• Estimated incidence: approximately 1 in 200,000 to 1 in 250,000 live births worldwide
• In Hong Kong, CGD is rare but recognised; the HKU Department of Paediatrics and Adolescent Medicine maintains a registry of primary immunodeficiencies, and CGD cases are diagnosed periodically

• Usually presents in infancy or early childhood (most within the first 2–5 years of life)
• X-linked forms tend to present earlier and more severely than autosomal recessive forms
• Rarely, milder autosomal recessive variants can present in adolescence or even young adulthood (so-called "variant CGD")

• Majority (~60–65%) are X-linked recessive → predominantly affects males ^[3][4]
• The remainder (~35–40%) are autosomal recessive → affects males and females equally

• Family history of CGD or recurrent severe infections/early death from infection in male relatives (for X-linked form)
• Consanguinity increases risk of autosomal recessive forms (relevant in some Hong Kong families of South Asian or Middle Eastern descent)

• BCG vaccination is given routinely at birth in Hong Kong → this is critically important because CGD patients are at high risk of disseminated BCG disease (BCGosis), which can be an early presenting feature ^[3][4]
• Tuberculosis remains endemic in Hong Kong, adding another layer of risk for CGD patients

When a neutrophil (or macrophage/monocyte) engulfs a microbe into a phagosome, two killing mechanisms operate:

1. Oxygen-dependent (oxidative) killing — the dominant mechanism
2. Oxygen-independent killing — via lysozyme, defensins, lactoferrin, etc.

The NADPH oxidase complex (also called phagocyte oxidase or phox) is the enzyme responsible for the respiratory burst:

NADPH + 2O₂ → NADP⁺ + H⁺ + 2O₂⁻ (superoxide)

Superoxide (O₂⁻) is then converted to other ROS:

• Hydrogen peroxide (H₂O₂) — via superoxide dismutase
• Hypochlorous acid (HOCl) — via myeloperoxidase (MPO) + Cl⁻ (this is essentially "bleach")
• Hydroxyl radicals (OH·)

These ROS are poured into the phagosome to kill the ingested microbe.

The NADPH oxidase is a multi-subunit enzyme assembled from components in two locations:

Upon phagocyte activation, the cytosolic subunits translocate to the membrane and assemble with the membrane-bound subunits to form the active oxidase complex.

This is one of the most commonly asked exam questions, and the logic is elegant:

• Catalase-negative bacteria (e.g., Streptococcus) produce their own H₂O₂ as a metabolic byproduct. Even in a CGD patient whose phagocytes cannot generate their own H₂O₂, the bacterium's H₂O₂ can still be used by the MPO system to generate HOCl → the bacterium essentially "kills itself"
• Catalase-positive bacteria (e.g., Staphylococcus aureus, Aspergillus, Serratia, Burkholderia, Nocardia) destroy their own H₂O₂ using their catalase enzyme → in CGD patients, there is no H₂O₂ from either source → the phagocyte cannot kill these organisms at all

This is why CGD patients are specifically susceptible to catalase-positive organisms — the catalase enzyme in these bacteria neutralises any residual H₂O₂, leaving the phagocyte completely defenceless.

Key pathophysiological consequences:

1. Recurrent severe infections — because catalase-positive organisms survive inside phagocytes
2. Granuloma formation — because the immune system's "Plan B" when it cannot kill an organism is to wall it off. Macrophages become epithelioid cells, fuse into giant cells, and are surrounded by T lymphocytes and fibroblasts → this forms a granuloma. In CGD, granulomas are non-caseating (unlike TB granulomas) and can form in virtually any organ ^[3][4]
3. Excessive inflammation — the defective NADPH oxidase also impairs the normal resolution of inflammation. Recent research shows that ROS are needed for the formation of neutrophil extracellular traps (NETs) and for signalling macrophage efferocytosis (clearance of apoptotic neutrophils). Without ROS, inflammation persists → this contributes to the inflammatory/autoimmune complications of CGD

• X-linked recessive (~65%) — CYBB mutations ^[1][3][4]
• Autosomal recessive (~35%) — NCF1, NCF2, CYBA, NCF4 mutations

• "Classic" CGD: < 1% residual NADPH oxidase activity → severe phenotype
• "Variant" CGD: 1–10% residual activity → milder phenotype, later presentation, better prognosis

(See table in Section 4)

• CGD falls under Table 5: Congenital defects of phagocyte number or function → specifically under defects of the respiratory burst
• This places CGD in the broader category of Phagocyte and Innate Immunity Defects within the Inborn Errors of Immunity ^[1][2]

