AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Chronic granulomatous disease (CGD), an inherited disorder of phagocytic cells, results from an inability of phagocytes to produce bactericidal superoxide anions (O^2-). This leads to recurrent life-threatening bacterial and fungal infections. Since its first description in the 1950s as a syndrome of recurrent infections, hypergammaglobulinemia, hepatosplenomegaly, and lymphadenopathy in boys 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. CGD is now known to be caused by a defect in the nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase enzyme of phagocytes. CGD refers to the characteristic granulomas that develop in response to chronic inflammation.

Pathophysiology

In response to phagocytosis neutrophils 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.

CGD is caused by a defect in phagocytic NADPH oxidase, which is responsible for producing O^2-. This 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). 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 the phagocyte NADPH oxidase otherwise know as phagocyte oxidase (phox).

Nitric oxide (NO) and other reactive nitrogen intermediates have a prominent microbicidal role in experimental animals but do not appear to have a critical role in human phagocytes.

The phox system is an NADPH oxidase enzyme complex consisting of 5 component proteins. Glycoprotein 91 (gp91) and protein 22 (p22) make up the b and a subunits of a membrane bound heterodimer referred to as flavocytochrome b558. Protein 47 (p47), protein (p67), and protein 40 (p40) exist together as the cytosolic components of phox. The membrane-bound (gp91 and p22) and cytosolic components (p47, p67, and p40) 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 other more toxic radicals, such as hydrogen peroxide mediated by superoxide dismutase and HOX.

The precise mechanism by which this intracellular bleach kills microorganisms is still debated. A number of additional cytosolic oxidase factors (rac1, rac2) and a membrane-associated factor, rap1A, have recently been identified as having important roles in oxidase activation and function. CGD results from defects in gp91, p22, p47, and p67. Thus far, no cases related to a defect in p40 have been reported. An immunodeficiency syndrome similar to CGD was described in 1 patient secondary to a mutation involving rac2 (guanosine triphosphate [GTP]–bound signaling protein).

The most common molecular defect in CGD is a mutation in the CYBB (cytochrome B, b subunit) gene that is located on the X chromosome and that encodes for gp91 (the b subunit of cytochrome b558). The resulting syndrome is commonly called X-linked CGD (X-CGD). Gp91 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%.

The second most common mutation occurs in the NCF1 gene on chromosome 7 that encodes for p47. 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 >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 p67) and CYBA (which encodes p22) 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 complete absence or greatly diminished level of the affected protein. In the remaining 5%, a normal level of defective protein is produced. The 4 forms of the disease are referred to as X91 (X-linked, gp91), A22 (autosomal, p22), 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 p47 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 a number of 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 the infecting microorganisms.

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.

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 1 registry of patients with CGD Aspergillus infection was the leading cause of death, and B cepacia infection was the second most common.

The diagnosis of CGD 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.

Frequency

United States

The exact incidence of CGD is unknown. Analysis of data submitted to a recently established national registry suggest that the incidence of CGD in the United States is about 1 case per 200,000-250,000 population (up to 20 patients with CGD born each year), with no apparent racial or ethnic predilection.

International

Surveys from Sweden and other parts of the world suggest a frequency of about 1 case in 220,000-500,000 population.

Mortality/Morbidity

A detailed study of the natural history of CGD is unavailable. The registry data suggest that both 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 entered in the registry.

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 the 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The hallmark of this disease 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 occur in up to 20% of patients with CGD.
• • Pneumonia is the most common presentation.
  • Fungal infections may be locally invasive or disseminated. Aspergillus species infection in CGD is often indolent, with mild or absent symptoms at the outset.
• A second characteristic manifestation of CGD is the development of granulomas in the skin, GI tract, and 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 2004 review of 140 patients with CGD, 33% had GI involvement, including granulomatous colitis, Crohnlike inflammatory bowel disease (IBD), GI obstruction (gastric, esophageal, duodenal, or other locations), perianal abscesses or fistulas, and esophageal dysmotility. Symptoms included abdominal pain (100%), diarrhea (33%), nausea and vomiting (24%), bloody diarrhea (6%), and constipation (4%) (Marciano, 2004). About 70% with GI involvement had hypoalbuminemia. All received with steroids. Typical treatment for endoscopically confirmed granulomas was prednisone 1 mg/kg/d. Relapse occurred in 71% after steroids were discontinued. Prednisone 2.5-5 mg/d was maintained for >1 y in 43%. Interferon-gamma (IFM-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.
  • Treatment of GI or GU granulomas with oral corticosteroids is safe and effective. Prednisone 1-2 mg/kg as an initial dose relieves symptoms of GI or GU obstruction. Although some reports show transient improvements of symptoms with antibiotic use, current recommendations are to use corticosteroids as monotherapy. Any underlying or concomitant infections should be ruled out before steroid treatment is begun. 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 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, though 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.
• On occasion, mothers who are carriers of X-CGD and who have hyperlyonization (ie, unequal representation of phagocytes expressing the normal and mutated gp91 genes) have a mild CGD phenotype. This usually occurs when the normal gene for gp91 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.

