Practice Essentials
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any of the five subunits of the NADPH oxidase complex responsible for the respiratory burst in phagocytic leukocytes. Patients with CGD are at increased risk of life-threatening infections with catalase-positive bacteria and fungi and inflammatory complications such as CGD colitis. The implementation of routine antimicrobial prophylaxis and the advent of azole antifungals has considerably improved overall survival.
Background
Chronic granulomatous disease (CGD) is a rare (∼1:250,000 births) disease caused by mutations in any one of the five components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes.
CGD is a primary immunodeficiency that affects phagocytes of the innate immune system and leads to recurrent or persistent intracellular bacterial and fungal infections and to granuloma formation. In approximately two thirds of patients, the first symptoms of CGD appear during the first year of life in the form of infections, dermatitis (sometimes seen at birth), gastrointestinal complications (obstruction or intermittent bloody diarrhea due to colitis), and a failure to thrive. The clinical picture can be quite variable, with some infants having several of these complications and others appearing to be far less ill. [1] Cutaneous disease occurs in 60-70% of patients. Rasamsonia has been identified as an emerging pathogen in this population. [2]
Also see Pediatric Chronic Granulomatous Disease.
Pathophysiology
Chronic granulomatous disease (CGD) is a genetically heterogeneous immunodeficiency disorder resulting from the inability of phagocytes to kill microbes they have ingested. This impairment in killing is caused by any of several defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which generates the microbicidal respiratory burst. In CGD, phagocytes ingest bacteria normally, but they cannot kill them. [3]
Patients with CGD are susceptible to severe and recurrent infections due to catalase-positive organisms and organisms resistant to nonoxidative killing. Catalase-negative bacteria, such as streptococci and pneumococci that have the capacity to generate hydrogen peroxide, are killed as they usually are. The intracellular survival of ingested bacteria leads to the development of granulomata in the lymph nodes, skin, lungs, liver, gastrointestinal tract, and/or bones.
CGD is usually inherited in an X-linked recessive fashion. Most patients (approximately 80%) 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. [4] However, among chronic granulomatous disease subtypes, the autosomal recessive (AR) forms may be associated with milder disease. The extent to which environmental and secondary genetic factors influence phenotypic expression of disease is unknown. A wide variety of molecular defects have been described in the genes for the gp91phox component, the p22phox component, [5] and the p67phox component. These defects include frame shifts; deletions; and nonsense, missense, splice-region, and regulatory-region mutations. [6, 7, 8]
In contrast, a GT deletion at the beginning of exon 2 accounts for the defective genetic function in almost all patients with p47phox deficiency. [9] Another protein, p40phox, has been implicated in the regulation of the NADPH oxidase, but no individual with a mutation in the protein has been found to date. A new variant of CGD has been described; this form is caused by an inhibitory mutation in Rac2, which regulates activity of the neutrophil respiratory burst and actin assembly. [10]
Etiology
The main defect in chronic granulomatous disease (CGD) is a failure of neutrophils, monocytes, macrophages, and eosinophils to mount a respiratory burst and, therefore, to generate superoxide anions and other reactive oxygen species derived from superoxide, such as hydrogen peroxide. This renders the patients susceptible to severe, recurrent bacterial and fungal infections. The intracellular survival of ingested bacteria leads to the development of granulomata in the lymph nodes, skin, lungs, liver, gastrointestinal tract, and/or bones.
Leukocytes ingest bacteria but do not kill them because of a defect in the production of the superoxide anion.
Most infections in CGD are caused by Staphylococcus aureus. Infections are also caused by unusual opportunistic organisms such as Chromobacterium violaceum; Serratia marcescens; and Nocardia, Legionella, and atypical Mycobacteria species.
BCG vaccination may cause CGD.
Fungal infections in CGD patients have been reported to account for approximately 20% of infections. The most common fungal infections in these patients are caused by Aspergillus species. The spectrum of infection caused by Aspergillus species varies from flulike pneumonia to life-threatening invasive aspergillosis. The most common form of aspergillosis in chronic granulomatous disease patients is Aspergillus pneumonia, which can be accompanied by dissemination to the ribs, chest wall, and soft tissues. Infections with Aspergillus species, particularly of the lungs or bones, are difficult to eradicate.
The most common infecting organisms, on the basis of the type and site of infection, include the following [11] :
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Pneumonia - Aspergillus species , Staphylococcus aureus, Nocardia, and Serratia species and Burkholderia cepacia (formerly Pseudomonas cepacia) [12]
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Subcutaneous, liver, or perirectal abscess - Staphylococcus, Serratia, and Aspergillus species
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Lung abscess - Aspergillus species
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Brain abscess - Aspergillus species
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Suppurative adenitis - Staphylococcus and Serratia species
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Osteomyelitis - Can arise from hematogenous spread of organisms ( S aureus, Salmonella species, S marcescens) or contiguous invasion of bone, seen typically with non– Aspergillus fumigatus pneumonia, such as Aspergillus nidulans spreading to the ribs or vertebral bodies [1]
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Bacteremia and/or fungemia -Salmonella and Candida species and B cepacia
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Other frequently encountered catalase-positive microbial agents - Escherichia coli species, Listeria species, Klebsiella species, and Nocardia.
Epidemiology
Frequency
United States
The exact incidence of chronic granulomatous disease (CGD) is unknown. CGD affects approximately 1 infant per 200,000-250,000 live births.
International
The prevalence of CGD varies among the populations investigated, with studies reporting variations from 1 case per 1 million individuals to 1 case per 160,000 individuals. [13, 14]
Race
Chronic granulomatous disease affects persons of all races.
Sex
Approximately 80% of patients with CGD are male, because the main cause of the disease is a mutation in an X-chromosome–linked gene. However, defects in autosomal genes may also underlie the disease and cause CGD in both males and females. [1]
Age
Symptom onset typically occurs at a young age, although the diagnosis has been at an older age in some patients. [15, 16, 17] Typically, patients with CGD have recurrent pyogenic infections that start in the first year of life. Occasionally, the onset may be delayed until the patient is aged 10-20 years.
Prognosis
The long-term survival of patients who develop symptoms after the end of the first year of life is significantly better than that of patients whose illness starts in infancy. Survival rates are variable but improving; approximately 50% of patients survive to age 30-40 years. Infections are less common in adults than in children, but the propensity for severe life-threatening bacterial infections persists throughout life.
Fungal infections remain a major determinant of survival in chronic granulomatous disease (CGD). Morbidity secondary to infection or granulomatous complications remains significant for many patients, particularly those with the X-linked form. X-linked patients generally have more severe disease, and this is generally in those with lower residual superoxide production. Survival in CGD has increased over the years, but infections are still major causes of morbidity and mortality. [18] Currently, the annual mortality rate is 1.5% per year for persons with autosomal recessive CGD and 5% for those with X-linked CGD.
Since the advent of prophylactic antibiotics, antifungals, and interferon-gamma (INF-gamma), the prognosis for patients with CGD has improved. Patients living to their 30s and 40s is now common.
Patients with CGD and modest residual production of reactive oxygen intermediates (ROIs) have significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. The production of residual ROI is predicted by the specific NADPH oxidase mutation, regardless of the specific gene affected, and is a predictor of survival in patients with CGD. [19]
Patient Education
Good hygiene of the skin is an important element of treatment because the skin is a common portal of entry in serious infections. To prevent infections, chronic granulomatous disease (CGD) patients should receive lifelong antibiotics and antifungal prophylaxis.
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Scanning electron micrograph of Aspergillus species.
