Everything You Need to Know About Chronic granulomatous disease for Step 1

Chronic granulomatous disease (CGD) is one of those immunodeficiencies that shows up everywhere in Step questions because it’s mechanistically clean: one broken enzyme → one missing immune function → a predictable list of organisms and tests. If you can connect NADPH oxidase → respiratory burst → catalase-positive infections → abnormal DHR/NBT, you’ll unlock a ton of immunology vignettes.

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Where CGD Fits (Big Picture)

CGD is a phagocyte dysfunction disorder (innate immunity) where neutrophils/macrophages can ingest microbes but can’t reliably kill certain ones due to impaired reactive oxygen species (ROS) generation.

First Aid cross-reference (typical placement): Immunology → Immunodeficiencies → Phagocyte dysfunction (CGD is classically listed alongside LAD and Chediak-Higashi).

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Definition (What It Is)

Chronic granulomatous disease = inherited defect in NADPH oxidase (most commonly) leading to impaired respiratory burst in phagocytes.

• Usually X-linked recessive (most common)
• Can also be autosomal recessive variants

Core consequence: decreased formation of superoxide ($O_2^-$) → decreased downstream ROS (including $H_2O_2$-derived killing) → susceptibility to certain pathogens and granuloma formation.

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Pathophysiology (How the Defect Causes the Symptoms)

Normal Respiratory Burst (What You’re Supposed to Do)

In neutrophils/macrophages, NADPH oxidase generates superoxide:

$NADPH + 2O_2 \rightarrow NADP^+ + 2O_2^- + H^+$

Then superoxide helps form other ROS, and myeloperoxidase (MPO) can use $H_2O_2$ to generate hypochlorite (bleach):

$H_2O_2 + Cl^- \xrightarrow{MPO} HOCl$

CGD: The Key Failure

In CGD, NADPH oxidase is defective → you can’t generate superoxide efficiently → reduced respiratory burst → reduced intracellular killing.

Why “Catalase-Positive” Matters

Some bacteria/fungi produce catalase, which breaks down their own hydrogen peroxide:

$2H_2O_2 \xrightarrow{catalase} 2H_2O + O_2$

• If an organism is catalase-negative, it tends to accumulate some $H_2O_2$, and the host can “steal” that $H_2O_2$ to help kill it (even if NADPH oxidase is weak).
• If an organism is catalase-positive, it destroys its own $H_2O_2$, so the phagocyte has much less oxidant substrate to use → CGD patients are especially vulnerable.

Why Granulomas Form

Persistent infection + chronic macrophage activation → granulomatous inflammation. Granulomas can become large enough to cause obstruction (classically GI/GU).

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High-Yield Organisms (Memorize These)

Classic Step list: Catalase-positive organisms
Think: “Cats Need PLACESS to Hide” (mnemonic varies, but the organisms are the point)

High-yield association: Aspergillus catalase-positive + CGD = recurrent/severe fungal pneumonia.

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Clinical Presentation (How It Shows Up)

CGD usually presents in infancy/early childhood, but milder variants can present later.

Common Presentations

• Recurrent infections with catalase-positive organisms
  • Pneumonia, lymphadenitis, osteomyelitis, skin infections
• Abscess formation (especially S. aureus)
• Granulomas causing obstructive symptoms
  • GI: vomiting, abdominal pain, obstruction
  • GU: urinary obstruction
• Inflammatory complications (CGD can have significant inflammation even beyond infection)

“Vignette language” to recognize

• “Recurrent infections with catalase-positive organisms”
• “Pneumonia with Aspergillus”
• “Deep-seated abscesses”
• “Granulomas causing obstruction”
• “Abnormal oxidative burst testing”

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Diagnosis (The Tests You Must Know)

1) Dihydrorhodamine (DHR) Flow Cytometry — Best Test

• Normal: neutrophils fluoresce (oxidative burst converts DHR → rhodamine)
• CGD: decreased/absent fluorescence

X-linked carrier pattern (high yield): mosaic pattern with two populations of neutrophils (some normal, some abnormal).

2) Nitroblue Tetrazolium (NBT) Test — Older Classic

• Normal: turns blue (positive test = normal oxidative burst)
• CGD: fails to turn blue (remains colorless)

Differentiate from MPO Deficiency (Classic Trick)

Both affect oxidative pathways, but:

Step takeaway: If they emphasize recurrent severe infections + catalase-positive + granulomas, it’s CGD.

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Treatment (Step-Relevant Management)

Infection Prevention

• TMP-SMX prophylaxis (bacterial)
• Itraconazole prophylaxis (fungal—especially Aspergillus coverage)
• Interferon-γ can reduce severe infections (classically taught)

Treat Active Infections Aggressively

• Culture-directed antibiotics/antifungals; low threshold for imaging (e.g., suspected abscess).

Curative Option

• Hematopoietic stem cell transplant (HSCT) can be curative in appropriate candidates.

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High-Yield Associations & “Buzz Phrases”

Must-know pairings

• CGD ↔ catalase-positive organisms
• CGD ↔ abnormal DHR / negative NBT
• CGD ↔ granulomas + obstruction
• CGD ↔ Aspergillus pneumonia

Genetics you should be ready to identify

• Most common: X-linked recessive
  • More males affected
  • Carrier females may show mosaicism on DHR

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First Aid–Style Rapid Review (Exam-Day Summary)

Chronic granulomatous disease

• Defect: NADPH oxidase → ↓ respiratory burst
• Inheritance: usually XLR
• Tests: ↓ DHR fluorescence; NBT negative
• Susceptible to: catalase-positive organisms (S. aureus, Serratia, Burkholderia cepacia, Nocardia, Aspergillus)
• Clinical: recurrent infections + granulomas (can obstruct)
• Tx: TMP-SMX + itraconazole prophylaxis, IFN-γ, consider HSCT

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Practice-Style Mini-Vignettes (What They’re Really Testing)

1. Boy with recurrent pneumonia and Serratia infections; neutrophils don’t fluoresce on DHR.
   → CGD due to NADPH oxidase defect.

2. Patient with severe Aspergillus pneumonia; NBT test stays colorless.
   → CGD (Aspergillus is catalase-positive).

3. Recurrent infections + granulomatous lesions causing urinary obstruction.
   → Think CGD granulomas.