Practice Essentials
Chronic granulomatous disease (CGD), an inherited disorder of phagocytic cells, results from an inability of phagocytes to produce bactericidal superoxide anions (O2-). [1, 2] This consequently interferes with the production of hydroxyl radical (OH-), hydrogen peroxide (H2O2), peroxynitrite anion (ONOO-), and oxyhalides, products that play a critical role in killing certain pathogenic bacterial and fungal agents. These deficits lead to recurrent, life-threatening bacterial and fungal infections. In addition, most patients with chronic granulomatous disease have dysregulated T-helper (Th)-17 lymphocyte–controlled inflammation.
CGD is known to be caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH), reduced form, oxidase enzyme complex of phagocytes. Chronic granulomatous disease refers to the characteristic granulomas that develop in response to chronic inflammation.
The nitroblue tetrazolium (NBT) and dihydrorhodamine (DHR) tests, as well as genetic testing, are indicated in the workup of CGD. Antimicrobial prophylaxis, early and aggressive treatment of infections, and interferon-gamma are the cornerstones of current therapy for this disease.
Since its first description in the 1950s as a syndrome of recurrent infections, hypergammaglobulinemia, hepatosplenomegaly, and lymphadenopathy, in males who invariably died in the first decade of life, notable advances have been made in the understanding of this disease. The outlook for affected patients has also improved.
Although chronic granulomatous disease was once fatal in childhood, current preventive therapies and early detection of infectious complications allow 90% of children with the disorder to reach adulthood. [3]
Signs and symptoms of chronic granulomatous disease
The hallmark of CGD is early onset of severe, recurrent bacterial and fungal infections. Common presentations of the condition include the following:
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Skin infections
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Pneumonia
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Lung abscesses
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Suppurative lymphadenitis
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Diarrhea secondary to enteritis
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Perianal or perirectal abscesses
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Hepatic or splenic abscesses
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The two most frequent findings on histologic examination of CGD lesions are infection and postinfectious granulomas
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A characteristic manifestation of CGD is the development of granulomas in the skin, gastrointestinal (GI) tract, and genitourinary (GU) tract
Workup in chronic granulomatous disease
The standard assay for phagocytic oxidase activity is the NBT test, while the DHR test is now widely and commercially available and should be considered the preferred screening and diagnostic test for CGD. Testing for specific gene mutation is useful to establish the genetic inheritance pattern of CGD and to aid in family counseling.
Imaging studies such as chest radiography and computed tomography (CT) scanning are valuable in the diagnosis and management of pulmonary and hepatosplenic infections.
Workup for infections is an essential part of the work up for CGD.
Management of chronic granulomatous disease
Daily prophylaxis of bacterial infections with trimethoprim-sulfamethoxazole (TMP-SMZ; Bactrim) is indicated. Moreover, interferon-gamma is now recommended as life-long therapy for infection prophylaxis in CGD.
Patients with superficial or deep infections (vs those with obstructing granulomas) should receive aggressive antibiotics; the initial route is parenteral.
Hematopoietic stem cell transplantation (HSCT) is the only curative therapeutic modality currently available for CGD.
Despite the increased risk of wound healing associated with surgical intervention, surgery is still an important tool for patients with complications of this disease. Operative treatment may be required to relieve obstruction of ureters from large granulomas, drainage of abscesses, and aggressive removal of established infection, especially in the lung and liver.
Pathophysiology
In response to phagocytosis, neutrophils normally increase their oxygen consumption, which has been termed the respiratory or oxidative burst. The clinical significance of the respiratory burst was made evident when neutrophils from patients with CGD were shown to have a lack of increased oxygen consumption.
Phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is responsible for producing the superoxide anion, O2-. The superoxide anion is generated by transferring electrons from the reduced NADPH to molecular O2 in response to physiologic stimuli, such as phagocytosis. This reaction is mediated by phagocyte NADPH oxidase, otherwise known as phagocyte oxidase (phox). The superoxide anion is then converted to relatively bactericidal reactive oxidants, such as hydroxyl radical (OH-), hydrogen peroxide (H2O2), peroxynitrite anion (ONOO-), and oxyhalides (HOX-, in which the X moiety is most commonly chlorine).