Physical

The early descriptions of children with CGD characterized them as presenting with lymphadenopathy, hepatosplenomegaly, growth failure, and stigmata of chronic skin infections. These physical findings are observed less commonly now than before because most patients are identified and treated in early infancy or childhood. Infected patients sometimes present without the typical symptoms of infection (ie, fever, leukocytosis).

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Hyper–immunoglobulin M (IgM) syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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 p47 deficiency.
  • The NBT test can be useful in identifying X-linked carrier female individuals when peripheral phagocytes consist of 2 cell populations: 1 that reduces NBT to formazan and 1 that does not.
  • The NBT is limited by its subjectivity, need for 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 results from the NBT test 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
• • With the recent wide availability of flow cytometric instruments in clinical pathology laboratories, a test based on DHR reduction has been developed.
  • 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, though a specialized instrument is required.
  • Deficiencies of gp91 (no activity, no DHR conversion) and p47 (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-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 CGD and the large number of unique mutations preclude standardized genetic testing. Therefore, individual genetic analysis remains the domain of specialized research laboratories.
  • Mutations currently can be identified in nearly all patients and in about 90% of mothers of affected children.
  • Identification of the precise molecular defect in individual patients takes on added importance with the recent initiation of gene-therapy trials in CGD.
• 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 p22, p47, or p67 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 1 of 2 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 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.

Imaging Studies

• Imaging studies such as chest radiography and CT imaging are valuable in the diagnosis and management of pulmonary and hepatosplenic infections.

Histologic Findings

The 2 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 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. Similar granulomatous infiltrations of the skin and lungs are described.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Antimicrobial prophylaxis, early and aggressive treatment of infections, and IFN-gamma are the cornerstones of current therapy for CGD. Hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)–compatible donor can cure CGD. 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.

• 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 a number of 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 has been used as daily prophylaxis; however, the effectiveness of this treatment has not been proven.
  • Ketoconazole is ineffective in reducing fungal infections in CGD patients.
  • 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. A randomized double-blind placebo-controlled study showed that itraconazole prophylaxis in CGD prevented serious and superficial fungal infections. Adverse effects included rash, increased liver-function values, and headache; these resolved after itraconazole was discontinued.
• 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).
  • 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 IFN-gamma during severe infectious episodes has been advocated.
  • Patients presenting with granulomatous manifestations may respond to intravenous antimicrobial therapy. However, corticosteroids are the treatment of choice and are used in patients who do not appear to have obvious infection, especially in patients with GI or GU obstruction to decrease the time of obstruction without increasing the risk of infection.
• Prophylaxis to improve WBC function
  • Based on preliminary observations suggesting the efficacy of IFN-gamma, a multi-institutional, randomized double-blind placebo-controlled study of IFN-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. 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.
  • IFN-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 IFN-ƒ× is not completely understood, but it most likely includes augmentation of oxidant-independent antimicrobial pathways. In a subset of patients with X91- CGD an increase in functional gp91 was produced.
  • Recent data have suggested that IFN-gamma partially corrects the oxidative burst defect in a subset of circulating monocytes. Induction of a dose-dependent increase in neutrophil aspergillicidal activity and FcgR1 expression are additional possible explanations for the beneficial role of IFN-gamma in CGD.
  • Long-term IFN-gamma therapy was safe in a 9-year open-label study that concluded in 2001. In that study, 76 patients accounting for 328.4 patient-years had no life-threatening event or delay in growth or development related to IFN-gamma. Adverse effects were reported by 38% of patients and included fever (most common event; treated with acetaminophen), headache, myalgias, fatigue, irritability, and flu-like 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 IBD.
  • IFN-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 this disease.
  • At least 24 patients who have undergone SCT for CGD were reported to the International Bone Marrow Transplant Registry of the Center for International Blood and Marrow Transplant Research (CIBMTR). Several case reports of successful SCTs are published in the literature.
  • Because of the paucity of transplantations performed to date, meaningful assessment of the likelihood of successful outcome after SCT in CGD cannot be made.
  • 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 SCT exists. This risk has led to reluctance among treating physicians in recommending or using this therapeutic procedure.
• Gene therapy
  • Gene therapy for CGD is attractive for a number of 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 gp91, 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 a report of adoptive transfer of ex vivo modified cells into human patients.
  • 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.

