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 or rising titers indicate recent streptococcal infection. Peak levels occur 3-6 weeks after pharyngitis, precisely matching this patient's timeline. 1
• Anti-DNase B antibodies: More sensitive than ASO alone, particularly useful when ASO may be falsely negative. 1
• Throat culture: May be negative at presentation (3 weeks post-infection) as the organism is often cleared by the immune response, but should still be obtained. 1, 3

Inflammatory Markers:

• Elevated ESR and CRP: Acute phase reactants are universally elevated during active ARF and useful for monitoring disease activity. 1, 3

Cardiac Findings:

• Prolonged PR interval on ECG: A minor Jones criterion, though not specific for ARF. 1
• Echocardiographic findings: Pathological mitral regurgitation (jet length ≥2 cm, peak velocity >3 m/s, pansystolic in at least one envelope, seen in at least two views) and possible morphological valve changes including annular dilation, chordal elongation, or leaflet tip beading. 1

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C. Pathogenesis

ARF results from molecular mimicry where antibodies generated against group A streptococcal M-protein cross-react with structurally similar human cardiac tissues (particularly myosin and valve proteins), triggering an autoimmune inflammatory cascade in genetically susceptible individuals. 2, 4, 5

Pathogenic Mechanism

Initial Infection Phase:

• Group A streptococcal pharyngitis introduces M-protein antigens that share structural epitopes with human cardiac myosin, valve proteins, and other tissues. 2, 4
• The immune system generates antibodies and T-cell responses against these streptococcal antigens. 4, 5

Autoimmune Response (14-21 Day Latency):

• Molecular mimicry: Anti-streptococcal antibodies cross-react with cardiac tissues due to structural similarities between streptococcal M-protein and human cardiac proteins. 2, 4, 5
• T-cell mediated inflammation: CD4+ T cells recognizing streptococcal antigens also recognize cardiac self-antigens, infiltrating cardiac tissue and causing inflammation. 4, 5
• This autoimmune reaction affects multiple organs, explaining the systemic manifestations (joints, heart, skin, subcutaneous tissue, and potentially brain in Sydenham chorea). 2, 6

Cardiac Pathology:

• Valvulitis: The mitral valve is most commonly affected, with the anterior leaflet tip showing abnormal coaptation. The characteristic verrucous vegetations (described at autopsy) represent inflammatory lesions along the valve closure line. 1, 2
• Myocarditis: Aschoff bodies (pathognomonic granulomas with Anitschkow cells) form in the myocardium. 2, 5
• Pericarditis: Fibrinous pericardial inflammation causes the friction rub. 2, 7

Genetic Susceptibility:

• Only 3% of untreated GAS pharyngitis cases progress to ARF (during epidemics; less in endemic situations), indicating genetic predisposition plays a critical role alongside environmental factors. 1, 2

Progression to Chronic Disease:

• Without secondary prophylaxis, recurrent GAS infections trigger repeated ARF episodes, causing cumulative valvular damage with progressive fibrosis, calcification, and stenosis—ultimately resulting in chronic rheumatic heart disease. 2, 5

Critical Management Implications

• Immediate penicillin therapy to eradicate residual GAS, even if throat culture is negative. 1, 7
• Initiate lifelong secondary prophylaxis with benzathine penicillin G 1.2 million units IM every 3-4 weeks, as this patient has carditis with likely residual heart disease (prophylaxis for 10 years or until age 40, whichever is longer, possibly lifelong). 1, 7
• Anti-inflammatory therapy with salicylates or corticosteroids (if severe carditis) for symptom management. 7

1, 3, 2, 7, 4, 5, 6