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:
Skin infections
Pneumonia
Lung abscesses
Suppurative lymphadenitis
Diarrhea secondary to enteritis
Perianal or perirectal abscesses
Hepatic or splenic abscesses
The two most frequent findings on histologic examination of CGD lesions are infection and postinfectious granulomas
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.
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.
View Image
Scanning electron micrograph of Aspergillus species.
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.
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.
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.
The hallmark of chronic granulomatous disease (CGD) is early onset of severe, recurrent bacterial and fungal infections.
Over three quarters of patients present during the first 5 years of life.
The most commonly involved organs are those that serve as barriers against the entry of microorganisms from the environment, including the skin, lungs, GI tract, lymph nodes, liver, and spleen.
Common presentations include the following:
Skin infections
Pneumonia
Lung abscesses
Suppurative lymphadenitis
Diarrhea secondary to enteritis
Perianal or perirectal abscesses
Hepatic or splenic abscesses
Other presentations include the following:
Osteomyelitis
Septicemia
Fungal infections
Fungal infections occur in up to 20% of patients with chronic granulomatous disease. Pneumonia is the most common presentation. Fungal infections may be locally invasive or disseminated. Aspergillus species infection in chronic granulomatous disease is often indolent, with mild or absent symptoms at the outset.
Granulomas
A second characteristic manifestation of CGD is the development of granulomas in the skin, GI tract, and genitourinary (GU) tract. At diagnosis, some patients present with symptoms related to these granulomas, including GI or GU obstruction.
Granulomas, nodular masses of inflammatory tissue, form in response to persistent antigenic stimulus (chronic infections) or because of lack of negative feedback by oxygen radicals on proinflammatory cytokines. Granuloma formation in the GI or GU tract can be the presenting symptom in CGD. Symptoms of GI granulomas include dysphagia, nausea, vomiting, abdominal pain, and obstruction. Granulomas can be found throughout the GI tract. Common sites of obstruction include the gastric outlet, esophagus, and duodenum. Symptoms of GU obstruction include dysuria, incontinence, abdominal discomfort, and urinary retention.
In a review of 140 patients with chronic granulomatous disease, 33% had GI involvement, including granulomatous colitis, Crohnlike inflammatory bowel disease (IBD), GI obstruction (eg, gastric, esophageal, duodenal), perianal abscesses or fistulas, and esophageal dysmotility.[10] Symptoms included abdominal pain (100%), diarrhea (33%), nausea and vomiting (24%), bloody diarrhea (6%), and constipation (4%). About 70% of patients with GI involvement had hypoalbuminemia. All subjects recovered with steroid therapy. Typical treatment for endoscopically confirmed granulomas was prednisone at 1 mg/kg/day. Relapse occurred in 71% after steroids were discontinued. Prednisone (2.5-5 mg/d) was maintained for more than 1 year in 43% of the patients. Interferon-gamma was not associated with increased GI involvement or granuloma formation. Growth delay was seen in 30%; whether this was due to GI involvement or steroid use was unclear. Among those with GI involvement, 89% had X91, versus 11% with autosomal recessive CGD.
Watchful treatment of GI or GU granulomas that cause obstruction or symptoms with oral corticosteroids is effective. Prednisone at 1-2 mg/kg/day as an initial dose relieves symptoms of GI or GU obstruction. Although some reports show transient improvements of symptoms with antibiotic use these granulomata are often sterile. Coadministration of oral antibiotics may be used. Any obvious underlying or concomitant infections should be ruled out before steroid treatment is begun, to prevent exacerbation. Corticosteroids, anti-inflammatory, and immunosuppressive effects are believed to counteract the unsuppressed inflammation that results in CGD due to the lack of oxygen-radical suppression of proinflammatory cytokines.
Skin infections or granulomatous dermatitis occurs in almost two thirds of patients.
Other
Other than unexplained fevers, constitutional symptoms are not associated with CGD.
Chronic or recurrent infections in childhood can lead to failure to thrive, with impairment of physical growth; however, most adults with CGD appear to attain their expected growth potential.