Surgical Care

Patients requiring surgery are at risk for postoperative wound infections and sepsis due to catalase-producing organisms, especially S aureus.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Antimicrobials

These agents are used prophylactically to prevent infections in susceptible individuals or to treat active infections.

Drug Category: Biologic response modifiers

These agents regulate the immune system by a variety of mechanisms, including enhancing activity of macrophages and cytotoxic actions of T lymphocytes.

Drug Category: Antifungal agents

Mechanism of action may involve increasing the permeability of the cell membrane, which, in turn, causes intracellular components to leak.

Drug Category: Immunomodulators

These agents suppress an overactive immune system that leads to formation of granulomas.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• 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 transfusion, leading to hemolytic complications after subsequent transfusions.
• For this reason, carefully examine the Kell-antigen status in CGD patients with CGD who require a blood transfusion.

Prognosis

• The prognosis for patients with CGD has improved over the last 2 decades. Although no formal studies of the natural history of this disease have been conducted, the current median survival duration for a patient with CGD is estimated to be about 20-25 years, with a mortality rate of 2-3% per year. 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 p47-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 definition of prognosis for individual patients difficult.
• 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 (Liese, 1996). Of 11 patients in whom CGD was diagnosed after adolescence, 8 had X-CGD. However, all 8 patients had small but detectable quantities of cytochrome b558.
• A case report describes a previously healthy 67-year-old man with X-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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider this diagnosis in patients with frequent infections with catalase-positive organisms may lead to poor patient outcomes.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Barton LL, Moussa SL, Villar RG, Hulett RL. Gastrointestinal complications of chronic granulomatous disease: case report and literature review. Clin Pediatr (Phila). Apr 1998;37(4):231-6. [Medline].
• Berendes H, Bridges RA, Good RA. A fatal granulomatosus of childhood: the clinical study of a new syndrome. Minn Med. May 1957;40(5):309-12. [Medline].
• Bjorgvinsdottir H, Ding C, Pech N, et al. Retroviral-mediated gene transfer of gp91phox into bone marrow cells rescues defect in host defense against Aspergillus fumigatus in murine X-linked chronic granulomatous disease. Blood. Jan 1 1997;89(1):41-8. [Medline].
• Carson MJ, Chadwick DL, Brubaker CA, et al. Thirteen boys with progressive septic granulomatosis. Pediatrics. Mar 1965;35:405-12. [Medline].
• Danziger RN, Goren AT, Becker J, et al. Outpatient management with oral corticosteroid therapy for obstructive conditions in chronic granulomatous disease. J Pediatr. Feb 1993;122(2):303-5. [Medline].
• Del Giudice I, Iori AP, Mengarelli A, et al. Allogeneic stem cell transplant from HLA-identical sibling for chronic granulomatous disease and review of the literature. Ann Hematol. Mar 2003;82(3):189-92. [Medline].
• Dohil M, Prendiville JS, Crawford RI, Speert DP. Cutaneous manifestations of chronic granulomatous disease. A report of four cases and review of the literature. J Am Acad Dermatol. Jun 1997;36(6 Pt 1):899-907. [Medline].
• Gallin JI, Malech HL. Update on chronic granulomatous diseases of childhood. Immunotherapy and potential for gene therapy [clinical conference]. JAMA. Mar 16 1990;263(11):1533-7. [Medline].
• Gallin JI, Alling DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med. Jun 12 2003;348(24):2416-22. [Medline].
• Goebel WS, Mark LA, Billings SD, et al. Gene correction reduces cutaneous inflammation and granuloma formation in murine X-linked chronic granulomatous disease. J Invest Dermatol. Oct 2005;125(4):705-10. [Medline].
• Gorlach A, Lee PL, Roesler J, et al. A p47-phox pseudogene carries the most common mutation causing p47-phox-deficient chronic granulomatous disease. J Clin Invest. Oct 15 1997;100(8):1907-18. [Medline].
• Heyworth PG, Cross AR, Curnutte JT. Chronic granulomatous disease. Curr Opin Immunol. Oct 2003;15(5):578-84. [Medline].
• International Chronic Granulomatous Disease Cooperative Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. N Engl J Med. Feb 21 1991;324(8):509-16. [Medline].
