Phagocyte & Complement Disorders: CGD, LAD, Hyper-IgE, Complement Deficiencies

Chronic granulomatous disease · Leukocyte adhesion deficiency · Hyper-IgE syndrome (STAT3, DOCK8) · Hemophagocytic syndromes · Complement deficiencies (C1-C9, MBL) · Paroxysmal nocturnal hemoglobinuria
🧬 Key concepts: CGD (NADPH oxidase, catalase+ organisms, DHR test). LAD (CD18 deficiency, delayed cord separation). Hyper-IgE (STAT3, eczema, staphylococcal abscesses). Complement (Neisseria, SLE, encapsulated bacteria).

📖 Phagocytic cell & complement disorders

🦠 Chronic granulomatous disease (CGD)
NADPH oxidase defect → impaired intracellular killing. Recurrent catalase-positive organisms (S. aureus, Serratia, Nocardia, Aspergillus, Burkholderia). Granuloma formation (lung, GI, GU). DHR test diagnostic.
🔗 Leukocyte adhesion deficiency (LAD)
CD18 deficiency → impaired adhesion, chemotaxis. Delayed umbilical cord separation, severe periodontitis, recurrent soft tissue infections, leukocytosis. Flow cytometry (CD11/CD18).
🩸 Complement deficiencies
Early complement (C1-C4): SLE-like disease. Terminal complement (C5-C9): Neisseria infections (meningococcal, gonococcal). MBL deficiency: mild increased infection risk.
⚡ Hyper-IgE syndrome (STAT3, DOCK8)
STAT3: coarse facies, retained primary teeth, scoliosis, eczema, staphylococcal abscesses, elevated IgE, pneumatoceles. DOCK8: severe viral infections, allergies, lymphoma.
⚠️ Red flags for phagocyte disorders: Delayed umbilical cord separation (>3 weeks), chronic periodontitis, deep-seated abscesses, catalase-positive organisms, persistent leukocytosis.

🩺 Diagnostic approach to phagocyte & complement disorders

1
CGD evaluation – Dihydrorhodamine (DHR) test (flow cytometry) – absent neutrophil oxidative burst. Confirmatory genetic testing (CYBB, NCF1, etc.).
2
LAD evaluation – Flow cytometry for CD11/CD18 (integrin expression). CBC (marked leukocytosis). Delayed cord separation.
3
Complement workup – CH50 (total complement hemolytic activity), AH50 (alternative pathway). Low CH50 → individual component assay. C3, C4 levels.
4
Hyper-IgE syndrome – Elevated serum IgE (>2000 IU/mL), eosinophilia, clinical features (eczema, abscesses, retained primary teeth, scoliosis). STAT3 or DOCK8 genetic testing.
📌 Clinical pearl: A child with recurrent catalase-positive bacterial infections (Staph, Serratia, Nocardia, Aspergillus) and granulomatous colitis → CGD until proven otherwise.

📋 Stepwise management of phagocyte & complement disorders

1
CGD – Prophylactic TMP-SMX (bacteria), itraconazole (Aspergillus), IFN-γ (controversial). HSCT is curative. Avoid plants with catalase (mulch, potting soil).
2
LAD – Aggressive antibiotic therapy, prophylactic TMP-SMX. HSCT is definitive treatment.
3
Complement deficiencies – Vaccination against encapsulated bacteria (meningococcal, pneumococcal, Hib). Prophylactic antibiotics (penicillin). Fresh frozen plasma for acute severe infections (rare).
4
Hyper-IgE (STAT3) – Prophylactic TMP-SMX, antifungal (fluconazole), skin care, treat abscesses. IVIG may benefit (for DOCK8). HSCT for DOCK8.
5
Hemophagocytic lymphohistiocytosis (HLH) – Immunosuppression (dexamethasone, etoposide, ciclosporin). HSCT for familial HLH.
🚨 Emergency: CGD patient with fever and pulmonary infiltrate → suspect Aspergillus pneumonia. Immediate voriconazole, bronchoalveolar lavage, consider surgical debridement.

🧠 Reflex prompts: phagocyte & complement disorders

🦠 Child with recurrent Staph aureus abscesses, pneumonia with Serratia, and chronic granulomatous colitis. DHR test abnormal. Diagnosis?
Chronic granulomatous disease (CGD). Prophylaxis with TMP-SMX, itraconazole.
🔗 Infant with delayed umbilical cord separation (>3 weeks), leukocytosis, and recurrent skin infections. Flow cytometry shows absent CD18. Diagnosis?
Leukocyte adhesion deficiency (LAD). HSCT curative.
🩸 Teenager with recurrent meningococcal meningitis. CH50 is <5% of normal. Most likely complement defect?
Terminal complement deficiency (C5-C9). Vaccinate against meningococcus.
⚡ 5-year-old with eczema, recurrent staphylococcal abscesses, coarse facies, retained primary teeth, and IgE 5000 IU/mL. Diagnosis?
Hyper-IgE syndrome (STAT3 deficiency). TMP-SMX, antifungals.
🩸 Child with SLE-like illness (nephritis, arthritis, rash) and low C1q, C4, CH50. Likely complement defect?
Early complement deficiency (C1q, C1r/s, C4, C2). Risk of SLE.
🦠 Which organism is classically associated with CGD?
Catalase-positive bacteria: S. aureus, Serratia marcescens, Nocardia, Burkholderia, and Aspergillus.
🔬 What is the diagnostic test for CGD?
Dihydrorhodamine (DHR) assay – measures neutrophil oxidative burst.
💊 What is the prophylaxis for Aspergillus in CGD?
Itraconazole or voriconazole.
🧬 Which gene is most commonly mutated in X-linked CGD?
CYBB (gp91phox).
💉 What vaccine is crucial for terminal complement deficiency?
Meningococcal (MenACWY, MenB), pneumococcal, Hib.