In general, carriers of CGD are asymptomatic. However, carriers of X-CGD have a notable incidence of discoid lupus erythematosus, photosensitivity, Raynaud phenomenon, and aphthous ulcers.
In some cases, mothers who are carriers of X-CGD and who have hyperlyonization (ie, unequal representation of phagocytes expressing the normal and mutated gp91phox genes) have a mild CGD phenotype. This usually occurs when the normal gene for gp91phox is expressed in less than about 10% of phagocytes. These women are occasionally misidentified as having autosomal recessive disease, which may lead to misinformation with regard to family planning.
The early descriptions of children with CGD had characterized these patients as presenting with lymphadenopathy, hepatosplenomegaly, growth failure, and stigmata of chronic skin infections.[11] These physical findings are observed less commonly now than before because most patients are identified and treated in early infancy or childhood.
At times, infected patients present without the typical symptoms of infection (ie, fever, leukocytosis).
The following tests are indicated in chronic granulomatous disease (CGD).
Nitroblue tetrazolium (NBT) test
The standard assay for phagocytic oxidase activity is the NBT test. The colorless compound NBT is reduced to blue formazan by the activity of the phox enzyme system. Several versions of the test exist; each has advantages and disadvantages.
The most efficient and informative version is the NBT slide test, in which a drop of whole blood is placed on a microscope slide coated with an activating agent, such as lipopolysaccharide or phorbol ester. Phagocytes adhering to the slide are activated and develop blue inclusions on incubation with NBT. The number of NBT-positive cells is scored under a microscope. This test is often preferred because of the small amount of blood required and the lack of a need for specialized equipment. Although the result is nonquantitative, an experienced technologist can differentiate normal phagocytes reliably from low-level phox activity observed in some cases of p47phox deficiency.
The NBT test can be useful in identifying X-linked carrier female individuals when peripheral phagocytes consist of 2 cell populations: one that reduces NBT to formazan and one that does not.
The NBT test is limited by its subjectivity, need for an experienced technician, and false-negative results that cause the diagnosis of CGD to be missed. False-negative findings occur when formazan accumulates in cells with low levels of active NADPH oxidase. These patients clinically have the disease, but their NBT test results are negative.
In an alternative technique, leukocytes are isolated from blood and incubated with NBT in a test tube. Formazan is solubilized by addition of an organic solvent, and the blue color intensity is read by a spectrophotometer.
Dihydrorhodamine (DHR) test
This flow cytometric test is now widely and commercially available and should be considered the preferred screening and diagnostic test for CGD, being the most accurate diagnostic test for the disease.
Phagocytic cells reduce DHR to the strongly fluorescent compound rhodamine. Individual fluorescent cells can then be counted, and the amount of fluorescence per cell is quantified with flow cytometry.
This test combines the best features of the slide and tube NBT tests, although a specialized instrument is required.
Deficiencies of gp91phox (no activity, no DHR conversion) and p47phox (low activity, minimal DHR conversion) can be distinguished with this method. X-linked carriers of CGD can also be identified with the DHR test.
Genetic testing
Specific gene mutation is useful to establish the genetic inheritance pattern and aid in family counseling. Although the family history is sometimes informative in cases of X-linked CGD (X-CGD), the high incidence of new mutations and the appearance of male subjects with autosomal recessive mutations make some type of laboratory confirmation important.
The low incidence of chronic granulomatous disease and the large number of unique mutations preclude standardized genetic testing. Therefore, individual genetic analysis remains the domain of specialized research laboratories.
Mutations can currently be identified in nearly all patients and in about 90% of mothers of affected children.
Other tests
When screening results are inconclusive or when additional confirmation is required, other assays of phagocyte oxidative metabolism can be performed in research laboratories capable of studying phagocytes.
On Western blot analysis, failure to detect the p22phox, p47phox, or p67phox products can be taken as evidence of autosomal recessive mutation in the corresponding gene.
Prenatal diagnosis
Prenatal diagnosis for siblings of affected patients can be achieved in one of two ways. When a mutation is precisely identified in the affected child, chorionic villus biopsy can be performed to obtain enough DNA to identify affected fetuses. As an alternative, dinucleotide repeat polymorphisms linked to the CYBB gene may be useful in the prenatal diagnosis of X-CGD.
