Pediatric Chronic Granulomatous Disease 

Updated: Aug 07, 2019
Author: Lawrence C Wolfe, MD; Chief Editor: Cameron K Tebbi, MD 

Overview

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]  This consequently interferes with the production of hydrogen peroxide (H2O2), hypochlorous acid (HOCI), and hydroxyl radicals (OH.), 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.

The nitroblue tetrazolium (NBT) and dihydrorhodamine (DHR) tests, as well as genetic testing, are indicated in the workup of chronic granulomatous disease. 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.

Chronic granulomatous disease is now 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.

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.[2]

Signs and symptoms

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

Another characteristic manifestation of CGD is the development of granulomas in the skin, gastrointestinal (GI) tract, and genitourinary (GU) tract.

Workup

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 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.

The two most frequent findings on histologic examination of CGD lesions are infection and postinfectious granulomas.

Management

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 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, normally 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 chronic granulomatous disease were shown to have a lack of increased oxygen consumption.

Chronic granulomatous disease is caused by a defect in phagocytic NADPH oxidase, which is responsible for producing O2-. This superoxide anion is then converted to relatively bactericidal reactive oxidants, such as hydroxyl radical (OH-), hydrogen peroxide (H2 O2), 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 known 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. Numerous additional cytosolic oxidase factors (rac1, rac2) and a membrane-associated factor, rap1A, have been identified as having important roles in oxidase activation and function. Chronic granulomatous disease 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 chronic granulomatous disease was described in one patient secondary to a mutation involving rac2 (guanosine triphosphate [GTP]–bound signaling protein).

The most common molecular defect in chronic granulomatous disease 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).[3] The resulting syndrome is commonly called X-linked chronic granulomatous disease (X-CGD). Gp91 deficiency accounts for 50-70% of all cases of chronic granulomatous disease. 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 that encodes for p47. This mutation is the most common autosomal recessive form of the disease, accounting for 20-40% of all cases of chronic granulomatous disease. 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 p67) and CYBA (which encodes p22) are rare, accounting for fewer than 10% of all cases of chronic granulomatous disease. Both of these mutations result in the autosomal recessive forms of chronic granulomatous disease.

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+,-, oro 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 chronic granulomatous disease phagocyte can kill numerous microorganisms despite its defects because most microorganisms endogenously produce hydrogen peroxide, which the chronic granulomatous disease–affected phagocyte can modify and use against the organism in the phagosome. Bacteria and fungi that cause most infections in chronic granulomatous disease 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.[4]

Whereas both Pseudomonas aeruginosa and Burkholderia cepacia (also known as Pseudomonas cepacia) are catalase-positive organisms, the former is a rare pathogen in chronic granulomatous disease because chronic granulomatous disease neutrophils can kill P aeruginosa organisms by means of nonoxidative mechanisms. B cepacia is an important cause of infections in chronic granulomatous disease perhaps because of as-yet unexplained abilities to resist killing in neutrophil-mediated nonoxidative pathways.[5]

Fungal infections occur in as many as 20% of patients with chronic granulomatous disease. 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 chronic granulomatous disease. 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 chronic granulomatous disease, Aspergillus infection was the leading cause of death (see the image below), and B cepacia infection was the second most common.

Scanning electron micrograph of Aspergillus specie 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.

Epidemiology

Frequency

United States

The exact incidence of chronic granulomatous disease (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.[6]

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 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.[7]

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 chronic granulomatous disease 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. Chronic granulomatous disease is probably undiagnosed in some patients because they have a clinically mild phenotype.

 

Presentation

History

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 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.

  • A second characteristic manifestation of chronic granulomatous disease 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 chronic granulomatous disease. 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.[8] Symptoms included abdominal pain (100%), diarrhea (33%), nausea and vomiting (24%), bloody diarrhea (6%), and constipation (4%). About 70% with GI involvement had hypoalbuminemia. All recovered with steroids. Typical treatment for endoscopically confirmed granulomas was prednisone at 1 mg/kg/d. Relapse occurred in 71% after steroids were discontinued. Prednisone (2.5-5 mg/d) was maintained for more than 1 y in 43%. 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 chronic granulomatous disease.

    • Watchful treatment of GI or GU granulomas that cause obstruction or symptoms with oral corticosteroids is effective. Prednisone at 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 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 chronic granulomatous disease 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 chronic granulomatous disease.

  • Chronic or recurrent infections in childhood can lead to failure to thrive with impairment of physical growth, though most adults with chronic granulomatous disease appear to attain their expected growth potential.

  • In general, carriers of chronic granulomatous disease 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 chronic granulomatous disease 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 chronic granulomatous disease characterized them as presenting with lymphadenopathy, hepatosplenomegaly, growth failure, and stigmata of chronic skin infections.[9]

  • 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.

