A 35-year-old Indian woman with a history of recurrent infections (catalase-positive organisms) and poor wound healing presents with a skin biopsy showing impaired neutrophil oxidative burst. Her neutrophils fail to produce superoxide anion (O₂⁻) during respiratory burst. Laboratory testing reveals normal glucose-6-phosphate dehydrogenase activity. Which of the following best explains the biochemical defect underlying her recurrent infections?

Explanation

## Chronic Granulomatous Disease (CGD): The Role of NADPH in Neutrophil Oxidative Burst ### The Pentose Phosphate Pathway Connection to Immunity **Key Point:** The pentose phosphate pathway is not just about carbohydrate metabolism—it is the PRIMARY source of NADPH in all cells, and NADPH is absolutely essential for the neutrophil respiratory burst and bacterial killing. ### The Respiratory Burst Mechanism ```mermaid flowchart TD A[Glucose-6-phosphate]:::outcome --> B[Pentose Phosphate Pathway]:::outcome B --> C[NADPH production]:::outcome C --> D[NADPH oxidase NOX2 activation]:::action D --> E[O₂ → O₂⁻ superoxide anion]:::outcome E --> F[Superoxide dismutase: O₂⁻ → H₂O₂]:::action F --> G[Myeloperoxidase: H₂O₂ → HOCl hypochlorous acid]:::action G --> H[Bacterial killing]:::action I[Normal G6PD activity]:::outcome -.->|Present in this case| C J[Defective NOX2]:::urgent -.->|This patient's defect| D ``` ### Why This Patient Has Normal G6PD but Still Defective Respiratory Burst | Component | Status in This Patient | Explanation | |-----------|------------------------|-------------| | **G6PD enzyme** | **Normal** (confirmed by testing) | NADPH production is intact | | **NADPH availability** | **Adequate** | The pentose phosphate pathway is functioning | | **NADPH oxidase (NOX2)** | **Defective** | Cannot use NADPH to generate superoxide | | **Superoxide production** | **Absent** | No O₂⁻ generated despite adequate NADPH | | **Catalase-positive organisms** | **Recurrent infections** | Catalase-producing bacteria (Staphylococcus aureus, Serratia, Burkholderia, Nocardia) survive because H₂O₂ is neutralized | **High-Yield:** Chronic Granulomatous Disease (CGD) is an X-linked (85%) or autosomal recessive (15%) immunodeficiency caused by mutations in genes encoding NADPH oxidase subunits (most commonly CYBB gene encoding NOX2 gp91phox). The key biochemical defect is the inability to generate superoxide, NOT a deficiency in NADPH production. ### Diagnostic Clue: The Nitroblue Tetrazolium (NBT) Test In CGD: - **NBT test:** Remains colourless (no blue formazan precipitate) because no superoxide is produced - **Dihydrorhodamine (DHR) flow cytometry:** No fluorescence (confirms absent respiratory burst) ### Why This Is NOT the Other Options **Glucose-6-phosphate dehydrogenase deficiency:** - Would cause impaired NADPH production → impaired respiratory burst - But the stem explicitly states **normal G6PD activity**, ruling this out - Would also present with haemolytic anaemia (not mentioned) **Catalase deficiency:** - Catalase breaks down H₂O₂ to water and O₂ - Deficiency would actually INCREASE H₂O₂ accumulation and bacterial killing - Catalase-negative organisms would be problematic, not catalase-positive ones - Acatalasia is extremely rare and does NOT cause recurrent infections **Myeloperoxidase deficiency:** - Myeloperoxidase uses H₂O₂ to generate hypochlorous acid (HOCl) - Deficiency impairs the final step of bacterial killing - However, patients with MPO deficiency are usually asymptomatic or have mild infections - The respiratory burst (superoxide production) would still be NORMAL - The stem specifically states the defect is in superoxide production **Clinical Pearl:** CGD patients present with recurrent infections by catalase-positive organisms because these bacteria produce catalase, which breaks down the H₂O₂ that would otherwise kill them. Organisms like Staphylococcus aureus, Serratia, Burkholderia, Nocardia, and Aspergillus are classic culprits. Diagnosis is made by NBT test or DHR flow cytometry showing absent respiratory burst. **Mnemonic:** **SCAB** = Staphylococcus aureus, Catalase-positive, Aspergillus, Burkholderia (common organisms in CGD) **Warning:** Do NOT confuse G6PD deficiency with CGD. Both involve NADPH, but: - **G6PD deficiency:** Impaired NADPH production → haemolytic anaemia, NOT immunodeficiency - **CGD:** Normal NADPH production but defective NOX2 enzyme → recurrent infections, NOT haemolysis [cite:Robbins 10e Ch 5; Harrison 21e Ch 375]