When these DNA detection methods are not available, fetal blood can be sampled and an NBT slide test performed.
Chorionic villus sampling is technically preferred because of its applicability early in gestation and the reduced risk of fetal loss.
If parents are not considering termination of a pregnancy, newborns can be tested by using the slide NBT or flow cytometric DHR tests because affected fetuses do not appear to be at increased risk of infection in utero.
Other laboratory findings
Other than the specific tests of phagocyte oxidative metabolism that help in establishing the diagnosis, no consistent or characteristic laboratory findings define this disease.
Most patients have white blood cell (WBC) counts that are within the reference range or elevated, with further increases during infectious episodes.
Phagocyte morphology, phagocytic cell-surface adhesion proteins, chemotaxis, and phagocytosis are normal.
Patients may have anemia of chronic disease.
The erythrocyte sedimentation rate can be elevated even between infections.
Hypergammaglobulinemia is a common feature of the illness and is believed to represent a host response to recurrent or persistent infection.
The two most frequent findings on histologic examination of the lesions observed in CGD are infection and postinfectious granulomas.
Frequent sites of infection are the skin, lymph nodes, lungs, liver, spleen, bones, and joints; the brain and the GI and GU tracts are less commonly involved.
Histologic findings consist of suppurative lesions with collections of phagocytic cells, predominantly neutrophils, with the causative bacteria or fungi and abscess formation.
Granulomatous involvement of the GI and GU tracts is not uncommon. Biopsy of these lesions shows necrotic granulomas with pigmented histiocytes and macrophages. These are most often sterile.
Similar granulomatous infiltrations of the skin and lungs are described.
Antimicrobial prophylaxis, early and aggressive treatment of infections, and interferon-gamma are the cornerstones of current therapy for chronic granulomatous disease (CGD). Hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)–compatible donor can cure CGD.[12] However, this approach is fraught with clinically significant morbidity and a finite risk of death. HSCT remains a controversial therapeutic modality in this disease, even when stem cells from a matched sibling donor are available.[13, 14, 15]
Infection prophylaxis
Daily prophylaxis of bacterial infections with trimethoprim-sulfamethoxazole (TMP-SMZ; Bactrim) is indicated in CGD.
TMP-SMZ prophylaxis reduces the incidence of bacterial infections in CGD without increasing the incidence of fungal infections.
Although numerous other antibiotics have been used, the selective concentration of TMP-SMZ in phagocytes, its broad spectrum of microbicidal activity, and its lack of activity against anaerobic GI flora make this the antimicrobial of choice for prophylaxis in CGD.
In patients with sulfa allergies, TMP alone or a cephalosporin can be used as daily prophylaxis; however, the effectiveness of this treatment has not been proven.
Ketoconazole is ineffective in reducing fungal infections in patients with CGD.
Itraconazole prophylaxis against fungal infections is somewhat problematic. A prospective, open-label study of long-term itraconazole prophylaxis demonstrated excellent tolerance and a significantly lowered rate of Aspergillus infections versus historical controls.[16] If Aspergillus infection occurs, consult the treatment guidelines from the Infectious Diseases Society of America.[17] A randomized, double-blind, placebo-controlled study showed that itraconazole prophylaxis in chronic granulomatous disease prevented serious and superficial fungal infections.[18] Adverse effects included rash, increased liver-function values, and headache; these resolved after itraconazole was discontinued. Newer formulations of itraconazole may allow more reliable blood levels and more consistent prophylaxis.
Treatment of established infection
Patients with superficial or deep infections (vs those with obstructing granulomas) should receive aggressive antibiotics; the initial route is parenteral. Treatment usually requires antibiotic coverage for several weeks and should be associated with clear physical signs of resolution and systemic improvement (eg, decreased WBC count and decreased erythrocyte sedimentation rate if elevated at presentation).
Ciprofloxacin with or without additional medication for staphylococcal infection is a common first choice in patients with CGD. If no response is noted within the first 24-48 hours, coverage should be broadened to include additional antistaphylococcal agents (including coverage for methicillin-resistant S aureus), gram-negative possibilities, and Nocardia species.
