A 35-year-old man from Bangalore with a history of recurrent Neisseria meningitidis infections (2 episodes in the past 18 months) presents to the clinic for evaluation. Serum complement levels show: C5 = 2% (normal 10–20%), C6 = 8% (normal 10–20%), C7 = 12% (normal 10–20%), C8 = 5% (normal 10–20%), C9 = 15% (normal 10–20%). What is the most appropriate next step in management?

Explanation

## Clinical Diagnosis: Terminal Complement Deficiency (C5–C9 Deficiency) **Key Point:** This patient has a deficiency in the **terminal complement pathway** (C5–C9 lytic complex). The pattern of multiple low terminal components with recurrent *Neisseria meningitidis* infection is pathognomonic. ### Complement Pathway Overview ```mermaid flowchart TD A[Complement Activation]:::outcome --> B{Pathway}:::decision B -->|Classical| C[C1, C4, C2]:::outcome B -->|Alternative| D[Factor B, Factor D, C3]:::outcome B -->|Lectin| E[MBL, MASP]:::outcome C --> F[C3 convertase]:::outcome D --> F E --> F F --> G[C5 convertase]:::outcome G --> H[Terminal Pathway: C5-C9]:::outcome H --> I[Membrane Attack Complex]:::outcome I --> J[Cell lysis]:::action ``` ### Why Terminal Deficiency → Meningococcal Infection **High-Yield:** The membrane attack complex (MAC = C5b-6-7-8-9) is the **only complement component that directly lyses gram-negative bacteria** like *Neisseria meningitidis*. Deficiency in C5–C9 prevents MAC formation, leaving the patient unable to kill encapsulated organisms. **Clinical Pearl:** Patients with terminal complement deficiency have a **600–10,000-fold increased risk** of meningococcal disease (compared to 1:100,000 in the general population). ### Immediate Management Strategy | Intervention | Rationale | |---|---| | **Meningococcal vaccine (MenACWY + MenB)** | Prevents infection; must be given before antibiotics (antibiotics reduce vaccine response) | | **Pneumococcal vaccine (PCV20 or PCV15 + PPSV23)** | Covers another common encapsulated organism | | **Prophylactic penicillin V** | Lifelong chemoprophylaxis (penicillin V 250 mg BD or rifampin 600 mg daily) | | **Genetic counseling** | Autosomal recessive inheritance; siblings at risk | | **Educate on early antibiotic use** | Patient should carry antibiotics and seek care immediately for fever/meningeal signs | **Warning:** Do NOT delay vaccination for complement testing or genetic confirmation. Vaccination should occur immediately upon diagnosis of terminal complement deficiency. ### Why This Is NOT a Deficiency of C3 or Early Components C3 and C4 are part of the **early pathway** (classical, alternative, lectin). If C3 were deficient: - Patient would have recurrent infections with *encapsulated organisms* (meningococcus, pneumococcus) AND atypical organisms - Autoimmune disease (SLE-like) would be common - C3 level would be markedly low Here, C3 and C4 are presumed normal (not listed as abnormal), and the defect is isolated to C5–C9.