A 32-year-old woman presents with recurrent pyogenic infections (Staphylococcus aureus, Streptococcus pneumoniae) and a history of angioedema. Laboratory investigation shows normal C3 and C4 levels, but defective opsonization and impaired MAC formation. Which complement component deficiency best explains her clinical presentation?

Explanation

## Clinical Presentation of C5 Deficiency ### Case Analysis The patient has: - Recurrent pyogenic infections (encapsulated organisms) - Angioedema (complement-mediated) - Normal C3 and C4 (early and middle pathway intact) - Defective opsonization and impaired MAC formation **Key Point:** C5 is the critical junction between the amplification phase (C3 activation) and the terminal lytic phase (MAC formation). Deficiency of C5 specifically impairs both anaphylatoxin generation (C5a) and MAC assembly (C5b-9), while leaving C3 and C4 levels normal. ### Pathophysiology of C5 Deficiency ```mermaid flowchart TD A[Complement activation<br/>C1q or C3b]:::outcome --> B[C3 convertase activated]:::action B --> C{C3 cleavage}:::decision C -->|Normal C3 levels| D[C3b opsonization occurs]:::action C -->|C5 present| E[C5 convertase forms]:::action E --> F[C5a anaphylatoxin<br/>C5b-9 MAC]:::action E -->|C5 ABSENT| G[No C5a, no MAC]:::urgent D --> H[Opsonization intact]:::outcome G --> I[Impaired MAC formation<br/>Impaired chemotaxis]:::urgent G --> J[Recurrent pyogenic infections]:::urgent ``` ### Comparison: Why Not the Other Options? | Component | Clinical Phenotype | C3/C4 Levels | Opsonization | MAC | Infection Pattern | | --- | --- | --- | --- | --- | --- | | **C5 deficiency** | Pyogenic infections + angioedema | Normal | Intact | Absent | *Staph*, *Strep* | | C1-INH deficiency | Hereditary angioedema only | Normal | Normal | Normal | No infections | | C3 deficiency | Severe pyogenic infections | **Low** | Absent | Absent | Overwhelming | | Properdin deficiency | Meningococcal/gonococcal | Normal | Intact | Intact | *Neisseria* only | **Clinical Pearl:** C5 deficiency creates a unique dual phenotype: (1) impaired MAC formation → recurrent pyogenic infections, and (2) loss of C5a chemotactic gradient → impaired neutrophil recruitment. Patients are NOT susceptible to *Neisseria* (unlike properdin deficiency) because opsonization via C3b is intact. **High-Yield:** The key discriminator is **normal C3 and C4 with defective MAC formation**. This pattern is pathognomonic for terminal pathway defects (C5, C6, C7, C8, C9). Among these, C5 deficiency is the most common and causes the most severe phenotype because C5a is the most potent anaphylatoxin. **Mnemonic:** **"C5 = Crossroads"** — C5 is where the amplification loop (C3 opsonization) meets the terminal attack phase (MAC). Lose C5, lose MAC but keep opsonization. [cite:Harrison 21e Ch 297]