The newer antifungals (eg, voriconazole, posaconazole) should be considered for expected fungal infection instead of amphotericin because of decreased toxicity (although they require special consideration with renal dysfunction) and proven efficacy. In established fungal infection, treatment doses of antifungal agents should continue for as long as 6 months.
For poorly responsive infections leading to prolonged consolidation in the lung or large abscesses in the liver, surgical debulking or drainage should be considered. This is especially true of suspected fungal infections and even more so if the chest wall or vertebrae are affected. Prolonged postoperative antibiotics are necessary to deal with slow wound healing and the propensity for wound infection that follows major surgery in these patients.
When an infection breaks through prophylaxis and when it is life-threatening or poorly responsive to antibiotics, growth factor or dexamethasone-induced granulocyte transfusions from healthy donors may improve the outcome.
High-dose interferon-gamma during severe infectious episodes has been advocated.
Patients who present with granulomatous manifestations may have some response to intravenous antimicrobial therapy. However, low-dose corticosteroids are the treatment of choice and are cautiously used in patients who do not appear to have obvious infection (even in the absence of biopsy), especially in patients with GI or GU obstruction, to decrease the time of obstruction without increasing the risk of infection. Prednisone (1 mg/kg) is administered and continues for at least a week until symptoms begin to resolve. A slow taper over 4-6 weeks should be used to avoid recurrence of obstructive symptoms. Chronic treatment with low-dose prednisone or every-other-day treatment may be necessary for resistant obstructive symptoms. Treatment with corticosteroids always increases the risk of infection; thus, increased vigilance in patients throughout steroid treatment is required.
Prophylaxis to improve WBC function
Based on preliminary observations suggesting the efficacy of interferon-gamma, a multi-institutional, randomized, double-blind, placebo-controlled study of interferon-gamma 50 mcg/m2/dose 3 times per week in patients with CGD showed that it was well tolerated and that it reduced the frequency of serious infections.[19] The relative risk of a serious infection was 67% lower in the treated group than in the untreated group. Therapy seemed to benefit the youngest children the most.
Interferon-gamma does not correct or enhance phagocyte superoxide production in the vast majority of patients with CGD. The exact mechanisms underlying the beneficial effect of interferon-gamma are not completely understood but most likely include augmentation of oxidant-independent antimicrobial pathways. In a subset of patients with X91-CGD, an increase in functional gp91phox was produced.
Data have suggested that interferon-gamma partially corrects the oxidative burst defect in circulating phagocytes from patients with variant X-linked CGD (X-CGD) or recessive CGD. Induction of a dose-dependent increase in neutrophil aspergillicidal activity and FcgR1 expression are additional possible explanations for the beneficial role of interferon-gamma in CGD.
Long-term interferon-gamma therapy was safe in a 9-year open-label study that concluded in 2001.[20] In that study, 76 patients (accounting for 328.4 patient-years) had no life-threatening event or delay in growth or development related to interferon-gamma. Adverse effects were reported by 38% of patients and included fever (most common event; treated with acetaminophen), headache, myalgias, fatigue, irritability, and flulike syndrome. Three (4%) of 76 patients withdrew from the study because of adverse effects. The study showed no increase in proinflammatory symptoms, such as granuloma formation or inflammatory bowel disease (IBD).
Interferon-gamma is now recommended as life-long therapy for infection prophylaxis in CGD.
Curative approaches (HSCT)
HSCT is the only curative therapeutic modality currently available for CGD.
