What are the management and treatment options for patients with complement C3 deficiency?

Management and Treatment of Complement C3 Deficiency

Patients with C3 deficiency require aggressive vaccination against encapsulated bacteria, antimicrobial prophylaxis, prompt treatment of infections, and monitoring for renal complications, as C3 deficiency predisposes to severe recurrent infections and immune complex-mediated kidney disease.

Vaccination Strategy

Meningococcal Vaccination

• Administer a 2-dose primary series of MenACWY vaccine 8-12 weeks apart for patients aged 9 months through 55 years with C3 deficiency 1
• For infants aged 2-23 months, use MenACWY-CRM with age-appropriate dosing schedules 1
• For patients ≥10 years, add serogroup B meningococcal vaccination: MenB-FHbp (3 doses at 0,1-2, and 6 months) or MenB-4C (2 doses ≥1 month apart) 1
• Booster doses are critical:
  • Children <7 years: first booster at 3 years, then every 5 years 1
  • Children ≥7 years and adults: booster every 5 years for MenACWY 1
  • For MenB: booster at 1 year after primary series, then every 2-3 years 1

Pneumococcal Vaccination

• Administer polyvalent pneumococcal vaccine as C3 deficiency dramatically increases risk of invasive pneumococcal disease 2, 3
• This is essential given the recurrent pneumococcal infections documented in C3-deficient patients 2, 4

Haemophilus Influenzae Vaccination

• Include anti-Haemophilus vaccine in the immunization schedule 2, 3

Antimicrobial Prophylaxis

Initiate prophylactic antibiotics to prevent recurrent infections 5:

• Amoxicillin (first-line option)
• Trimethoprim/sulfamethoxazole (alternative)
• Azithromycin (alternative)

The rationale is that C3 deficiency causes severe defects in opsonization and bacterial clearance, leading to recurrent pyogenic infections from encapsulated organisms 4, 3.

Management of Acute Infections

• Treat all infections promptly and aggressively with appropriate antimicrobials 5
• Consider plasma infusion during severe pyogenic infections to temporarily restore opsonic activity (can enhance serum opsonic function for up to 36 hours) 4
• Hospitalize for serious infections given the fulminant nature of bacterial infections in complement-deficient patients 3

Immunoglobulin Replacement Therapy

Consider intravenous immunoglobulin (IVIG) replacement for patients with associated hypogammaglobulinemia and impaired antibody responses 6:

• C3 deficiency often leads to decreased memory B cells and poor responses to polysaccharide antigens 6
• IVIG has shown clinical improvement in C3-deficient patients with antibody defects 6

Renal Monitoring and Management

Screening and Monitoring

• Perform complete urinalysis with sediment evaluation for dysmorphic hematuria and casts 5
• Measure 24-hour urine protein (significant if >500 mg/day) 5
• Monitor renal function tests (creatinine, BUN) regularly 5
• C3 deficiency is associated with C3 glomerulopathy, membranoproliferative glomerulonephritis (MPGN), and mesangiopathic glomerulonephritis 5, 4

Treatment of Renal Complications

For immune complex-mediated MPGN with nephrotic syndrome and progressive kidney function decline:

• Oral cyclophosphamide or mycophenolate mofetil plus low-dose corticosteroids (limited to <6 months) 5

For C3 glomerulopathy with monoclonal gammopathy:

• Target the B cell or plasma cell clone producing the monoclonal immunoglobulin 5

Diagnostic Workup

Initial Laboratory Assessment

• Measure serum C3, C4, and CH50 levels (C3 will be absent or severely reduced; CH50 will be zero) 1, 5
• Measure AH50 (alternative pathway activity) - will be zero in C3 deficiency 1
• Assess for complement consumption by measuring factor B and C4 levels 1

Genetic and Immunologic Testing

• Genetic screening for C3 gene mutations 5, 6
• Test for mutations in regulatory proteins: complement factors H, I, B, CD46, and CFHR 1-5 5
• Evaluate for autoantibodies: C3 nephritic factor (C3Nef) and anti-factor H antibodies 5
• The identification of compound heterozygous mutations helps confirm diagnosis and assess family members 6

Immunological Evaluation

• Assess memory B cell populations (often decreased in C3 deficiency) 6
• Measure immunoglobulin levels (IgG, IgA, IgM) to identify hypogammaglobulinemia 6
• Test antibody responses to protein and polysaccharide antigens 6

Critical Pitfalls to Avoid

• Do not delay vaccination while awaiting genetic confirmation - start immunizations immediately upon clinical suspicion 1
• Do not assume normal immunoglobulin levels mean adequate antibody function - functional testing is essential 6
• Do not overlook renal screening even in asymptomatic patients - glomerulonephritis can develop insidiously 5, 4
• Ensure vaccines are given at least 2 weeks before any complement inhibitor therapy if that becomes relevant 1
• Remember that both CH50 and AH50 will be zero in C3 deficiency, distinguishing it from isolated classical or alternative pathway defects 1

Patient Education

• Educate patients about their extreme predisposition to infections from encapsulated bacteria (S. pneumoniae, N. meningitidis, H. influenzae) 3
• Emphasize the importance of seeking immediate medical attention for fever or signs of infection 3
• Counsel about the need for lifelong vigilance and adherence to prophylactic measures 3