 

DDx

 

Workup

Laboratory Studies

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 p47 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 is limited by its subjectivity, need for experienced technician, and false-negative results that cause the diagnosis of chronic granulomatous disease to be missed. False-negative findings occur when formazan accumulates in cells with low levels of active adenine dinucleotide phosphate (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 chronic granulomatous disease. This test should be considered the most accurate diagnostic test for chronic granulomatous 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 gp91 (no activity, no DHR conversion) and p47 (low activity, minimal DHR conversion) can be distinguished with this method. X-linked carriers of chronic granulomatous disease 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 chronic granulomatous disease (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.

    • Identification of the precise molecular defect in individual patients takes on added importance with the recent initiation of gene-therapy trials in chronic granulomatous disease.

  • 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 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 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 two most frequent findings on histologic examination of the lesions observed in chronic granulomatous disease 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 genitourinary (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.

 

Treatment

Medical Care

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 chronic granulomatous disease.[10] 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.[11, 12, 13]

Infection prophylaxis

Daily prophylaxis of bacterial infections with trimethoprim-sulfamethoxazole (TMP-SMZ; Bactrim) is indicated in chronic granulomatous disease.

TMP-SMZ prophylaxis reduces the incidence of bacterial infections in chronic granulomatous disease 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 chronic granulomatous disease.

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 chronic granulomatous disease.

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.[14] If Aspergillus infection occurs, consult the treatment guidelines from the Infectious Diseases Society of America.[15, 16] A randomized double-blind placebo-controlled study showed that itraconazole prophylaxis in chronic granulomatous disease prevented serious and superficial fungal infections.[17] 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 drug for staphylococcal infection is a common first choice in patients with chronic granulomatous disease. 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 Staphylococcus 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 genitourinary (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 chronic granulomatous disease showed that it was well tolerated and that it reduced the frequency of serious infections.[18] 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 chronic granulomatous disease. The exact mechanisms underlying the beneficial effect of interferon-gamma is not completely understood but most likely includes augmentation of oxidant-independent antimicrobial pathways. In a subset of patients with X91–chronic granulomatous disease, an increase in functional gp91 was produced.

Data have suggested that interferon-gamma partially corrects the oxidative burst defect in circulating phagocytes from patients with variant X-linked chronic granulomatous disease (X-CGD) or recessive chronic granulomatous disease. 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 chronic granulomatous disease.

Long-term interferon-gamma therapy was safe in a 9-year open-label study that concluded in 2001.[19] 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 chronic granulomatous disease.

Curative approaches (HSCT)

HSCT is the only curative therapeutic modality currently available for this disease.

At least 24 patients who have undergone HSCT for chronic granulomatous disease 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 HSCTs are published in the literature.[20]

Because of the paucity of transplantations performed to date, meaningful assessment of the likelihood of successful outcome after HSCT in chronic granulomatous disease cannot be made.

A study by Yonkof et al for the United States Immunodeficiency Network reported that transplant-related survival improved in patients with chronic granulomatous disease 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.[21]

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.

A study by Marsh et al indicated that allogeneic hematopoietic stem cell transplantation (HSCT) is curative for IBD associated with chronic granulomatous disease (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.[22]

Gene therapy

Gene therapy for chronic granulomatous disease 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 gp91, stable correction of only 5-10% of circulating phagocytes may be adequate to substantially improve the clinical outcome.

The primary disadvantage of chronic granulomatous disease 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 chronic granulomatous disease have come from animal studies, in vitro studies of cells derived from human bone marrow, and a reports of 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.[23] 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 chronic granulomatous disease 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 chronic granulomatous disease.

Surgical Care

Despite the increased risk of wound healing associated with surgical intervention, surgery is still an important tool for these patients.

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 chronic granulomatous disease found that those undergoing thoracic surgery (stemming from persistent pulmonary infections) was accompanied by 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.[24]

 

Medication

Antimicrobials

Class Summary

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

Trimethoprim-sulfamethoxazole (TMP-SMZ, Cotrimoxazole, Septra, Bactrim)

Antimicrobial drug of choice administered prophylactically to prevent infections in patients with CGD.

Biologic response modifiers

Class Summary

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

Interferon gamma 1b (Actimmune)

Indicated in CGD to reduce frequency and severity of bacterial infections (50 mcg = 1 million IU).

Antifungal agents

Class Summary

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

Itraconazole (Sporanox)

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.

Voriconazole (VFEND)

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.

Posaconazole (Noxafil)

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.

Immunomodulators

Class Summary

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

Prednisone (Deltasone, Orasone)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) activity.

 

Follow-up

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 chronic granulomatous disease (CGD) who have this gene deletion can become sensitized to Kell antigens after 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.

Prognosis

The prognosis for patients with chronic granulomatous disease has improved over the last two 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 chronic granulomatous disease (gp91phox deficient) to be 37.8 years, and for those with autosomal recessive chronic granulomatous disease, 49.6 years.[7] The highest mortality rate is in early childhood. The usual cause of death is infection. However, chronic granulomatous disease 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 chronic granulomatous disease.[25] Of 11 patients in whom chronic granulomatous disease was diagnosed after adolescence, 8 had X-linked chronic granulomatous disease. However, all 8 patients had small but detectable quantities of cytochrome b 558.

A case report describes a previously healthy 67-year-old man with X-linked chronic granulomatous disease 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.