A Japanese study, by Yanagimachi et al, found that patients (n=91) who underwent HSCT for CGD had 3-year overall, event-free, and graft versus host disease–free, event-free survival rates of 73.7%, 67.6%, and 57.0%, respectively. Survival was poorer in patients with NCF2 or CYBA gene mutations than in those with CYBB mutations. The 21 patients who died in the study primarily represented transplant-related cases of mortality.[21]
A study by Grunebaum et al of patients (median age 9.1 years) with autosomal recessive p47phox CGD who underwent allogeneic HSCT using either related and unrelated donors found that the rate of CGD-associated infections was reduced from 0.38 per person-years in the year before the transplant to 0.06 per person years after transplantation. In addition, inflammatory bowel disease became less frequent, and steroid use was reduced. Two-year overall and event-free survival incidences of 92.3% and 82.1%, respectively, were reported; at 5 years, the incidences came to 85.7% and 77.0%, respectively. A 17.9% cumulative incidence of graft failure and second HSCT was also reported.[22]
A study by Yonkof et al for the United States Immunodeficiency Network reported that transplant-related survival improved in patients with CGD who underwent allogeneic HSCT at age 14 years or younger (93% vs 82% at 60 months posttransplant). In the total patient group, however, the procedure was not found to improve overall survival.[23]
Anecdotal experience suggests that engraftment of 10-20% normal donor phagocytes may be sufficient for a clinically significant benefit.
Transplantation with matched sibling bone marrow or cord blood is likely to be most successful if performed in infancy or early childhood, when the risk of death from infection or graft versus host disease is minimal. However, even under these circumstances, a small but finite risk of mortality from HSCT is noted. This risk has led to reluctance among treating physicians in recommending or using this therapeutic procedure.
In a retrospective study by Alonso García et al of children with CGD who were treated with HSCT, complications were higher in patients who received the transplant from an unrelated donor. In children who received the transplant from a sibling donor, the 2-year incidences of graft failure and chronic graft versus host disease were both 11.1%, while for those with an unrelated donor, the incidences were 37.08% and 26.7%, respectively. The entire group had a 5-year overall survival rate of 77.3%.[24]
A study by Marsh et al indicated that allogeneic HSCT is curative for IBD associated with CGD. The investigators reported that by 2 years posttransplant, IBD had resolved in all surviving evaluable patients in the study with a history of the condition.[25]
Gene therapy
Gene therapy for CGD is attractive for numerous reasons. The exact genetic defect can usually be identified. The cells lacking the functional gene product and their precursors are accessible in blood or bone marrow. Because carriers of X-CGD are rarely symptomatic, unless less than 10% of phagocytes express the normal gene for gp91phox, stable correction of only 5-10% of circulating phagocytes may be adequate to substantially improve the clinical outcome.
The primary disadvantage of CGD as a candidate disease for gene therapy is that the gene-modified cells do not have a selective advantage over defective host cells. This is because the phox genes are required only in the terminally differentiated phagocyte.
Published results of gene therapy in CGD have come from animal studies, in vitro studies of cells derived from human bone marrow, and research into adoptive transfer of ex vivo modified cells into human patients. A report in two patients who underwent reduced-intensity transplant conditioning and gene transfer led to improvement in phagocyte superoxide-generating activity.[26] Long-term follow up studies are required to document the safety of the gene insertion and the possibility of deleterious effects.
With current techniques, partial temporary correction of the phagocyte defect may be possible as an adjunct to medical therapy of acute or chronic infection. However, durable, clinically significant correction of CGD with gene therapy awaits improved methods for gene transfer, targeting of hematopoietic stem cells, and control of genetic expression. When these problems are solved, safe, practical gene therapy will become the treatment of choice for CGD.
Despite the increased risk of wound healing associated with surgical intervention, surgery is still an important tool for patients with CGD.
Surgery 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.
Patients who require surgery are at risk for postoperative wound infections and sepsis due to catalase-producing organisms, especially S aureus.
A retrospective study by Feingold et al of patients with CGD found that those undergoing thoracic surgery (stemming from persistent pulmonary infections) suffered significant morbidity and a relatively poor long-term survival rate, with the hazard ratio for death rising to 3.71. In the study, 35 out of 258 patients required thoracic surgery, with overall survival probabilities at 5- and 10-year follow-up calculated at 75% and 62%, respectively. Negative prognostic factors included chest wall resection and an estimated blood loss of over 500 mL.[27]
Large deletions in the region of the CYBB gene are known to delete adjacent genes, such as XK, the gene that controls the expression of the Kell blood group antigen.
