Chronic granulomatous disease (CGD) is usually inherited in an X-linked recessive fashion. Most patients (approximately 90%) are males, who have hemizygous mutations on the X-linked gene coding for gp91phox. The gene responsible for this form of the disease has been mapped to the p21.1 region of the X chromosome. However, among CGD subtypes, the autosomal recessive (AR) forms may be associated with milder disease. CGD is a disorder resulting from the inability of phagocytes to kill microbes they have ingested. The normal functioning reaction is mediated by the phagocyte NADPH oxidase otherwise know as phagocyte oxidase (phox). When this is non functioning there is impairment in killing caused by any of several defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which generates the microbicidal respiratory burst. In a normal response to phagocytosis neutrophils increase their oxygen consumption, which has been termed the respiratory or oxidative burst. Typically superoxide anion is generated by transferring electrons from reduced NADPH to molecular O2 in response to physiologic stimuli, such as phagocytosis. This superoxide anion is then converted to relatively bactericidal hydrogen peroxide and other reactive oxidants, hence the oxidative burst. Without this ability a person is susceptible to a broad range of bacterial and fungal infections, which can be life threatening.
Why is there granuloma formation?
When CGD patients become infected they often have extensive inflammatory reactions. The excessive inflammation is thought to be due to failure to degrade chemoattractants and antigens, leading to persistent neutrophil accumulation. Impaired killing of the intracellular microorganisms by macrophages may lead to persistent cell- mediated immune activation and granuloma formation.
Granulomas will typically develop in the skin, gastrointestinal tract (GI) and genitourinary tract (GU). At diagnosis, some patients present with symptoms related to these granulomas. Symptoms of GI granulomas include dysphagia, nausea, vomiting, abdominal pain, and obstruction and symptoms of GU obstruction include dysuria, incontinence, abdominal discomfort, and urinary retention.
What is the treatment?
Management of chronic granulomatous disease revolves around two goals:
- Early diagnosis so that antibiotics can be given to prevent infections, and
- Educating the patient and care givers about the condition so that prompt treatment can be given if an infection occurs.
Typicaly trimethoprim/sulfamethoxazole is prescibed to prevent bacterial infections. Fungal infection is commonly prevented with itraconazole.
Interferon, is also precsibed for the prevention of infection in CGD. It has been shown to prevent infections in CGD patients by 70% and to reduce the severity of infections. It has the ability to give CGD patients more immune function and therefore greater ability to fight off infections.
Gene therapy is currently being studied as a possible treatment. CGD is well-suited for gene therapy becuase it is caused by a mutation in single gene which only affects one body system (the hematopoietic system).