What is chronic granulomatous disease?

Chronic granulomatous disease (CGD) is an inherited immunodeficiency in which the NADPH oxidase of neutrophils and macrophages does not work, so these cells can engulf microbes but cannot make superoxide and the other oxidants of the respiratory burst. Patients have recurrent, deep bacterial and fungal infections and form granulomas that can obstruct the stomach outlet or urinary tract. About two-thirds of cases are X-linked, caused by CYBB variants affecting gp91phox; the rest are autosomal recessive.

What organisms cause infections in chronic granulomatous disease?

The classic organisms are Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia and Aspergillus, and Aspergillus is the leading cause of death. They are traditionally explained as catalase-positive organisms that break down their own hydrogen peroxide, leaving the phagocyte with no oxidant to use against them. Catalase alone does not appear to be a major virulence factor in animal models, so it is best to memorize the specific list.

How is chronic granulomatous disease diagnosed?

The test of choice is dihydrorhodamine (DHR) flow cytometry, in which stimulated neutrophils from a patient with CGD show absent or greatly reduced fluorescence. In the older nitroblue tetrazolium (NBT) test, the cells fail to turn blue. An abnormal DHR should be confirmed with genetic testing, which also identifies the subtype. Myeloperoxidase deficiency can make the DHR look abnormal even though superoxide production and NBT staining are normal.

What is the treatment for chronic granulomatous disease?

Standard prevention is lifelong daily trimethoprim-sulfamethoxazole plus an antifungal such as itraconazole, and many centers add interferon gamma-1b injections three times weekly, which reduced serious infections in a placebo-controlled trial. Infections are treated aggressively with culture-directed antimicrobials and abscess drainage, and granulomatous complications often need corticosteroids. Allogeneic hematopoietic stem cell transplantation is the only established cure, and gene therapy is under study.

Is chronic granulomatous disease X-linked or autosomal recessive?

Both forms exist. About two-thirds of cases are X-linked recessive, caused by variants in CYBB, which encodes gp91phox, so they affect boys, and carrier mothers show two populations of neutrophils on DHR testing. The rest are autosomal recessive, most often from NCF1 variants affecting p47phox; these patients often have some residual oxidase activity and relatively good survival.

What is the life expectancy with chronic granulomatous disease?

Survival has improved greatly and is now about 90% at age 10, according to GeneReviews. With prophylaxis and treatment, most affected people live into mid- to late adulthood, and people with NCF1-related disease have relatively good survival, with more than 80% living beyond age 40. Hematopoietic stem cell transplantation can cure the disease.

Chronic Granulomatous Disease: Organisms, DHR & Treatment

Chronic granulomatous disease (CGD) is an inherited defect of the phagocyte NADPH oxidase (NOX2): neutrophils and macrophages engulf microbes normally but cannot make superoxide, so the respiratory burst fails and certain bacteria and fungi survive inside them. Patients get deep, recurrent infections with a short list of catalase-positive organisms (S. aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, Aspergillus) plus granulomas that can obstruct the stomach outlet or urinary tract, and about two-thirds of cases are X-linked (CYBB, gp91phox). The test of choice is dihydrorhodamine (DHR) flow cytometry, which shows little or no oxidative burst, and management is TMP-SMX + itraconazole prophylaxis, interferon-γ, and hematopoietic stem cell transplant (HSCT) for cure.

Quick check · free practice questionStep 1

A 2-year-old boy is brought to the physician due to fever, productive cough, and shortness of breath. Since birth, he has had recurrent respiratory infections requiring multiple courses of antibiotics. His immunizations are up to date, but he is in the 10th percentile for both height and weight. Temperature is 38°C (100.3°F). Physical examination reveals diffuse bilateral wheezing and cervical lymphadenopathy. Flow cytometric analysis of his serum using dihydrorhodamine fails to demonstrate fluorescence, indicating impaired oxidative burst in neutrophils. This patient is at greatest risk of infection with which of the following organisms?

