What is the role of the complement system pathway in clinical practice and how is it managed?

Complement System Pathway: Clinical Role and Management

Overview of the Complement System

The complement system is a critical component of innate immunity that functions through three distinct activation pathways—classical, lectin, and alternative—all converging at C3 convertase to generate effector molecules that eliminate pathogens, clear immune complexes, and regulate inflammation. 1, 2, 3

Three Activation Pathways

• Classical Pathway: Activated by antibody-antigen complexes (IgG or IgM bound to antigens), involving C1q, C1r, C1s, C4, and C2 components 1, 2
• Lectin Pathway: Triggered by mannose-binding lectin (MBL) or ficolins binding to carbohydrate patterns on pathogens, utilizing MASP-2 proteases 1, 2
• Alternative Pathway: Continuously activated at low levels through spontaneous C3 hydrolysis, amplifying complement activation via factors B, D, and properdin 1, 3

All three pathways converge at C3 convertase, which cleaves C3 into C3a (anaphylatoxin) and C3b (opsonin), ultimately forming C5 convertase that generates C5a and C5b, initiating the membrane attack complex (MAC/C5b-9) 1, 3

Physiological Functions

The complement system serves multiple essential roles beyond simple pathogen lysis, including homeostatic maintenance, immune surveillance, and bridging innate and adaptive immunity. 3, 4

• Host defense: Direct killing of bacteria through MAC formation and opsonization for phagocytosis 4, 5
• Immune complex clearance: Silent removal of apoptotic cells and immune complexes to prevent autoimmunity 3, 4
• Inflammatory signaling: Anaphylatoxins C3a and C5a recruit and activate immune cells 3, 4
• Adaptive immunity modulation: Opsonization facilitates antigen presentation and B-cell activation 4

Clinical Indications for Complement Testing

Primary Screening Scenarios

Measure CH50 (classical pathway) as the initial screening test in patients with recurrent neisserial infections, unexplained bacterial respiratory infections, or lupus-like autoimmune manifestations. 6

• Recurrent meningococcal or gonococcal infections: Strongly suggests terminal complement component deficiency (C5-C9) 6
• Recurrent sinopulmonary infections with encapsulated organisms: Indicates possible early classical pathway deficiency (C1, C2, C4) 6
• Young patients with SLE-like disease: Early complement deficiencies, particularly C4, predispose to autoimmune syndromes 6

Critical Specimen Handling

Blood specimens must be placed on ice or refrigerated immediately after drawing, as complement proteins degrade rapidly with warming, causing falsely low results. 6

Diagnostic Algorithm for Complement Deficiency

Initial Testing Pattern Interpretation

A CH50 of 0 with normal AH50 indicates classical pathway-specific defect (C1, C2, or C4), while low CH50 with low or normal AH50 suggests consumption or regulatory defects (factor H or I). 6

• Both CH50 and AH50 low: Measure factor B and C4 simultaneously—if both are low, complement consumption is confirmed and underlying trigger must be identified 6
• Normal C3 and C4 do not exclude complement deficiency: Partial deficiencies and specific component defects may not lower these screening tests 6
• MBL deficiency: Both CH50 and AH50 will be normal, requiring specific MBL testing if clinically suspected 6

Advanced Diagnostic Workup for C3 Glomerulopathy

For immunoglobulin-negative but C3-positive membranoproliferative glomerulonephritis (C3 glomerulopathy), perform genetic screening and autoantibody evaluation to identify alternative pathway dysregulation. 1, 7

• Genetic screening: Test for mutations in C3, complement factors H, I, B, CD46 (membrane cofactor protein), and CFHR 1-5 1, 7
• Autoantibody testing: Measure C3 nephritic factor (C3Nef) and anti-factor H antibodies 1, 7
• Age-based etiology: Genetic causes more common in children; autoantibodies more likely in adults 1

Vaccination Requirements for Complement Deficiency

Mandatory Immunizations

All patients with primary complement deficiencies must receive meningococcal, pneumococcal, and Haemophilus influenzae type b vaccines, as they face dramatically increased risk of invasive infections from encapsulated organisms. 1

Meningococcal Vaccination Protocol

• Ages 6 weeks-18 months: 4-dose series of HibMenCY at 2,4,6, and 12-15 months 1
• Ages 9-23 months: 2-dose primary series of MCV4-D, administered 3 months apart 1
• Ages ≥2 years: 2-dose primary series of MCV4 (MCV4-D or MCV4-CRM), administered 2 months apart 1
• Revaccination: Every 5 years with MCV4 (or MPSV4 for those >55 years who have not received MCV4) 1

Pneumococcal Vaccination Protocol

• Ages 2-5 years: 1 dose PCV13 if received 3 doses before age 24 months; 2 doses (8 weeks apart) if incomplete schedule 1
• Ages 6-18 years: Single dose PCV13 if not previously received 1
• Ages ≥19 years: Single dose PCV13 (if PPSV23 previously given, administer PCV13 ≥1 year after last PPSV23) 1
• PPSV23 timing: Administer ≥8 weeks after PCV13, with second dose 5 years later 1

