.g., azithromycin) if penicillin-allergic

2. Anti-inflammatory Therapy

Arthritis: Aspirin 80-100 mg/kg/day in divided doses (max 4-8 g/day) - traditional first line; NSAIDs (naproxen 10-20 mg/kg/day BID) are effective. Continue for 1-2 weeks after symptoms resolve.
Carditis without heart failure: Aspirin or NSAIDs; no proven benefit of corticosteroids for long-term valve outcome
Carditis with heart failure: Corticosteroids (prednisone) in addition to standard heart failure management

3. Secondary Prophylaxis (most important long-term measure)

Benzathine penicillin G 1.2 million units IM every 4 weeks (every 3 weeks in high-risk patients)

Duration guidelines:

Severity	Duration
ARF without carditis	5 years or until age 21
ARF with carditis, no residual valve disease	10 years or until age 21
ARF with carditis + residual RHD (mild)	10 years or until age 40
Severe valvular disease or post-valve surgery	Lifelong

A 2024 Cochrane systematic review (PMID 39312290) confirmed the benefit of long-term antibiotic prophylaxis for preventing recurrence and progression to rheumatic heart disease.

Rheumatic Heart Disease (RHD) - The Key Complication

Cumulative valve damage from recurrent ARF episodes leads to chronic RHD
Mitral stenosis is the hallmark chronic lesion (fibrosis and fusion of leaflets/subvalvular apparatus over years)
Peak prevalence of RHD: 3rd and 4th decades of life
Most significant cause of acquired valvular heart disease in developing countries

Key Clinical Pearls

Arthritis responds dramatically to aspirin/NSAIDs - if it doesn't, reconsider the diagnosis
Chorea may appear as isolated manifestation weeks after the infection, when other markers (ESR, CRP, ASO) may have normalized
PR prolongation is a minor criterion only when carditis is not already a major criterion
Echocardiography can detect subclinical carditis missed by auscultation alone
Secondary prophylaxis is the cornerstone of preventing RHD - even one missed dose raises recurrence risk
Monoarthritis counts as a major criterion in high-risk populations (not in low-risk) - a 2015 AHA revision

Sources: Goldman-Cecil Medicine, International Edition (2-Vol Set); Firestein & Kelley's Textbook of Rheumatology, 2-Vol Set; Cochrane Database of Systematic Reviews, 2024 (PMID 39312290)

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