CGD at a glance

Feature	What to know
Defect	NADPH oxidase (NOX2) → no superoxide → no respiratory burst; phagocytosis itself is normal
Inheritance	X-linked recessive CYBB (gp91phox) in about two-thirds; the rest autosomal recessive, mostly NCF1 (p47phox)
Organisms	S. aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia, Aspergillus
Infections	Pneumonia, suppurative lymphadenitis, liver abscess, osteomyelitis, skin abscesses
Inflammation	Granulomas obstructing the gastric outlet or urinary tract; Crohn-like colitis
Age at diagnosis	Mostly before age 5; milder cases can surface in adolescence or adulthood
Best test	DHR flow cytometry: little or no fluorescence after stimulation
Classic test	Nitroblue tetrazolium (NBT): cells fail to turn blue
Prevention	Daily TMP-SMX + itraconazole; interferon-γ three times weekly
Cure	Allogeneic HSCT

Pathophysiology: the respiratory burst, step by step

Inside the phagosome, NOX2 moves electrons from NADPH onto oxygen, and the products cascade:

NADPH oxidase: $\text{NADPH} + 2\,\text{O}_2 \rightarrow \text{NADP}^+ + 2\,\text{O}_2^{\bullet-} + \text{H}^+$
Dismutation (superoxide dismutase or spontaneous): $2\,\text{O}_2^{\bullet-} + 2\,\text{H}^+ \rightarrow \text{H}_2\text{O}_2 + \text{O}_2$
Myeloperoxidase (MPO): $\text{H}_2\text{O}_2 + \text{Cl}^- + \text{H}^+ \rightarrow \text{HOCl} + \text{H}_2\text{O}$ (hypochlorous acid, "bleach")

In CGD step 1 fails, so steps 2 and 3 run dry even though MPO is present. The NADPH comes from the pentose phosphate pathway, which is why severe G6PD deficiency sits on the differential (see the pentose phosphate pathway visual hack).

Why catalase-positive organisms? The classic explanation: catalase-negative bacteria such as streptococci make H₂O₂ but cannot break it down, so they supply the CGD phagocyte with the oxidant that kills them; catalase-producing pathogens like S. aureus and most gram-negative rods scavenge both their own and the host's H₂O₂. Use this logic on the exam, but don't over-apply it: catalase alone does not seem to be a significant virulence factor in animal models, and CGD patients have developed chronic infections with catalase-negative Actinomyces. Memorize the organism list rather than deriving it from a catalase test.

Why granulomas? NOX2 also helps regulate inflammation. Without it, neutrophil activity is poorly controlled, so patients develop granulomas and Crohn-like colitis that are treated with corticosteroids, not just antibiotics.

Genetics: which subunit is broken

gp91phox and p22phox form the membrane flavocytochrome b558; p47phox, p67phox and p40phox are cytosolic subunits that join it (with Rac2) on activation.

Gene	Protein	Inheritance	Share of CGD
CYBB	gp91phox (NOX2), membrane	X-linked recessive	About 65–70%
NCF1	p47phox, cytosolic	Autosomal recessive	About 20%
CYBA	p22phox, membrane	Autosomal recessive	About 7%
NCF2	p67phox, cytosolic	Autosomal recessive	About 7%
NCF4	p40phox, cytosolic	Autosomal recessive	Under 1%

A sixth gene, CYBC1, accounts for only a few patients.

X-linked disease is generally worse. Compared with autosomal recessive CGD, males with X-linked CGD are diagnosed earlier and have more perirectal abscesses, suppurative adenitis, gastric outlet and urinary obstruction, and higher mortality at a young age.
Residual superoxide predicts survival. Patients with NCF1 (p47phox) variants have relatively good survival (beyond age 40 in more than 80%).
Carrier mothers of X-linked CGD show two neutrophil populations on DHR because of X-inactivation. They are usually healthy but can have discoid-lupus-like skin lesions and aphthous ulcers, and when fewer than about 20% of their neutrophils are DHR-positive they become susceptible to CGD-type infections.