Critical timing consideration: MCV4-D should be administered ≥4 weeks after PCV13 due to reduced antibody response to pneumococcal serotypes when given simultaneously. 1

Antibiotic Prophylaxis

Consider daily prophylactic antibiotics (penicillin or macrolides for penicillin-allergic patients) for terminal pathway deficiencies despite vaccination, given the extreme infection risk. 6

Therapeutic Complement Inhibition

Eculizumab (Soliris) - C5 Inhibitor

Eculizumab is a monoclonal antibody that specifically binds complement protein C5, preventing cleavage to C5a and C5b, thereby blocking MAC formation and terminal complement activation. 8

FDA-Approved Indications

• Paroxysmal nocturnal hemoglobinuria (PNH): Reduces terminal complement-mediated intravascular hemolysis 8
• Atypical hemolytic uremic syndrome (aHUS): Inhibits complement-mediated thrombotic microangiopathy 1, 8
• Generalized myasthenia gravis (gMG): Reduces C5b-9 deposition at neuromuscular junction in anti-AChR antibody-positive adults 8
• Neuromyelitis optica spectrum disorder (NMOSD): Inhibits aquaporin-4-antibody induced C5b-9 deposition in anti-AQP4 antibody-positive adults 8

Critical Safety Requirements

Eculizumab dramatically increases risk of life-threatening meningococcal infections; complete or update meningococcal vaccination at least 2 weeks prior to first dose unless delay risks outweigh infection risk. 8

• Mandatory vaccination: Comply with current ACIP recommendations for meningococcal vaccination in complement inhibitor recipients 8
• Persistent infection risk: Patients remain at increased risk for invasive meningococcal disease even after vaccination 8
• Antibiotic prophylaxis: Long-term antimicrobial prophylaxis with penicillin (or macrolides for penicillin-allergic patients) recommended for duration of treatment 1
• Immediate evaluation: Monitor for early signs of meningococcal infection and evaluate immediately if suspected 8

Pharmacokinetics and Monitoring

• Free C5 target: Concentrations <0.5 mcg/mL correlate with complete blockade of terminal complement activity 8
• Steady state: Achieved 4 weeks after treatment initiation 8
• Plasma exchange interaction: Increases eculizumab clearance 250-fold, reducing half-life to 1.26 hours; supplemental dosing required 8

Disease-Specific Management

Atypical Hemolytic Uremic Syndrome (aHUS)

Initiate eculizumab within 4-8 hours of aHUS diagnosis, as delays are associated with increased morbidity and mortality; do not wait for complete diagnostic workup. 1

• Diagnostic criteria: Combination of platelet consumption (platelets <150,000/mm³ or 25% reduction), microangiopathic hemolysis (negative Coombs, elevated LDH, reduced haptoglobin, schistocytes), and renal involvement (elevated creatinine, hematuria/proteinuria) 1
• Vaccination timing: Do not delay eculizumab for vaccination completion if patient has life-threatening disease 1
• Discontinuation risk: Eculizumab discontinuation carries risk of aHUS recurrence and renal failure; thorough risk factor assessment essential before stopping 1

C3 Glomerulopathy

For immune complex-mediated MPGN with nephrotic syndrome and progressive renal decline, administer oral cyclophosphamide or mycophenolate mofetil plus low-dose corticosteroids for less than 6 months. 1, 7

• Monoclonal gammopathy association: If C3 glomerulopathy occurs with monoclonal gammopathy, target the B-cell or plasma cell clone producing monoclonal immunoglobulin 7
• Nephropathology consultation: Due to rarity and importance of proper classification, have experienced nephropathologists evaluate all MPGN biopsies 1

Systemic Lupus Erythematosus Monitoring

Measure C3 and C4 at initial SLE assessment and every 3 months during active disease to monitor disease activity and treatment response. 6

• Low C4 correlation: Particularly associated with active lupus nephritis 6
• Immunosuppression compatibility: Complement deficiency does not preclude use of corticosteroids or disease-modifying agents for lupus-like disease 6

Common Clinical Pitfalls

Specimen Handling Errors

The most common cause of falsely low complement levels is improper specimen handling—always refrigerate immediately after drawing. 6

Delayed Vaccination

Do not delay meningococcal vaccination while awaiting complete diagnostic workup, as patients are at immediate risk for life-threatening infections. 6

Incomplete Evaluation

Comprehensive complement analysis should be performed even in the absence of hypocomplementemia, as specific component defects may not lower C3 and C4. 7

Specialist Referral Indications

Consult immunology or complement specialists for all confirmed complement deficiencies to ensure comprehensive evaluation, appropriate genetic testing, and optimal long-term management. 6

• Specialized testing access: Many complement tests are only available through select research or clinical laboratories (University of Iowa, National Jewish Health) 1
• Complex disease management: Institutions with greater experience in complement disorders provide superior diagnostic and therapeutic guidance 1, 7