What is the step‑by‑step pathophysiologic algorithm of rheumatic heart disease, from group A streptococcal pharyngitis to chronic valvular damage and the role of secondary penicillin prophylaxis?

Pathophysiologic Algorithm of Rheumatic Heart Disease

Step 1: Initial Infection with Group A Streptococcus

The pathophysiologic cascade begins with group A β-hemolytic streptococcal (GAS) pharyngitis in a genetically susceptible host, though streptococcal skin infections have also been implicated. 1, 2

• The GAS infection need not be symptomatic to trigger the disease process, and at least one-third of acute rheumatic fever cases result from inapparent streptococcal infections where patients never had recognized pharyngitis. 3
• Approximately 15% of school-age children are asymptomatic GAS carriers, complicating the distinction between true infection and carriage. 3
• Critical pitfall: Group C and G streptococcal pharyngitis can present identically to GAS pharyngitis but do NOT cause acute rheumatic fever. 3

Step 2: Latency Period and Autoimmune Activation (14-21 Days)

After the initial GAS infection, a latency period of 14-21 days occurs before acute rheumatic fever (ARF) manifests, during which molecular mimicry triggers an autoimmune inflammatory response. 3

• Antibodies and T-cells generated against group A streptococcal M-protein cross-react with structurally similar human cardiac tissue antigens in genetically susceptible individuals. 3
• This aberrant host innate and adaptive immune response results in loss of self-tolerance and subsequent cross-reactivity with host tissues, particularly cardiac structures. 2

Step 3: Acute Rheumatic Fever Manifestations

ARF presents with major manifestations including carditis (characterized by new heart murmur and pericardial friction rub indicating pancarditis), polyarthritis, erythema marginatum, and subcutaneous nodules, along with minor manifestations such as fever and malaise. 3

Laboratory Confirmation:

• Elevated or rising anti-streptolysin O (ASO) titers (elevated in approximately 80% of ARF cases, with peak levels occurring 3-6 weeks after pharyngitis) and/or anti-DNase B antibodies. 3
• Elevated acute phase reactants (ESR and CRP). 3
• Possible prolonged PR interval on ECG. 3

Cardiac Involvement:

• After recovery from the initial episode of RF, 60-65% of patients develop valvular heart disease. 1
• Echocardiography with Doppler should be performed immediately to fully characterize the valvulitis and assess for pathological mitral and/or aortic regurgitation. 3

Step 4: Progression to Chronic Rheumatic Heart Disease

Recurrent GAS infections lead to repeated ARF episodes, causing progressive valvular damage through chronic inflammation that results in commissural fusion, leaflet thickening, chordal shortening, and eventual calcification. 3

• Each recurrence of ARF potentially worsens rheumatic heart disease, as patients with previous ARF are at extremely high risk for recurrent attacks when GAS pharyngitis develops. 4
• RF recurrences lead to progressive valve damage, which in turn can cause atrial fibrillation and heart failure. 1
• The chronic inflammatory process transforms acute valvulitis into chronic RHD with stenosis and/or regurgitation. 3

Step 5: Critical Role of Secondary Penicillin Prophylaxis

Continuous antimicrobial prophylaxis with benzathine penicillin G is required to prevent recurrent ARF and progressive cardiac damage, as recurrent ARF can occur even with appropriate treatment of symptomatic GAS infections. 3, 4

Gold Standard Regimen:

• Benzathine penicillin G 1,200,000 units intramuscularly every 4 weeks (600,000 units for children <27 kg) is approximately 10 times more effective than oral antibiotic regimens (0.1% versus 1% recurrence rate, RR 0.07,95% CI 0.02 to 0.26). 4, 5
• For high-risk populations or patients with recurrence despite adherence to the 4-week regimen, administration every 3 weeks should be considered. 4, 6

Duration Stratified by Cardiac Involvement:

Cardiac Status	Prophylaxis Duration
No carditis	5 years or until age 21 (whichever is longer) [4]
Carditis without residual valvular disease	10 years or until age 21 (whichever is longer) [4]
Carditis with residual valvular disease	10 years or until age 40 (whichever is longer), often lifelong [1,4]

Mechanism of Protection:

• Antibiotics work by reducing the carriage of group A Streptococcus and thus reducing the risk of infection. 5
• Moderate-certainty evidence shows that antibiotics overall (oral or intramuscular) probably reduce the risk of recurrence of rheumatic fever substantially (0.7% versus 1.7% with no antibiotics, RR 0.39,95% CI 0.22 to 0.69). 5
• People with early or mild RHD likely have the greatest capacity to benefit from intramuscular antibiotic prophylaxis (8.1% recurrence with antibiotics versus 0.7% without, RR 0.09,95% CI 0.03 to 0.29). 5

Step 6: End-Stage Disease Without Prophylaxis

Without adequate secondary prophylaxis, progressive valve damage necessitates lifesaving cardiac surgery, and patients without access to such treatment often die prematurely from RHD and its complications, with mean age of death <25 years in some studies. 1

• RHD remains the most-common cardiovascular disease in young people aged <25 years worldwide. 1
• An estimated 233,000-468,164 individuals die from RHD each year globally. 1
• Long-term complications include heart failure, atrial fibrillation, stroke, infective endocarditis, and pregnancy-related complications. 1

Critical Management Caveat:

• Prophylaxis should continue even after valve surgery, including prosthetic valve replacement. 6
• Throat swab specimens should be obtained from ALL household contacts of a child with acute rheumatic fever, and positive contacts should be treated regardless of symptoms. 3, 4