Important to the process are the glycoprotein gp91phox and the protein p22phox—encoded by the CYBB (NOX2) and CYBA genes, respectively—which make up the b and a subunits of a membrane-bound heterodimer referred to as flavocytochrome b558. Also essential are proteins p40phox, p47phox, p67phox, and Rac2 (encoded by NCF4, NCF1, NCF2, and RAC2, respectively). (Mutations in the above genes can result in the development of CGD.)
The membrane-bound gp91phox and p22phox and the cytosolic components p40phox, p47phox, p67phox, and Rac2 assemble at the phagolysosome membrane in response to inflammatory stimuli such as phagocytosis. The assembled enzyme complex transports electrons from cytosolic NADPH across the membrane to molecular oxygen inside the phagolysosome to generate superoxide and the other toxic radicals. Bactericidal activity is likely due to direct action of ROS and of superoxidase–mediated activation of other pathways. The precise mechanism by which this intracellular bleach kills microorganisms is still debated.
The cause of chronic granulomatous disease is an inherited defect in one of the six components of phagocyte NADPH oxidase enzyme complex.
The most common molecular defect in chronic granulomatous disease is a mutation in the CYBB (cytochrome B, b subunit) gene, which is located on the X chromosome and that encodes for gp91phox (the b subunit of flavocytochrome b558). [4] The resulting syndrome is commonly called X-linked CGD (X-CGD). Gp91phox deficiency accounts for 50-70% of all cases of CGD. More than 350 mutations in the CYBB gene are known, and thus far, all are unique to individual families. Data from analyses of carriers suggests that de novo mutations occur in about 10% of cases.
The second most common mutation occurs in the NCF1 gene on chromosome 7, which encodes for p47phox. This mutation is the most common autosomal recessive form of the disease, accounting for 20-40% of all cases of CGD. Unlike CYBB, which has more than 350 mutations, the NCF1 mutation is highly conserved to a single deletion in more than 90% of patients.
Mutations in the genes NCF2 (which encodes p67phox) and CYBA (which encodes p22phox) are rare, accounting for fewer than 10% of all cases of CGD. Both of these mutations result in the autosomal recessive forms of CGD.
About 95% of the mutations mentioned above result in the complete absence or a greatly diminished level of the affected protein. In the remaining 5%, a normal level of defective protein is produced. The four forms of the disease are referred to as X91 (X-linked, gp91phox), A22 (autosomal, p22phox), A47, and A67 CGD. The superscript +, -, or o is added to denote a normal level, a reduced level, or complete absence of the affected subunit.
Less than 10% of patients have the X-linked variant form of CGD (X91-), which has a relatively mild clinical course. Most of these patients have low but detectable levels of flavocytochrome b588, and their phagocytes can generate measurable amounts of superoxide. Defects in p47phox also seem to be associated with enzymatic and clinical deficiency less profound than that observed in other forms. Diagnosis in adulthood is not uncommon in these patients with residual phox activity.