Severe Combined Immunodeficiency (SCID)

• Defect: Impaired B and T cell development ^[3][4]
• Organisms: Opportunistic — PJP, CMV, Candida, disseminated BCG
• Key differentiators from CGD:
  • SCID presents much earlier (often weeks of life) and is far more severe — FTT, intractable diarrhoea, oral thrush from birth
  • Lymphopenia (low absolute lymphocyte count) is the hallmark — CGD has normal lymphocytes ^[3]
  • Absent thymic shadow on CXR ^[3]
  • SCID patients do NOT typically form granulomas (they lack the T cells needed for granuloma organisation)
  • Fatal without treatment (HSCT or gene therapy) ^[3]

Cotrimoxazole is the first-line antibacterial prophylactic agent in CGD ^[5].

Why is this high yield?

If TMP-SMX intolerant: alternatives include ciprofloxacin or dicloxacillin, though evidence is less robust.

Itraconazole is the first-line antifungal prophylactic agent in CGD ^[5].

If itraconazole intolerant or refractory: posaconazole (better tolerated, broader spectrum) or voriconazole may be used.

Paediatric formulation note: Itraconazole oral solution (10 mg/mL) has better bioavailability than capsules in children because it does not require gastric acid for absorption. Always prescribe the solution for young children, and take on an empty stomach (unlike capsules, which need food).

Aspergillus species are the leading cause of death in CGD.

Paediatric dosing alert: Voriconazole dosing in children aged 2–12 is approximately DOUBLE the adult weight-based dose because children have higher CYP2C19 activity and faster hepatic clearance. Therapeutic drug monitoring (TDM) is mandatory.

HK-specific consideration: In Hong Kong, where TB is endemic and BCG is given at birth, CGD patients may present with BCG lymphadenitis/dissemination as their first infection ^[3][5][6]. Early aggressive anti-mycobacterial treatment is critical. All subsequent live vaccines are contraindicated in CGD.

• In severe, life-threatening infections that are not responding to antimicrobial therapy, granulocyte transfusions (from normal donors whose neutrophils have intact oxidative burst) can be considered
• This provides temporary normal neutrophil killing function to the patient
• Logistically challenging (granulocytes have a very short shelf-life and must be irradiated); reserved for salvage situations

Risks of steroids in CGD: This is a genuine clinical dilemma — corticosteroids are immunosuppressive and CGD patients are already immunodeficient. Therefore:

• Use the lowest effective dose for the shortest possible duration
• Always ensure the patient is on antimicrobial prophylaxis
• Monitor closely for breakthrough infections
• Consider steroid-sparing agents early

HSCT is the only currently established curative treatment for CGD ^[5][12].

• Most common type of infection in all age groups is pneumonia, typically caused by Staphylococcus aureus, Aspergillus species, Burkholderia cepacia, and enteric gram-negative bacteria ^[8]
• Why the lungs? The lungs are in continuous contact with the external environment via inhaled air → constant exposure to airborne bacteria and fungal spores (especially Aspergillus conidia). Normal alveolar macrophages would kill these organisms via the oxidative burst; in CGD, they survive and proliferate ^[3][8]
• Each episode of pneumonia causes cumulative parenchymal damage

• This is the single leading cause of mortality in CGD
• Aspergillus fumigatus conidia (spores) are ubiquitous in the environment — we all inhale them daily. In healthy individuals, alveolar macrophages and neutrophils kill conidia through the oxidative burst. In CGD, these spores germinate into invasive hyphae that penetrate pulmonary tissue
• Clinical features: Insidious fever, chest pain, non-productive cough, haemoptysis; may present with the "halo sign" on CT chest (ground-glass opacity surrounding a pulmonary nodule — represents haemorrhagic infarction around invading hyphae)
• Complications of IPA: Lung abscess, empyema, invasion into chest wall or mediastinum, haematogenous dissemination to brain (cerebral aspergillosis — usually fatal)

• Mechanism: Recurrent pneumonia → chronic airway inflammation → destruction of bronchial wall elastic tissue and smooth muscle → irreversible airway dilatation
• This is a cumulative, progressive complication — the more pneumonia episodes, the worse the bronchiectasis
• Leads to chronic productive cough, recurrent exacerbations, and progressive decline in lung function
• Paediatric impact: Impairs exercise tolerance, school attendance, growth; may eventually require consideration of lung transplantation in severe cases (though HSCT ideally prevents progression to this stage)

