What is the diagnosis for a patient presenting with malaise, fever, rash, subcutaneous nodules, and a new heart murmur 3 weeks after a painful pharyngitis?

Acute Rheumatic Fever (ARF)

A. Diagnosis

This 15-year-old girl has acute rheumatic fever (ARF), a post-streptococcal autoimmune disease presenting with classic major manifestations including carditis (new murmur and friction rub), polyarthritis (migratory), erythema marginatum (irregular circular rash), and subcutaneous nodules following group A streptococcal pharyngitis. 1

Clinical Reasoning

The constellation of findings 3 weeks after painful pharyngitis is pathognomonic for ARF:

Major Manifestations Present:

• Carditis: New heart murmur and pericardial friction rub indicate pancarditis (endocarditis, myocarditis, and pericarditis). The small verrucous vegetations near the mitral valve closure line are characteristic Aschoff bodies/nodules of rheumatic valvulitis. 1, 2
• Polyarthritis: The migratory nature affecting larger joints (forearm involvement suggests wrist/elbow) is typical of ARF arthritis, which characteristically responds rapidly to salicylates and resolves without joint deformity. 1
• Erythema marginatum: The irregular circular rash is a pathognomonic skin manifestation of ARF. 1
• Subcutaneous nodules: These firm, painless nodules typically occur over bony prominences and are highly specific for ARF. 1

Minor Manifestations:

• Fever and malaise are consistent with the systemic inflammatory response. 1, 3

Diagnostic Confirmation

• The 3-week latency period between pharyngitis and symptom onset is the classic 14-21 day symptom-free interval characteristic of ARF pathogenesis. 2
• The age (15 years) falls within the peak demographic (5-15 years) for both GAS pharyngitis and initial ARF attacks. 1, 3
• Echocardiography with Doppler should be performed immediately to fully characterize the valvulitis, assess for pathological mitral and/or aortic regurgitation, and document baseline cardiac status. 1

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B. Expected Serologic Findings

Elevated or rising anti-streptolysin O (ASO) titers and/or anti-DNase B antibodies are expected, along with evidence of recent group A streptococcal infection, elevated acute phase reactants (ESR and CRP), and possible prolonged PR interval on ECG. 1, 3

Specific Laboratory Findings

Evidence of Preceding GAS Infection:

• ASO titers: Elevated in approximately 80% of ARF cases, with peak levels occurring 3-6 weeks after pharyngitis. 1
• Anti-DNase B antibodies: More sensitive than ASO alone; combined testing increases diagnostic sensitivity to >95%. 1
• Throat culture may be negative by the time ARF manifests (3 weeks post-infection), but should still be obtained. 1, 4

Inflammatory Markers:

• Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) reflecting acute inflammation. 1, 3
• These are considered minor criteria in the Jones diagnostic framework. 1

Cardiac Findings:

• Prolonged PR interval on ECG (first-degree AV block) is a minor criterion. 1
• ECG may also show other conduction abnormalities or signs of pericarditis. 1

Important Caveat

• At least one-third of ARF cases result from asymptomatic GAS infections, so negative throat culture does not exclude the diagnosis when clinical criteria are met. 1, 4

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C. Pathogenesis

ARF results from molecular mimicry whereby antibodies and T-cells generated against group A streptococcal M-protein cross-react with structurally similar human cardiac tissue antigens, triggering an autoimmune inflammatory response in genetically susceptible individuals. 2, 5, 6

Pathogenic Mechanism

Initial Trigger:

• Group A streptococcal pharyngitis (not skin infection) initiates the cascade. 1, 5
• The M-protein serotypes of GAS share structural epitopes with human cardiac myosin, tropomyosin, and other cardiac proteins. 2, 5

Autoimmune Response:

• After a 14-21 day latency period, the immune system mounts a response against streptococcal antigens. 2, 7
• Molecular mimicry causes antibodies and activated T-cells to cross-react with cardiac tissue, valvular endothelium, synovium, and basal ganglia. 2, 5, 6
• This autoimmune attack occurs in genetically susceptible individuals, suggesting HLA associations and other genetic factors. 5, 8

Cardiac Pathology:

• Valvulitis primarily affects the mitral valve (anterior leaflet tip), with aortic involvement less common and rarely isolated. 1, 2
• The characteristic Aschoff bodies (granulomatous lesions with Anitschkow cells) form in the myocardium. 2, 6
• Verrucous vegetations along valve closure lines represent fibrinoid necrosis and inflammatory cell infiltration. 1, 2
• Pancarditis involves endocardium (valvulitis), myocardium (myocarditis with Aschoff bodies), and pericardium (pericarditis with friction rub). 2, 4

Progression to Chronic Disease:

• Recurrent GAS infections lead to repeated ARF episodes, causing progressive valvular damage. 2, 6
• Chronic inflammation results in valvular fibrosis, commissural fusion, calcification, and ultimately rheumatic heart disease with stenosis and/or regurgitation. 2, 6
• 60-65% of patients develop chronic valvular heart disease after the initial ARF episode. 2

Critical Management Implications

• Immediate penicillin therapy to eradicate residual GAS, even if throat culture is negative. 4
• Lifelong secondary prophylaxis with benzathine penicillin G (1.2 million units IM every 3-4 weeks) is essential to prevent recurrent GAS infections and progressive cardiac damage. 4
• For this patient with carditis and likely residual heart disease: prophylaxis for 10 years after the last episode or until age 40 (whichever is longer), sometimes lifelong. 4