Chronic Granulomatous Disease (CGD)
CGD is a rare, inherited primary immunodeficiency that primarily affects phagocytes (e.g., neutrophils, monocytes, and macrophages), rendering them unable to effectively kill certain bacteria and fungi due to a defective NADPH oxidase enzyme complex. This leads to recurrent, life-threatening infections and chronic inflammatory complications. The estimated birth prevalence in the UK and Ireland is approximately 8.5 per million.
Clinical Presentation and Diagnosis
Symptoms typically begin in the first two years of life, with most children diagnosed before age five. However, presentation can be delayed until later childhood or adulthood in milder cases.
Common Manifestations:
Infections: Characterized by recurrent abscesses in the skin, lymph nodes, lungs, and liver. Common pathogens are catalase-positive organisms such as Staphylococcus aureus, Aspergillus spp., Serratia marcescens, and Burkholderia cepacia.
Inflammatory Complications: Chronic inflammation can lead to the formation of granulomas, a hallmark of the disease. These can obstruct vital organs, particularly in the gastrointestinal and genitourinary tracts, leading to conditions like inflammatory bowel disease (Crohn’s-like colitis).
Diagnosis:
A high index of suspicion is needed for children with recurrent or unusual infections, especially with the characteristic pathogens.
The primary diagnostic test is the dihydrorhodamine (DHR) 123 test via flow cytometry. This test assesses the ability of neutrophils to produce a “respiratory burst.” A failure to produce this burst confirms the diagnosis.
Genetic testing is essential to determine the specific gene mutation, which is crucial for genetic counselling and predicting the disease’s severity. The most common form is X-linked CGD (~65-80%), caused by a mutation in the CYBB gene, which affects males. The remaining cases are autosomal recessive.
Management and Treatment
Management focuses on prophylaxis, treating acute infections, and considering curative therapies.
Prophylaxis:
Antibacterial prophylaxis: Lifelong daily cotrimoxazole is the cornerstone of bacterial infection prevention.
Antifungal prophylaxis: Daily itraconazole is essential to prevent severe fungal infections, particularly with Aspergillus.
Vaccines: The only routine immunisation to avoid is BCG due to the risk of disseminated infection. An annual flu vaccine is recommended.
Acute Infection Treatment:
Prompt and aggressive treatment with appropriate antibiotics and antifungals is critical. Patients may require longer courses or higher doses than the general population.
Surgical drainage of abscesses may be necessary.
Interferon-gamma injections can be used to boost neutrophil function in some patients, though this is less common now.
Recent Developments
Haematopoietic Stem Cell Transplantation (HSCT): This remains the only curative treatment option. Recent advances in conditioning regimens and improved donor matching (including haploidentical transplants) have made HSCT a more viable and safer option. It is increasingly considered earlier, especially for patients with severe disease, persistent infections, or significant inflammatory complications.
Gene Therapy: This is a rapidly evolving field for CGD, with ongoing clinical trials. The goal is to correct the genetic defect by introducing a functional copy of the gene into the patient’s own haematopoietic stem cells. Initial studies have shown transient correction of oxidase activity, with ongoing research focusing on improving long-term engraftment and reducing viral complications.
Targeted Anti-inflammatory Therapies: New research is exploring treatments for the non-infectious inflammatory aspects of CGD. Studies are looking at agents that target specific inflammatory pathways, such as TNF-alpha inhibitors, to manage conditions like CGD-related colitis without compromising the patient’s ability to fight infections.
CRISPR Gene Editing: Preclinical and early-phase clinical trials are exploring prime-editing and other gene-editing techniques to directly correct the mutation in the patient’s cells, potentially offering a more precise and durable cure than traditional gene therapy.