The organisms and where they strike

Hook for the big five: Some Nasty Bugs Survive Anyway (S. aureus, Nocardia, Burkholderia, Serratia, Aspergillus).

Organism	Typical CGD infection	Exam clue
Staphylococcus aureus	Liver abscess, skin abscess, lymphadenitis, osteomyelitis	Liver abscess occurs in up to 35% of patients
Burkholderia cepacia complex	Pneumonia, sepsis	Also a classic cystic fibrosis lung pathogen
Serratia marcescens	Osteomyelitis; skin infection	The most common CGD infection in infancy is a Serratia skin or bone infection
Nocardia	Pneumonia, osteomyelitis, brain abscess	Branching, weakly acid-fast rods
Aspergillus	Pneumonia, osteomyelitis, brain abscess	Leading cause of death; A. nidulans is almost exclusive to CGD

Rare bacteria considered pathognomonic for CGD: Granulibacter bethesdensis, Chromobacterium violaceum and Francisella philomiragia.

Classic stem clues

First infections involve the lymph nodes, lungs, liver, bone and skin.
Obstruction: vomiting from gastric outlet (pyloric) granulomas, or urinary obstruction from bladder granulomas.
Colitis: about 40–50% develop intestinal inflammation that resembles Crohn disease.
Labs: hypergammaglobulinemia and hematologic signs of chronic infection; antibody levels are not low.
Exposure history: mulch, compost, potting soil or leaf raking can cause fulminant fungal pneumonia from inhaled spores. Live bacterial vaccines (BCG, oral typhoid) are contraindicated.

Diagnosis: DHR vs NBT

Test	How it works	Normal result	CGD
DHR flow cytometry (preferred)	Stimulated neutrophils oxidize dihydrorhodamine 123 to fluorescent rhodamine 123	Strong fluorescence shift	Absent or greatly reduced shift
NBT slide test (older)	Superoxide reduces yellow NBT to blue-black formazan	More than 95% of cells turn blue	Cells do not turn blue (no formazan)

DHR is easier, more reliable, quantitative and more sensitive than NBT, and it can usually separate X-linked CGD, autosomal recessive CGD and X-linked carriers (two peaks).
NBT can be falsely normal in carriers (especially with skewed X-inactivation) and in hypomorphic CGD with residual activity.
Confirm with gene testing: an abnormal DHR should be followed by mutation analysis.
False-abnormal DHR: complete MPO deficiency gives an abnormal DHR because the dye's oxidation depends on MPO, but superoxide production and NBT staining are normal.
Galactomannan is unreliable here: the IDSA guideline does not recommend it for screening in CGD, where results are often negative despite invasive aspergillosis.

Treatment and prevention

Goal	Standard approach
Prevent bacterial infection	Lifelong daily TMP-SMX
Prevent fungal infection	Lifelong daily itraconazole (voriconazole or posaconazole are alternatives)
Immunomodulation	Interferon-γ-1b (FDA-approved for CGD): 50 mcg/m² subcutaneously three times weekly when body surface area is above 0.5 m²
Treat active infection	Aggressive, culture-directed therapy; drain abscesses; voriconazole for invasive aspergillosis; granulocyte transfusions can be lifesaving
Treat inflammation	Corticosteroids for obstructive granulomas and colitis
Cure	Allogeneic HSCT, best with matched donors at a younger age; gene therapy is under study

Interferon-γ evidence: in the placebo-controlled trial described in its FDA label (128 patients), serious infections occurred in 14 patients on interferon-γ-1b vs 30 on placebo, a 67% relative risk reduction. IDSA strongly recommends it as prophylaxis in CGD. Expect flu-like side effects (fever, headache, chills, fatigue).
Prognosis: survival is now about 90% at age 10, and with treatment most patients live into mid- to late adulthood.

