Chronic Granulomatous Disease (CGD)

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency characterized by phagocytes (neutrophils and monocytes) that possess normal chemotaxis, ingestion, and degranulation capabilities, but completely fail to kill catalase-positive microorganisms.
The underlying defect lies in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, preventing the respiratory burst necessary to generate microbicidal reactive oxygen species like superoxide and hydrogen peroxide.
Because the phagocytic vacuoles lack these microbicidal oxygen metabolites and remain abnormally acidic, ingested bacteria survive and induce the formation of exuberant inflammatory granulomas.
Approximately 65% of cases are inherited in an X-linked recessive manner, caused by pathogenic variants in the CYBB gene which encodes the gp91phox subunit.
Autosomal recessive forms account for the remaining 35% of cases, involving pathogenic variants in the genes NCF1 (encoding p47phox, ~25% of cases), NCF2 (encoding p67phox, ~5% of cases), and CYBA (encoding p22phox, <5% of cases).

The onset of clinical signs and symptoms typically occurs in early infancy, marked by recurrent, deep-seated, and indolent infections.
Classic infectious presentations include recurrent pneumonia, suppurative lymphadenitis, deep hepatic or subcutaneous abscesses, and multilocular osteomyelitis.
Patients exhibit a hallmark susceptibility to catalase-positive organisms; the most common pathogen is Staphylococcus aureus, while other sentinel pathogens include Burkholderia cepacia, Serratia marcescens, Nocardia, Salmonella, and fungal organisms like Aspergillus and Candida albicans.
Non-infectious inflammatory complications are a prominent feature, specifically the formation of granulomas that can cause severe mechanical obstruction of the gastric outlet (pylorus), urinary tract (ureters), or biliary tree.
Patients frequently develop a chronic granulomatous colitis or enteritis that closely mimics Crohn disease, with over 80% of CGD patients demonstrating positive serology for Crohn disease.
Other clinical sequelae include anemia of chronic disease, poor growth, chronic purulent dermatitis, restrictive lung disease, and prominent hepatosplenomegaly.

The diagnosis is primarily established using the dihydrorhodamine (DHR) reduction assay via flow cytometry, which measures phagocyte oxidant production through increased fluorescence when DHR is oxidized by intracellular hydrogen peroxide.
The DHR flow cytometric assay is highly sensitive and has largely replaced the older nitroblue tetrazolium (NBT) slide dye test.
The DHR assay is highly effective for identifying the X-linked carrier state in mothers by demonstrating a characteristic bimodal response to neutrophil stimulation.
Confirming the specific genetic subgroup via targeted DNA sequencing is strongly recommended for definitive diagnosis, prenatal diagnosis, and genetic counseling.
The erythrocyte sedimentation rate (ESR) serves as a crucial diagnostic adjunct; because deep tissue infections in CGD often yield negative cultures, the ESR acts as a vital surrogate marker to detect clinically silent infections and to meticulously track the response to antimicrobial therapy.

Patients require lifelong antimicrobial prophylaxis, specifically utilizing daily oral trimethoprim-sulfamethoxazole (TMP/SMX) to significantly reduce the frequency of bacterial infections.
Prophylactic administration of the antifungal agent itraconazole is routinely employed to prevent invasive fungal infections, particularly Aspergillus.
Prophylactic administration of subcutaneous interferon-gamma (50 mcg/m2 three times per week) is recommended as it significantly reduces the overall frequency of hospitalizations and severe infections.
Acute infections demand aggressive and prolonged courses of parenteral antibiotics (often lasting many weeks or months), and frequently necessitate surgical drainage of abscesses for both therapeutic and diagnostic utility.
Short pulses of systemic corticosteroids (e.g., prednisone 1-2 mg/kg for 4-6 days) are effectively utilized to manage obstructive granulomatous complications in the lungs, urinary tract, or gastrointestinal tract, and to manage severe granulomatous colitis.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only definitive, curative therapy for CGD and is strongly recommended early in life when a suitable sibling or unrelated donor is available.