Patients with CGD who have this gene deletion can become sensitized to Kell antigens after red blood cell (RBC) transfusion, leading to hemolytic complications after subsequent transfusions.
For this reason, carefully examine the Kell-antigen status in patients with chronic granulomatous disease who require a blood transfusion.
Clinical Context:
Continuous antifungal therapy effective in preventing infection due to Aspergillus species. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP–dependent synthesis of ergosterol, vital component of fungal cell membranes.
Clinical Context:
Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.
Clinical Context:
Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.
Clinical Context:
Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) activity.
What is pediatric chronic granulomatous disease (CGD)?What are the signs and symptoms of pediatric chronic granulomatous disease (CGD)?How is pediatric chronic granulomatous disease (CGD) diagnosed?What is included in the management of pediatric chronic granulomatous disease (CGD)?What is the pathophysiology of pediatric chronic granulomatous disease (CGD)?What is the US prevalence of pediatric chronic granulomatous disease (CGD)?What is the global prevalence of pediatric chronic granulomatous disease (CGD)?What is the morbidity and mortality associated with pediatric chronic granulomatous disease (CGD)?What are the racial predilections of pediatric chronic granulomatous disease (CGD)?What are the sexual predilections of pediatric chronic granulomatous disease (CGD)?At what age is pediatric chronic granulomatous disease (CGD) typically diagnosed?Which clinical history findings are characteristic of pediatric chronic granulomatous disease (CGD)?Which physical findings are characteristic of pediatric chronic granulomatous disease (CGD)?What are the differential diagnoses for Pediatric Chronic Granulomatous Disease?What is the role of a dihydrorhodamine (DHR) test in the workup of pediatric chronic granulomatous disease (CGD)?What is the role of genetic testing in the workup of pediatric chronic granulomatous disease (CGD)?Which second-line tests should be performed when screening test results are inconclusive for pediatric chronic granulomatous disease (CGD)?How is pediatric chronic granulomatous disease (CGD) diagnosed prenatally?Which lab findings are characteristic of pediatric chronic granulomatous disease (CGD)?What is the role of a nitroblue tetrazolium (NBT) test in the workup of pediatric chronic granulomatous disease (CGD)?What is the role of imaging studies in the workup of pediatric chronic granulomatous disease (CGD)?Which histologic findings are characteristic of pediatric chronic granulomatous disease (CGD)?How is pediatric chronic granulomatous disease (CGD) treated?What is the role of infection prophylaxis in the treatment of pediatric chronic granulomatous disease (CGD)?How are active infections treated in pediatric chronic granulomatous disease (CGD)?How is WBC function improved in patients with pediatric chronic granulomatous disease (CGD)?What is the role of HSCT in the treatment of pediatric chronic granulomatous disease (CGD)?What is the role of gene therapy in the treatment of pediatric chronic granulomatous disease (CGD)?What is the role of surgery in the treatment of pediatric chronic granulomatous disease (CGD)?Which medications in the drug class Antibiotics, Combos are used in the treatment of Pediatric Chronic Granulomatous Disease?Which medications in the drug class Immunomodulators are used in the treatment of Pediatric Chronic Granulomatous Disease?Which medications in the drug class Antifungal agents are used in the treatment of Pediatric Chronic Granulomatous Disease?Which medications in the drug class Biologic response modifiers are used in the treatment of Pediatric Chronic Granulomatous Disease?
Lawrence C Wolfe, MD, Associate Chief for Hematology and Safety, Division of Pediatric Hematology-Oncology, Cohen Children's Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Elisa Keefe, MD, Fellow, Department of Pediatric Hematology and Oncology, Cohen Children’s Medical Center and Feinstein Institute for Medical Research, Northshore Long Island Jewish Health System
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
Disclosure: Nothing to disclose.
Chief Editor
Cameron K Tebbi, MD, Director, Children's Cancer Research Group Laboratories
Disclosure: Nothing to disclose.
Additional Contributors
Sharada A Sarnaik, MBBS, Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Associate Hematologist/Oncologist, Children's Hospital of Michigan
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Naynesh R Kamani, MD, and Kevin J Curran, MD, to the original writing and development of this article.
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