• Non-infectious granulomas can form in the lung parenchyma and mediastinal lymph nodes
• May be mistaken for malignancy or sarcoidosis on imaging
• Can cause restrictive lung physiology if extensive

• Prevalence: Occurs in approximately 30–50% of CGD patients
• Pathophysiology: The GI tract is constantly exposed to trillions of commensal bacteria. In CGD, the defective neutrophil oxidative burst fails to contain these organisms at the mucosal barrier → chronic granulomatous inflammation of the bowel wall
• Additionally, NADPH oxidase is now known to play a role in neutrophil extracellular trap (NET) formation and in signalling the resolution of inflammation. Without this, inflammation becomes self-perpetuating
• CGD colitis is clinically and histologically almost indistinguishable from Crohn's disease — both produce non-caseating granulomas, transmural inflammation, skip lesions, strictures, and fistulae
• Symptoms: Chronic diarrhoea (which may be bloody), abdominal pain, perianal disease (fissures, fistulae, abscesses), weight loss, failure to thrive ^[3][6]
• Why this matters clinically: Any child with very-early-onset IBD (< 6 years) should be screened for CGD (DHR test) and other monogenic causes of IBD (e.g., IL-10/IL-10R deficiency)

• Granulomas can form anywhere along the GI tract and cause luminal narrowing/obstruction:
  • Oesophageal granulomas → dysphagia
  • Gastric outlet obstruction → persistent vomiting
  • Small bowel strictures → sub-acute intestinal obstruction
  • Colonic strictures → constipation, obstruction
• These obstructive complications often respond to corticosteroids (which shrink granulomas) but may require surgical intervention if medical therapy fails

• Perianal abscess and sepsis are common presenting features of CGD ^[3][6]
• Perianal fistulae may develop — analogous to perianal Crohn's
• Why? The perianal region is exposed to a high microbial load from faecal flora; defective neutrophil killing allows bacterial invasion of the perianal tissue → abscess → chronic fistula formation

• Liver is a common site of infection in CGD ^[3][8]
• Mechanism: The liver's reticuloendothelial system (Kupffer cells) filters bacteria from the portal venous blood. In CGD, Kupffer cells (which are macrophages with defective NADPH oxidase) trap but cannot kill organisms → intracellular survival → abscess formation
• Typically caused by Staphylococcus aureus (most common hepatic abscess organism in CGD)
• CGD liver abscesses have unique characteristics:
  • Often multiple, small, and densely packed (unlike the single large pyogenic abscess in immunocompetent patients)
  • May be very dense/firm on imaging, making percutaneous drainage difficult (the dense granulomatous tissue creates a "caseous" consistency)
  • Require prolonged IV antibiotic therapy (often 6–12 weeks) ± surgical drainage

• Hepatosplenomegaly is a near-universal finding in CGD ^[3][6]
• Mechanism: Chronic reticuloendothelial hyperplasia (macrophage expansion in liver and spleen from persistent antigenic stimulation) + hepatic granulomas + extramedullary haematopoiesis
• Over years, hepatic granulomas can cause portal hypertension via progressive hepatic fibrosis → ascites, varices, splenomegaly worsening

• Granulomas can form along the urinary tract, causing:
  • Ureteric obstruction → hydronephrosis → renal impairment if bilateral
  • Bladder outlet obstruction → urinary retention, overflow incontinence
• These are non-infectious granulomatous complications — they respond to corticosteroids
• Often detected incidentally on abdominal USS/CT during routine surveillance

• Less common than skin/lung infections, but recurrent UTIs can occur
• May be complicated by obstructing granulomas

• CGD patients are susceptible to osteomyelitis, particularly in the small bones of the hands/feet, ribs, and vertebrae
• Common organisms: Aspergillus (most common cause of CGD osteomyelitis — unlike in immunocompetent children where S. aureus dominates), Serratia marcescens, S. aureus
• Why these sites? Haematogenous seeding to metaphyseal regions with sluggish blood flow (same principle as standard paediatric osteomyelitis, but with different organisms)
• Requires prolonged antimicrobial therapy (6–12 weeks minimum)

• Less common than osteomyelitis; may occur by contiguous spread from adjacent osteomyelitis or haematogenous seeding

• Cutaneous abscess and lymphadenitis is the next most common presentation after pneumonia ^[8]
• Lymph nodes draining infected sites become involved; organisms persist within nodal macrophages
• Often requires prolonged antibiotics ± surgical excision/drainage
• The AOS exam stem describes this classic picture: recurrent cervical lymphadenitis since 6 months old, difficult to treat, culture growing S. aureus ^[6]

