What are the post‑streptococcal immune‑mediated syndromes, including acute rheumatic fever, post‑streptococcal glomerulonephritis, PANDAS, erythema nodosum, and serum‑sickness‑like reactions, and how are they diagnosed and managed?

Post-Streptococcal Immune-Mediated Syndromes

Post-streptococcal immune-mediated syndromes are delayed autoimmune complications following Group A Streptococcus (GAS) infection, primarily including acute rheumatic fever, post-streptococcal glomerulonephritis, post-streptococcal reactive arthritis, and the controversial PANDAS syndrome. 1, 2

Acute Rheumatic Fever (ARF)

Clinical Presentation and Timing

• ARF develops 14-21 days after GAS pharyngitis with a symptom-free interval, presenting as a febrile illness with multiple system involvement 1, 2
• The arthritis is migratory, transient, involves large joints, and responds rapidly to aspirin within 3 days 1, 2
• Major manifestations include arthritis, carditis/valvulitis, Sydenham chorea, erythema marginatum, and subcutaneous nodules 1, 2
• Carditis can lead to permanent valvular heart disease, making this the most serious long-term complication 1, 3

Diagnosis

• Requires evidence of recent streptococcal infection (elevated ASO titer) plus either two major Jones criteria OR one major and two minor criteria 2
• Electrocardiography, chest radiography, ESR, and ASO titer are the most useful initial tests 2
• Echocardiography is recommended to identify subclinical carditis, which may not be clinically apparent 2
• Minor criteria include fever, arthralgia, elevated inflammatory markers (ESR, CRP), and prolonged PR interval 2

Management

• Treat any documented acute GAS pharyngitis with standard 10-day antibiotic regimens (penicillin V, amoxicillin, or benzathine penicillin G IM) 4
• NSAIDs provide rapid symptom relief for arthritis, typically within 3 days 2
• Avoid aspirin in children due to Reye syndrome risk 4
• Patients with confirmed ARF require continuous antimicrobial prophylaxis (secondary prophylaxis) to prevent recurrent attacks 1

Secondary Prophylaxis Duration

• ARF with carditis and residual valvular disease: 10 years or until age 40 (whichever is longer), sometimes lifelong 1
• ARF with carditis but no residual heart disease: 10 years or until age 21 (whichever is longer) 1
• ARF without carditis: 5 years or until age 21 (whichever is longer) 1

Post-Streptococcal Glomerulonephritis (PSGN)

Clinical Presentation and Timing

• PSGN is an immune-complex mediated glomerular inflammation occurring after GAS pharyngitis or skin infection (impetigo) 5, 6
• Presents with microscopic or gross hematuria, hypertension, edema, and acute kidney injury 6, 2
• Can range from asymptomatic microscopic hematuria to severe presentations with proteinuria and elevated creatinine 2
• Most commonly affects children aged 2-6 years during winter months 7

Diagnosis

• Urinalysis showing hematuria with RBC casts is characteristic 6, 2
• Elevated ASO titer confirms recent GAS infection 6, 7
• Low C3 complement with normal C4 is typical, distinguishing it from other glomerulonephritides 6
• Imaging studies assess complications like pulmonary congestion or chronic kidney disease 5

Management

• Treatment is primarily supportive, focusing on managing hypertension, edema, and fluid overload 5, 6
• Antibiotics should be given to eradicate any active GAS infection, though they do not alter the course of established PSGN 5
• Prognosis in children is excellent, even with severe initial renal impairment 6
• Monitor for progression to chronic kidney disease, though this is rare in children 5

Critical Pitfall

• PSGN and ARF can occur simultaneously in the same patient, as they result from different antigenic epitopes on GAS, requiring treatment for both conditions 3

Post-Streptococcal Reactive Arthritis (PSRA)

Clinical Presentation and Timing

• PSRA occurs approximately 10 days after GAS pharyngitis, earlier than ARF 1
• The arthritis is cumulative, persistent, non-migratory, and does NOT respond readily to aspirin 1
• Can involve large joints, small joints, or axial skeleton, unlike ARF which primarily affects large joints 1