• Ishibashi F, Nunoi H, Endo F, et al. Statistical and mutational analysis of chronic granulomatous disease in Japan with special reference to gp91-phox and p22-phox deficiency. Hum Genet. May 2000;106(5):473-81. [Medline].
• Jirapongsananuruk O, Malech HL, Kuhns DB, et al. Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay. J Allergy Clin Immunol. Feb 2003;111(2):374-9. [Medline].
• Johnston RB. Clinical aspects of chronic granulomatous disease. Curr Opin Hematol. Jan 2001;8(1):17-22. [Medline].
• Kamani N, August CS, Campbell DE, et al. Marrow transplantation in chronic granulomatous disease: an update, with 6-year follow-up. J Pediatr. Oct 1988;113(4):697-700. [Medline].
• Kume A, Dinauer MC. Gene therapy for chronic granulomatous disease. J Lab Clin Med. Feb 2000;135(2):122-8. [Medline].
• Landing BH, Shirkey HS. A syndrome of recurrent infection and infiltration of viscera by pigmented lipid histiocytes. Pediatrics. Sep 1957;20(3):431-8. [Medline].
• Leung T, Chik K, Li C, Yuen P. Bone marrow transplantation for chronic granulomatous disease: long- term follow-up and review of literature. Bone Marrow Transplant. Sep 1999;24(5):567-70. [Medline].
• Liese JG, Jendrossek V, Jansson A, et al. Chronic granulomatous disease in adults. Lancet. Jan 27 1996;347(8996):220-3. [Medline].
• Malech HL, Nauseef WM. Primary inherited defects in neutrophil function: etiology and treatment. Semin Hematol. Oct 1997;34(4):279-90. [Medline].
• Malech HL. Progress in gene therapy for chronic granulomatous disease. J Infect Dis. Mar 1999;179 Suppl 2:S318-25. [Medline].
• Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics. Aug 2004;114(2):462-8. [Medline].
• Marciano BE, Wesley R, De Carlo ES, et al. Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis. Sep 1 2004;39(5):692-9. [Medline].
• Margolis DM, Melnick DA, Alling DW, Gallin JI. Trimethoprim-sulfamethoxazole prophylaxis in the management of chronic granulomatous disease. J Infect Dis. Sep 1990;162(3):723-6. [Medline].
• Meischl C, Roos D. The molecular basis of chronic granulomatous disease. Springer Semin Immunopathol. 1998;19(4):417-34. [Medline].
• Mouy R, Veber F, Blanche S, et al. Long-term itraconazole prophylaxis against Aspergillus infections in thirty-two patients with chronic granulomatous disease. J Pediatr. Dec 1994;125(6 Pt 1):998-1003. [Medline].
• Mouy R, Fischer A, Vilmer E, et al. Incidence, severity, and prevention of infections in chronic granulomatous disease. J Pediatr. Apr 1989;114(4 Pt 1):555-60. [Medline].
• Nakhleh RE, Glock M, Snover DC. Hepatic pathology of chronic granulomatous disease of childhood. Arch Pathol Lab Med. Jan 1992;116(1):71-5. [Medline].
• Ochs HD, Igo RP. The NBT slide test: a simple screening method for detecting chronic granulomatous disease and female carriers. J Pediatr. Jul 1973;83(1):77-82. [Medline].
• Rae J, Newburger PE, Dinauer MC, et al. X-Linked chronic granulomatous disease: mutations in the CYBB gene encoding the gp91-phox component of respiratory-burst oxidase. Am J Hum Genet. Jun 1998;62(6):1320-31. [Medline].
• Rosen GM, Pou S, Ramos CL, et al. Free radicals and phagocytic cells. FASEB J. Feb 1995;9(2):200-9. [Medline].
• Schapiro BL, Newburger PE, Klempner MS, Dinauer MC. Chronic granulomatous disease presenting in a 69-year-old man. N Engl J Med. Dec 19 1991;325(25):1786-90. [Medline].
• Segal BH, DeCarlo ES, Kwon-Chung KJ, et al. Aspergillus nidulans infection in chronic granulomatous disease. Medicine (Baltimore). Sep 1998;77(5):345-54. [Medline].
• Segal BH, Leto TL, Gallin JI, et al. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore). May 2000;79(3):170-200. [Medline].
• Thrasher AJ, Keep NH, Wientjes F, Segal AW. Chronic granulomatous disease. Biochim Biophys Acta. Oct 21 1994;1227(1-2):1-24. [Medline].
• Vowells SJ, Fleisher TA, Sekhsaria S, et al. Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in patients with chronic granulomatous disease. J Pediatr. Jan 1996;128(1):104-7. [Medline].
• Weening RS, Leitz GJ, Seger RA. Recombinant human interferon-gamma in patients with chronic granulomatous disease--European follow up study. Eur J Pediatr. Apr 1995;154(4):295-8. [Medline].
• Weening RS, Kabel P, Pijman P, Roos D. Continuous therapy with sulfamethoxazole-trimethoprim in patients with chronic granulomatous disease. J Pediatr. Jul 1983;103(1):127-30. [Medline].
• Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). May 2000;79(3):155-69. [Medline].
• Yang KD, Hill HR. Neutrophil function disorders: pathophysiology, prevention, and therapy. J Pediatr. Sep 1991;119(3):343-54. [Medline].

Article Last Updated: Sep 14, 2006