• In Hong Kong, where neonatal BCG vaccination is universal, CGD patients are at particular risk of:
  • Local BCGitis: enlarged, ulcerating BCG scar ( > 1.5 cm), ipsilateral axillary lymphadenopathy ^[6]
  • Disseminated BCGosis: M. bovis BCG spreads via bloodstream to multiple organs (lung, liver, bone marrow, lymph nodes) → can be fatal if untreated
• BCG dissemination in a Hong Kong infant is one of the most important presenting features of CGD ^[3][6]
• Requires prolonged multi-drug anti-mycobacterial therapy (isoniazid + rifampicin + ethambutol; pyrazinamide is ineffective against M. bovis)

• Rare but devastating complication
• Usually caused by Aspergillus (cerebral aspergillosis) via haematogenous dissemination from pulmonary focus
• Presents with headache, seizures, focal neurological deficits, altered consciousness
• High mortality; requires aggressive IV antifungal therapy (voriconazole crosses the blood-brain barrier well) ± neurosurgical drainage
• Why Aspergillus reaches the brain: Aspergillus hyphae are angioinvasive — they invade blood vessel walls, enter the bloodstream, and seed distant organs including the brain

• Less common than brain abscess; can be bacterial or fungal
• Again highlights the importance of aggressive prophylaxis and early treatment

• Mechanism: Granulomatous macrophages express 1α-hydroxylase, which converts 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D (calcitriol) → increased intestinal calcium absorption + increased bone resorption → hypercalcaemia
• This is the same mechanism seen in sarcoidosis and tuberculosis (any granulomatous disease)
• Glucocorticoids are specifically indicated for hypercalcaemia in CGD because they reduce calcitriol production by activated mononuclear cells ^[11]
• Clinical features in children: Polyuria, polydipsia, constipation, abdominal pain, irritability, poor feeding, failure to thrive. Severe hypercalcaemia can cause renal stones, nephrocalcinosis, and cardiac arrhythmias

• Persistent chronic inflammation → elevated hepcidin → sequestration of iron in macrophages → reduced iron availability for erythropoiesis → normocytic, normochromic anaemia with low serum iron but normal/elevated ferritin
• Contributes to fatigue and poor exercise tolerance

• Multiple contributing factors:
  • Chronic infection → catabolic state → increased energy expenditure
  • CGD colitis → malabsorption of nutrients
  • Recurrent hospitalisations → missed meals, psychosocial stress
  • Chronic steroid use (for granulomatous complications) → growth suppression
• Monitoring: Regular plotting on growth charts; involvement of paediatric dietitian

• Chronic illness from infancy → repeated hospitalisations, missed school, social isolation
• Anxiety and depression (especially in adolescents who understand their diagnosis)
• Impact on family — parental anxiety, sibling effects, financial burden
• Management: Multidisciplinary team including clinical psychologist, social worker, school liaison

• CGD patients have an increased incidence of:
  • Discoid lupus-like skin lesions (particularly in X-linked carrier females)
  • Autoimmune cytopenias (less common than in CVID but reported)
  • Inflammatory arthritis
• Why? The NADPH oxidase-derived ROS play a role in regulating T-cell activation and in the resolution of inflammation via clearance of apoptotic cells (efferocytosis). Without proper ROS signalling, there is impaired immune tolerance → predisposition to autoimmunity

• Mothers and sisters who are carriers of X-linked CGD (heterozygous CYBB mutations) can develop:
  • Discoid lupus
  • Photosensitive rash
  • Oral ulcers
  • Raynaud's phenomenon
• Mechanism: Due to random X-inactivation (lyonisation), some carriers have a skewed X-inactivation pattern resulting in a larger proportion of non-functional neutrophils. Even with partial oxidase function, the dysregulated inflammation can manifest as lupus-like disease
• Carriers are generally NOT susceptible to the severe infections seen in affected males, but should be monitored

If the patient undergoes curative HSCT:

• Graft-versus-host disease (GVHD) — acute or chronic
• Graft failure / rejection
• Infection during engraftment (profound neutropenia)
• Veno-occlusive disease (VOD/SOS) — especially with busulfan conditioning
• Late effects: Growth impairment, endocrine dysfunction (hypothyroidism, gonadal failure), infertility, secondary malignancy
• Paediatric consideration: Fertility preservation should be discussed and offered to adolescents before myeloablative conditioning