CGD vs its mimics

Disorder	Defect	Distinguishing clue	DHR result
CGD	NADPH oxidase	Catalase-positive abscesses, granulomas	Absent or low
MPO deficiency	Myeloperoxidase (no HOCl)	Usually asymptomatic; severe Candida mainly with diabetes	Can be abnormal, but superoxide production and NBT are normal
LAD type 1	CD18 (β2 integrin)	Cord separation after 3 weeks, no pus, persistently high WBC	Normal
Chédiak-Higashi	LYST	Oculocutaneous albinism, giant granules, neurologic problems, accelerated phase	Normal
Job syndrome (AD hyper-IgE)	STAT3 → weak Th17	Staph skin and lung abscesses, eczema, retained baby teeth, IgE over 2,000 IU/mL	Normal
IL-12/IFN-γ axis defects	IL12RB1, IFNGR1 and others	Disseminated BCG or nontuberculous mycobacteria, Salmonella	Normal

The DHR is normal in LAD, Chédiak-Higashi, Job syndrome and IL-12/IFN-γ defects because none of them damages the NADPH oxidase itself. An abnormal DHR points to CGD, but MPO deficiency can mimic it on the assay and severe G6PD deficiency can also blunt the burst.

Compare the granule defect in the Chédiak-Higashi mnemonic, the Th17 defect in the Job syndrome flowchart, and the mycobacterial pattern in the IL-12 receptor deficiency question.

Practice question

A 3-year-old boy has fever and right upper quadrant pain. CT shows a liver abscess, and the drained pus grows Staphylococcus aureus. At 18 months he had Serratia marcescens osteomyelitis of the foot, and last year a suppurative cervical lymph node was drained. His umbilical cord separated at 10 days. Neutrophil count and IgG are elevated; IgE is normal. Which finding is most likely?

A. Absent fluorescence shift in stimulated neutrophils on DHR flow cytometry
B. Absent CD18 on neutrophils by flow cytometry
C. Giant cytoplasmic granules on the blood smear
D. Absent myeloperoxidase with normal NBT reduction
E. Serum IgE above 2,000 IU/mL
F. Absent IL-12 receptor β1 on lymphocytes

Answer: A. S. aureus liver abscess, Serratia osteomyelitis and suppurative lymphadenitis in a boy is the catalase-positive pattern of X-linked CGD.

B (LAD-1): these abscesses contained pus and the cord separated on time; LAD makes no pus and delays cord separation.
C (Chédiak-Higashi): no albinism, neurologic problems or bleeding tendency.
D (MPO deficiency): usually asymptomatic; it can make DHR look abnormal, but superoxide and NBT are normal.
E (Job syndrome): IgE is normal and there is no eczema or retained teeth.
F (IL-12 receptor β1 deficiency): presents with mycobacteria or Salmonella, and the DHR is normal.

Next steps: if his mother is an X-linked carrier, her DHR will show two neutrophil populations. He needs TMP-SMX and itraconazole prophylaxis, interferon-γ, and an HSCT evaluation.

Key takeaways

CGD = NADPH oxidase (NOX2) defect → no superoxide → failed respiratory burst; ingestion is normal, killing is not.
Organisms: S. aureus, Burkholderia cepacia, Serratia, Nocardia and Aspergillus (the leading cause of death).
About two-thirds are X-linked (CYBB, gp91phox); NCF1 (p47phox) is the main autosomal recessive form and has better survival.
DHR flow cytometry is the test of choice; NBT (no blue formazan) is the classic alternative; MPO deficiency can give a false-abnormal DHR.
Granulomas obstruct the gastric outlet and urinary tract, and Crohn-like colitis affects about 40–50%.
Prophylaxis: TMP-SMX + itraconazole + interferon-γ; HSCT is the only established cure.