What are the typical presentation and management of Chronic Granulomatous Disease (CGD) in young males?

Presentation of Chronic Granulomatous Disease (CGD)

Primary Clinical Manifestations

CGD typically presents in young males with recurrent deep-seated infections, abscess formation with granulomas, and involvement of the lungs and lymph nodes as the most commonly affected organs. 1

Key Presenting Features

• Deep-seated infections and abscesses with granuloma formation are the hallmark presentation, distinguishing CGD from other immunodeficiencies 1
• Recurrent pneumonia is the most frequent clinical presentation, often severe and invasive 2, 3
• Lymphadenopathy and hepatosplenomegaly are commonly observed at presentation 2, 4
• BCG-itis (complications following BCG vaccination) occurs in approximately 30% of cases and may be the initial presenting sign 2

Age and Demographics

• Diagnosis typically occurs between 1.5 and 15 years of age, though presentation can occur earlier in severe cases 2
• X-linked CGD (affecting males) accounts for approximately 60-70% of cases, with autosomal recessive forms comprising the remainder 2, 3
• The disease occurs in approximately 1 in 200,000 live births 5

Characteristic Infectious Patterns

Bacterial Pathogens

The narrow spectrum of causative organisms is diagnostically important:

• Staphylococcus aureus is the most common bacterial pathogen, causing recurrent abscesses 3, 4
• Serratia marcescens causes severe invasive infections 2, 3
• Burkholderia cepacia complex organisms are characteristic 3
• Nocardia species cause pulmonary and disseminated infections 3
• Salmonella species (non-typhi) cause invasive disease 3

Critical diagnostic clue: All causative organisms are catalase-positive bacteria and fungi 4

Fungal Pathogens

• Aspergillus species (particularly A. fumigatus and A. nidulans) are the leading cause of mortality, with incidence rates of 26-45% in CGD patients 1, 3
• Invasive aspergillosis is the single most common infectious cause of death in CGD 1
• Candida species cause invasive infections 3

Organ System Involvement

Pulmonary Disease

• Lungs are the most frequently affected organ, with recurrent pneumonia and invasive fungal disease 2, 3
• Pneumatoceles may develop, particularly with Aspergillus infections 1

Lymphatic System

• Lymph node involvement is the second most common manifestation, presenting as unexplained lymphadenitis 2, 3
• Suppurative lymphadenitis with granuloma formation is characteristic 1

Other Organ Systems

• Liver abscesses occur frequently 2, 4
• Osteomyelitis may present as unexplained bone infection 2
• Skin abscesses are common, particularly in early childhood 2, 4

Inflammatory Complications

Beyond infections, CGD causes deregulated inflammation with granuloma formation that can mimic malignancy:

• Inflammatory bowel disease develops in a significant proportion of patients 6
• Mass-like granulomas can be mistaken for neoplasms (teratomas, gastric tumors, bladder tumors), leading to inappropriate surgical interventions 7
• Colitis may be present as part of the inflammatory phenotype 1

Critical Diagnostic Pitfalls

Misdiagnosis as Malignancy

A major pitfall is mistaking CGD granulomas for tumors, which has led to unnecessary and harmful surgical interventions 7:

• Mediastinal masses may be misidentified as teratomas on imaging 7
• Gastric and bladder masses have been confused with malignancies 7
• Always consider CGD in young males with mass lesions and recurrent infections before proceeding to aggressive surgery 7

Delayed Recognition

• CGD should be suspected in any child with recurrent infections, invasive fungal disease, BCG complications that are not self-limiting, unexplained lymphadenitis or osteomyelitis, and chronic inflammatory disorders 2
• The disease may be incidentally discovered during workup for other conditions (e.g., chest radiograph for aspiration) 7

Diagnostic Confirmation

Screening Test

The dihydrorhodamine-1,2,3 (DHR) assay is the diagnostic test of choice, demonstrating absent or severely reduced oxidative burst in neutrophils 2, 4

Genetic Testing

• Genetic analysis should be performed to establish molecular diagnosis and distinguish X-linked from autosomal recessive forms 2
• X-linked CGD involves mutations in CYBB gene (encoding gp91phox) 7
• Autosomal recessive forms involve mutations in genes encoding p22phox, p40phox, p47phox, or p67phox subunits 1, 2

Functional Testing

• Neutrophil chemiluminescence assays show severely depressed responses to fungal and bacterial antigens 4
• Intracellular killing assays demonstrate impaired bacterial killing 4
• CD107a degranulation assays may be performed but are more relevant for other primary immunodeficiencies 1

Initial Management Approach

Once CGD is recognized, immediate prophylactic therapy should be initiated 3, 4:

• Antibacterial prophylaxis with trimethoprim-sulfamethoxazole is standard 3
• Antifungal prophylaxis with itraconazole significantly reduces invasive fungal infections 3
• Interferon-gamma immunotherapy is recommended as prophylaxis and has been shown to reduce infection rates 1, 8, 3, 4

Definitive Treatment

Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for curative therapy in CGD patients 3, 6