Diagnosis

• All patients have serological evidence of recent GAS infection, though throat cultures may be negative in over half 1
• Distinguished from ARF by timing, aspirin response, and joint involvement pattern 1

Management and Monitoring

• Observe carefully for several months for clinical evidence of carditis, as some PSRA patients develop valvular heart disease 1
• Consider secondary prophylaxis for up to 1 year after symptom onset (Class IIb recommendation), though effectiveness is not well established 1
• If valvular disease develops, reclassify as ARF and continue secondary prophylaxis per ARF guidelines 1
• If no carditis develops after observation period, prophylaxis can be discontinued 1

Important Caveat

• It remains unclear whether PSRA represents a distinct syndrome or a manifestation of ARF, as the entity has been used inconsistently in literature 1

PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections)

Current Evidence Status

• The American Heart Association considers PANDAS "an unproven hypothesis" that requires careful consideration 1, 8, 4
• No causal relationship between GAS infections and these neuropsychiatric symptoms has been established by well-controlled studies 1, 4
• The concept was proposed in 1998, suggesting childhood OCD and/or tics may arise from post-streptococcal autoimmune processes similar to Sydenham chorea 1, 4

Clinical Features (If Considering This Diagnosis)

• Sudden onset of obsessive-compulsive symptoms and/or tics with temporal relationship to GAS infection 9
• Affects the basal ganglia through proposed autoimmune cross-reactivity with brain tissue 1, 2
• Distinguished from classic OCD by abrupt onset rather than gradual progression 8

What TO DO

• If a child presents with new-onset OCD or tics after strep throat, treat any documented acute streptococcal pharyngitis with standard 10-day antibiotic regimens (penicillin V, amoxicillin, or benzathine penicillin G IM) 4
• Refer to pediatric neurology and/or psychiatry for evaluation and management of neuropsychiatric symptoms with standard therapies for OCD/tic disorders 4

What NOT TO DO (Critical Pitfalls)

• DO NOT prescribe long-term prophylactic antibiotics for presumed PANDAS without documented recurrent streptococcal infections - this lacks evidence and promotes resistance 4
• DO NOT order extensive streptococcal testing (serial ASO titers, anti-DNase B) to diagnose or manage PANDAS - routine laboratory testing for GAS is not recommended 1, 8, 4
• DO NOT use immunoregulatory therapy (IVIG, plasma exchange) as routine treatment - this is not recommended (Class III recommendation) 1, 8

Laboratory Testing (If Pursued Despite Recommendations)

• ASO titer begins rising ~1 week after infection, peaks at 3-6 weeks 9
• Anti-DNase B titer begins rising 1-2 weeks after infection, peaks at 6-8 weeks, and may remain elevated longer than ASO 9
• Normal streptococcal antibody levels are higher in school-age children than adults, requiring age-specific reference ranges 9
• Positive results reflect past rather than present immunologic events and require careful clinical correlation 9

General Diagnostic Approach to Post-Streptococcal Syndromes

Evidence of Recent GAS Infection

• Obtain ASO titer first to detect recent GAS infection 9, 7
• If ASO is negative, obtain anti-DNase B titer, as it may remain elevated longer 9, 7
• Additional antibody markers include antihyaluronidase, antideoxyribonuclease B, and antistreptokinase 7

Inflammatory Markers

• Complete blood count, ESR, and CRP assess for systemic inflammation 2, 7
• These are particularly useful in ARF diagnosis and monitoring 2

Timing Considerations

• ARF: 14-21 days post-pharyngitis 1
• PSRA: ~10 days post-pharyngitis 1
• PSGN: Variable, typically 1-3 weeks post-pharyngitis or skin infection 5, 6

Chronic Carriers vs. Acute Infection

• Chronic GAS carriers have positive throat cultures without immunologic response (no rising antibody titers) 1
• Carriers are at very low risk for developing nonsuppurative complications like ARF 1
• A single course of appropriate antibiotic therapy should be administered to any patient with acute pharyngitis and positive GAS testing 1
• Routine post-treatment cultures are not recommended unless patients remain symptomatic 1