Chronic Granulomatous Disease (CGD)
Introduction
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency affecting phagocyte function.
- The disease occurs in approximately 4 to 5 per 1 million individuals.
- Neutrophils and monocytes in CGD demonstrate normal chemotaxis, ingestion, and degranulation.
- However, these cells are unable to kill catalase-positive microorganisms.
- This inability is caused by a defect in the generation of microbicidal oxygen metabolites.
Pathophysiology And Genetics
Molecular Mechanism
- Normal activation of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase involves multiple subunits.
- Cytoplasmic components (p47phox, p67phox, and Rac2) must translocate to the phagosomal membrane.
- At the membrane, they combine with transmembrane flavocytochrome b558 (composed of p22phox and gp91phox).
- The assembled NADPH oxidase catalyzes the transfer of an electron to molecular oxygen to form a superoxide radical.
- Superoxide is subsequently converted to hydrogen peroxide.
- In CGD, the phagocytic vacuoles lack these reactive oxygen species and remain abnormally acidic.
- Catalase-positive microbes destroy their own internally generated hydrogen peroxide and survive within the phagosome.
- Catalase-negative microbes generate sufficient hydrogen peroxide to cause their own destruction, even inside a CGD neutrophil.
Genetic Classification
CGD displays significant genetic heterogeneity resulting from pathogenic variants in different oxidase components.
| Inheritance | Affected Component | Proportion of Cases | Details |
|---|---|---|---|
| X-linked | gp91phox | ~65% | Caused by pathogenic variants in the CYBB gene located on the X chromosome. |
| Autosomal Recessive | p47phox | ~25% | Caused by pathogenic variants in the NCF1 gene on chromosome 7. |
| Autosomal Recessive | p67phox | ~5% | Caused by pathogenic variants in the NCF2 gene on chromosome 1. |
| Autosomal Recessive | p22phox | <5% | Caused by pathogenic variants in the CYBA gene on chromosome 16. |
Clinical Manifestations
The onset of clinical signs typically occurs in early infancy. The incidence of infections decreases in the second decade as other immune mechanisms mature, but the risk remains lifelong.
Infectious Complications
- Patients frequently present with recurrent pneumonia and suppurative lymphadenitis.
- Deep-seated hepatic, subcutaneous, and perirectal abscesses are common.
- Osteomyelitis can occur at multiple sites.
- Exuberant inflammatory reactions occur due to the failure of neutrophils to properly clear organisms.
Inflammatory And Granulomatous Features
- Granuloma formation is a hallmark of the disease.
- Granulomas frequently cause gastric outlet narrowing and pyloric obstruction.
- They can also cause ureteral and bladder outlet obstruction.
- Chronic granulomatous colitis simulating Crohn disease is a prominent feature.
- More than 80% of CGD patients demonstrate positive serology for Crohn disease.
Characteristic Pathogens
Patients are highly susceptible to catalase-positive bacteria and specific fungi.
| Pathogen Type | Organisms |
|---|---|
| Bacterial | Staphylococcus aureus is the most common offending pathogen. Sentinel organisms that are highly suspicious for CGD include Burkholderia cepacia, Nocardia, Serratia marcescens, Chromobacterium violaceum, and Granulibacter bethesdensis. B. cepacia can rapidly cause fatal septic shock in these patients. |
| Fungal | Aspergillus species frequently cause severe pneumonia and osteomyelitis. Aspergillus nidulans infections are seen almost exclusively in CGD and carry a high rate of mortality. Invasive Candida infections are also prevalent. |
Diagnosis
Diagnosis relies on demonstrating defective neutrophil oxidative burst and identifying the genetic variant.
| Diagnostic Test | Findings and Utility |
|---|---|
| Dihydrorhodamine (DHR) Assay | A flow cytometry-based assay that measures oxidant production. Defective cells show absent or reduced fluorescence. It is the most commonly used diagnostic test. It is also used to identify female carriers of X-linked CGD, who typically exhibit a bimodal cell population. |
| Nitroblue Tetrazolium (NBT) Test | A historical microscopic dye reduction test. It is now rarely used in clinical practice. |
| Genetic Sequencing | Establishes the specific genetic subgroup. It is highly recommended for the first affected patient in a family to facilitate genetic counseling and prenatal diagnosis. |
Management
Management involves aggressive infection prevention, prolonged treatment of active infections, and definitive cellular therapies.
Antimicrobial Prophylaxis
- Continuous administration of trimethoprim-sulfamethoxazole (TMP/SMX) is recommended to prevent bacterial infections.
- Itraconazole is administered daily as prophylaxis against fungal infections.
- Subcutaneous injections of interferon-gamma significantly reduce the frequency of serious infections and hospitalizations.
Treatment Of Active Infections
- Blood cultures and direct tissue cultures are frequently negative in CGD.
- The erythrocyte sedimentation rate (ESR) is a crucial tool for monitoring occult deep-seated infections.
- Bacterial infections require prolonged courses of parenteral antibiotics.
- Simple pneumonia may require 6 to 8 weeks of intravenous therapy.
- Antibiotics should be continued for at least one week after the ESR completely normalizes.
- If the ESR fails to trend downward, sequential addition of antimicrobials is required.
- Parenteral voriconazole should be added to empirically cover Aspergillus.
- Surgical drainage of abscesses is frequently necessary for both diagnostic and therapeutic purposes.
Management Of Inflammatory Complications
- Short courses of systemic corticosteroids are highly effective for managing granulomatous complications.
- Prednisone (1 to 2 mg/kg/day for 4 to 6 days) is used to shrink granulomas causing gastrointestinal or genitourinary obstruction.
Definitive Therapy
- Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known cure for CGD.
- HSCT is strongly recommended early in life if a suitable sibling or matched unrelated donor is available.