The CGD phagocyte can kill numerous microorganisms despite its defects because most microorganisms endogenously produce hydrogen peroxide, which the CGD-affected phagocyte can modify and use against the organism in the phagosome. Bacteria and fungi that cause most infections in CGD are catalase-positive organisms. These microorganisms produce catalase that breaks down endogenously produced hydrogen peroxide; the generation of oxygen radicals by a normally functioning phox system is needed to ensure the death of these infecting microorganisms. [5]
Whereas both Pseudomonas aeruginosa and Burkholderia cepacia (also known as Pseudomonas cepacia) are catalase-positive organisms, the former is a rare pathogen in CGD because CGD neutrophils can kill P aeruginosa organisms by means of nonoxidative mechanisms. B cepacia is an important cause of infections in CGD perhaps because of as-yet unexplained abilities to resist killing in neutrophil-mediated nonoxidative pathways. [6]
Fungal infections occur in as many as 20% of patients with CGD. The most common pathogens are Aspergillus fumigatus, Torulopsis glabrata (ie, Candida glabrata), and Candida albicans.Pneumonia is the most common presentation of fungal infection. Aspergillus nidulans, which is a rare pathogen in other patient populations, has emerged as a problematic pathogen in CGD. It causes locally invasive or disseminated disease that is more lethal than that caused by A fumigatus. In a review of a registry of patients with CGD, Aspergillus infection was the leading cause of death (see the image below), and B cepacia infection was the second most common.
The diagnosis of chronic granulomatous disease should be considered in any patient with recurrent infections with catalase-positive organisms; infections with unusual organisms such as Serratia marcescens, A nidulans, or B cepacia; or infections in sites normally considered to be rare in children, such as a Staphylococcus aureus infection in a liver abscess. Sepsis is a common cause of death in CGD.
Epidemiology
Frequency
United States
The exact incidence of CGD is unknown. Analysis of data submitted to a national registry suggests that the incidence of CGD in the United States is about 1 case per 200,000-250,000 population (as many as 20 patients with CGD are born each year), with no apparent racial or ethnic predilection.
International
Surveys from the Netherlands and other parts of the world suggest a frequency of about 1 case per 220,000-500,000 population. [7]
Mortality/Morbidity
A detailed study of the natural history of CGD is unavailable. The aforementioned US registry data suggest that morbidity and mortality rates are highest in patients with the X-linked form of the disease. A substantial number of patients in the registry died during the second and third decades of life, though some survived beyond the fourth decade. Approximately 80% of patients were alive at 5 years after they were entered in the registry. Even in the modern age of care for this disease, sporadic data suggest a potential excess in mortality in individuals aged 10-30 years. In a European study of 429 patients, based on 2000-2003 data, mean survival time for patients with X-linked CGD (gp91phox deficient) was 37.8 years, and for those with autosomal recessive CGD, 49.6 years. [8]
Race
No racial predilection is known.
Sex
About two thirds of cases are inherited as X-linked defects, and the remaining cases are inherited in autosomal recessive fashion. Of 368 patients from 318 kindreds reported to the CGD registry, 316 (86%) were male.
Age
Although the vast majority of affected individuals present with infections in early childhood, several reports describe affected patients who became symptomatic later than this. CGD is probably undiagnosed in some patients because they have a clinically mild phenotype.
Prognosis
The prognosis for patients with CGD has improved over the past decades. No formal studies of the natural history of this disease have been conducted, but as previously stated, a European study found the mean survival time for patients with X-linked CGD (gp91phox deficient) to be 37.8 years, and for those with autosomal recessive CGD, 49.6 years. [8] The highest mortality rate is in early childhood. The usual cause of death is infection. However, CGD has significant clinical heterogeneity in the severity of disease in affected patients.
Although in general, patients with the X-linked form of the disease have more severe disease and patients with the p47phox-deficient autosomal recessive form have milder disease, many patients are exceptions to this rule. Patients with identical genetic defects can have different clinical presentations, making it difficult to define the prognosis for individual patients.
A French retrospective study showed no significant difference in the frequency or severity of infections in patients with either X-linked or autosomally inherited CGD. [9] Of 11 patients in whom CGD was diagnosed after adolescence, 8 had X-linked CGD. However, all 8 patients had small but detectable quantities of flavocytochrome b558.
A case report describes a previously healthy 67-year-old man with X-linked CGD who developed P cepacia sepsis. He had a CYBB gene mutation consisting of a single base substitution that resulted in a quantitatively normal but dysfunctional cytochrome b. His neutrophils exhibited markedly deficient phox activity.
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Scanning electron micrograph of Aspergillus species.