Makindo Medical Notes

📚 Related Subjects: | Chronic Granulomatous Disease | Granulomatous Diseases

🧬 Key fact: The level of residual NADPH oxidase activity strongly correlates with disease severity and survival in Chronic Granulomatous Disease (CGD).

📘 About

• Chronic Granulomatous Disease (CGD) is a primary immunodeficiency disorder caused by defective phagocyte function.
• Characterised by recurrent bacterial and fungal infections, and by granuloma formation due to a persistent inflammatory response.
• Also historically known as Bridges–Good Syndrome.
• Typically presents in childhood but can appear later depending on genotype.

🧪 Aetiology & Pathophysiology

• Caused by defective NADPH oxidase complex in neutrophils and macrophages → failure to generate superoxide radicals for pathogen killing.
• Mutations in any of five genes encoding NADPH oxidase components can lead to disease (e.g., CYBB, CYBA, NCF1, NCF2, NCF4).
• Without oxidative burst, phagocytes can engulf but not destroy catalase-positive organisms.

🧬 Genetic Types

• 🧩 X-linked CGD (≈70%) — due to CYBB mutation; presents in early childhood, sometimes with lupus-like skin lesions.
• 🧬 Autosomal recessive CGD — due to other NADPH oxidase component defects; tends to present later with milder disease.
• Other forms:
  • AR cytochrome b–negative CGD
  • AR cytochrome b–positive CGD types I & II
  • Atypical granulomatous disease

🦠 Common Infections

• Aspergillus – pneumonia, lymphadenitis, osteomyelitis, brain abscess
• Candida – sepsis, liver abscess
• Nocardia – pneumonia, osteomyelitis, brain abscess
• Serratia marcescens – osteomyelitis, soft tissue infections, pneumonia
• Burkholderia (Pseudomonas) – pneumonia, sepsis
• Klebsiella – pneumonia, skin infections, lymphadenitis
• Staphylococcus aureus – soft tissue infections, liver abscess, osteomyelitis, sepsis

🧫 Key microbiological clue: Severe infections in CGD are typically caused by catalase-positive bacteria and fungi (e.g. Aspergillus, Serratia, Nocardia, Staphylococcus aureus) because they destroy their own hydrogen peroxide, depriving phagocytes of this compensatory oxidant source.

🩺 Clinical Features

• Recurrent pneumonia, abscesses (especially liver and skin), osteomyelitis, and lymphadenitis.
• Granulomatous inflammation may cause GI obstruction or urinary tract narrowing.
• Chronic inflammation can lead to growth failure or autoimmune-like features (e.g. discoid lupus).

🔬 Investigations

• FBC: normocytic anaemia, iron deficiency common due to chronic inflammation.
• Nitroblue Tetrazolium (NBT) Test: negative in CGD (no colour change to blue as neutrophils fail to produce superoxide).
• Dihydrorhodamine (DHR) flow cytometry: modern gold standard to assess oxidative burst activity.
• Hypergammaglobulinaemia may be seen.
• Genetic testing: confirms subtype (e.g. p47phox mutation).

💊 Management

• 🦠 Antimicrobial prophylaxis: lifelong antibiotics (e.g. co-trimoxazole) and antifungals (e.g. itraconazole).
• 💉 Interferon-γ therapy: boosts macrophage and neutrophil function, reducing infection rates.
• 🔪 Drainage and surgical management for abscesses.
• 💊 Steroids may be used for symptomatic granulomas causing obstruction.
• 💬 Psychological support and genetic counselling are essential for families.
• 🧫 Avoid live bacterial vaccines (e.g. BCG) due to risk of disseminated infection.
• 🧬 Haematopoietic stem cell transplantation (HSCT) may be curative in selected patients (best outcomes with HLA-identical sibling donor).
• 🧪 Emerging therapy: gene therapy using CRISPR/Cas9 to restore NADPH oxidase function offers future promise.

📊 Prognosis

• Residual NADPH oxidase activity strongly predicts disease severity — even small amounts correlate with milder disease and longer survival.
• With modern prophylaxis and supportive care, many patients survive well into adulthood.

📚 References

• Chronic Granulomatous Disease – NCBI
• Holland SM. Chronic Granulomatous Disease. Clin Rev Allergy Immunol. 2010;38(1):3–10.
• Marciano BE et al. Long-term follow-up of patients with chronic granulomatous disease. J Allergy Clin Immunol. 2015;135(2):370–377.

🧠 Teaching tip: CGD is an important differential for recurrent deep abscesses or infections with unusual catalase-positive organisms. Always remember: they can phagocytose, but cannot kill the pathogen effectively due to oxidative burst failure.