What are the clinical features, diagnostic criteria, treatment, and secondary prophylaxis for acute rheumatic fever?

Acute Rheumatic Fever: Clinical Overview

Pathophysiology

Acute rheumatic fever (ARF) is an autoimmune inflammatory disease triggered by group A β-hemolytic streptococcal (GAS) pharyngitis or skin infection in genetically susceptible individuals, occurring 14–21 days after the initial infection through molecular mimicry. 1, 2 Antibodies and T-cells generated against streptococcal M-protein cross-react with structurally similar cardiac tissue antigens, leading to loss of self-tolerance and pancarditis. 1, 2

Clinical Manifestations

Major Criteria (Jones Criteria)

• Carditis/Pancarditis: New heart murmur, pericardial friction rub, and pathological mitral and/or aortic regurgitation detected on echocardiography with Doppler 1, 2
• Polyarthritis: Migratory inflammation of large joints that responds rapidly to aspirin within days 3, 2
• Sydenham's chorea: Neurological manifestation that may occur in isolation 4
• Erythema marginatum: Characteristic rash 1, 2
• Subcutaneous nodules: Firm, painless nodules 1, 2

Minor Criteria

• Fever and malaise indicating systemic inflammatory response 2
• Elevated acute-phase reactants (ESR, CRP) 1, 2
• Prolonged PR interval on ECG 1, 2
• Arthralgia (in low-risk populations) or monoarthritis (in moderate-to-high-risk populations) 5

Laboratory Confirmation

• Approximately 80% of ARF patients exhibit elevated or rising anti-streptolysin O (ASO) titers, peaking 3–6 weeks after pharyngitis 1, 2
• Anti-DNase B antibodies provide additional confirmation of recent GAS infection 2
• Throat culture or rapid antigen detection test (though may be negative at presentation) 2

Diagnostic Approach

Diagnosis requires documented evidence of preceding GAS infection plus either two major manifestations OR one major and two minor manifestations from the Jones criteria. 6, 5

Critical Diagnostic Considerations

• At least one-third of ARF cases result from inapparent streptococcal infections without recognized pharyngitis 2
• Approximately 15% of school-age children are asymptomatic GAS carriers, complicating differentiation between true infection and carriage with concurrent viral pharyngitis 2
• Echocardiography with Doppler must be performed immediately at diagnosis to detect overt or subclinical carditis and establish baseline cardiac status 1, 2

Differential Diagnosis Pitfalls

Significant clinical overlap exists with Lyme disease, serum sickness, drug reactions, and post-streptococcal reactive arthritis (PSRA). 2, 6 Key distinguishing features of PSRA include:

• Onset approximately 10 days (not 14–21 days) after pharyngitis 2
• Does not respond readily to aspirin 2
• May involve small joints or axial skeleton 2
• Requires observation for several months for evidence of carditis 2

Group C and G streptococcal pharyngitis present identically to GAS pharyngitis but do NOT cause acute rheumatic fever. 4, 2

Acute Treatment

Eradication of Residual GAS

A full 10-day course of penicillin must be administered immediately at diagnosis, even if throat culture is negative, to eradicate any residual streptococci. 3, 2

• Oral penicillin V: 250 mg twice daily for 10 days (children <27 kg); 500 mg 2–3 times daily for 10 days (children ≥27 kg, adolescents, adults) 3
• Intramuscular benzathine penicillin G: Single injection of 600,000 units (<27 kg) or 1,200,000 units (≥27 kg) 3

Intramuscular benzathine penicillin G should be strongly considered for patients unlikely to complete oral therapy, those with personal or family history of ARF/RHD, and those with environmental risk factors. 3

Anti-Inflammatory Therapy

High-dose aspirin (acetylsalicylic acid) at 75–100 mg/kg/day for 4–6 weeks effectively controls arthritis and mild carditis, with rheumatic arthritis typically resolving within days. 3, 2 Corticosteroids are reserved for severe carditis. 2

Secondary Prophylaxis (Prevention of Recurrence)

Continuous antimicrobial prophylaxis is essential because patients with prior ARF have extremely high risk of recurrence with subsequent GAS infections, and recurrent attacks progressively worsen valvular damage even when symptomatic infections are treated optimally. 4, 1, 2 The GAS infection need not be symptomatic to trigger recurrence. 4, 3

Gold-Standard Regimen

Benzathine penicillin G 1,200,000 units intramuscularly every 4 weeks (600,000 units for children <27 kg) is the gold standard, providing approximately 10-fold greater protection than oral regimens (0.1% vs 1% recurrence rate; RR 0.07,95% CI 0.02–0.26). 1, 3, 2

For high-risk populations (children, adolescents, parents of young children, teachers, healthcare workers, military recruits, economically disadvantaged) or patients with recurrence despite adherence, administer benzathine penicillin G every 3 weeks. 1, 3

Alternative Regimens for Penicillin Allergy

Sulfadiazine or erythromycin are acceptable alternatives. 3, 7

Duration of Prophylaxis (Stratified by Cardiac Involvement)

Cardiac Status	Duration
No carditis	5 years or until age 21 (whichever is longer) [4,1,3]
Carditis without residual valvular disease	10 years or until age 21 (whichever is longer) [4,1,3]
Carditis with residual valvular disease	10 years or until age 40 (whichever is longer); often lifelong [4,1,3]
Post-valve surgery	Indefinitely, including after prosthetic valve replacement [1]

Household Contact Management

Throat swab specimens must be obtained from ALL household contacts of a child with ARF, and any positive contacts must receive treatment regardless of symptoms. 1, 2 This prevents transmission and potential ARF development in genetically susceptible family members. 2

Long-Term Outcomes

• Following the first ARF episode, 60–65% of patients develop chronic rheumatic heart disease (RHD) 1
• Recurrent GAS infections cause repeated ARF attacks, producing progressive valve damage including commissural fusion, leaflet thickening, chordal shortening, and calcification, culminating in atrial fibrillation and heart failure 1
• RHD causes an estimated 233,000–468,000 deaths annually worldwide, with mean age at death often below 25 years in the absence of adequate secondary prophylaxis 1
• Despite prophylaxis recommendations, recurrent rheumatic fever occurs in 18.7% of patients, underscoring the critical importance of continuous antimicrobial prophylaxis 2