Chronic Granulomatous Disease

Clinical characteristics.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory response resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis); granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. CGD may present anytime from infancy to late adulthood; however, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival.

Diagnosis/testing.

CGD is diagnosed by tests that measure neutrophil superoxide production via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex: the dihydrorhodamine (DHR) test has largely replaced the nitroblue tetrazolium (NBT) test, the oldest and most recognized diagnostic test for CGD. CGD is caused by pathogenic variants in one of five genes that encode the subunits of phagocyte NADPH oxidase: biallelic pathogenic variants in CYBA, NCF1, NCF2, and NCF4 cause autosomal recessive CGD (AR-CGD); mutation of CYBB causes X-linked CGD.

Management.

Treatment of manifestations: A definitive microbiologic diagnosis is essential to proper treatment of infections. Newer azole drugs (voriconazole, posaconazole, isovuconazole) have expanded therapeutic options for fungal infections. Long courses of antimicrobials are often needed for adequate treatment. Abscesses may require percutaneous drainage or excisional surgery. Simultaneous administration of antimicrobials and corticosteroids can help resolve the associated heightened inflammatory response, including colitis.

Prevention of primary manifestations: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known cure for CGD; however, indications for and timing of HSCT are yet to be resolved. Antibacterial and antifungal prophylaxis is the cornerstone of prevention; immunomodulatory therapy with interferon gamma (IFN-gamma) is part of the prophylactic regimen in many centers.

Surveillance: Regular follow-up visits can aid in early detection and treatment of asymptomatic or minimally symptomatic infections and noninfectious complications such as colitis, pulmonary granulomas, and pulmonary fibrosis.

Agents/circumstances to avoid: (1) Decayed organic matter (e.g., mulching, gardening, leaf raking, house demolition) as inhalation of fungal spores can result in fulminant pneumonitis; (2) bacille Calmette-Guérin (BCG) vaccination; (3) persons with CGD and McLeod neuroacanthocytosis syndrome: blood transfusions that are Kell antigen positive.

Evaluation of relatives at risk: Early diagnosis of relatives at risk allows for prompt initiation of antimicrobial prophylaxis and other treatment.

Pregnancy management: The major concern during the pregnancy of a woman known to have CGD is use of prophylactic antimicrobials: trimethoprim, a folic acid antagonist, is discontinued during pregnancy because of the high risk for birth defects. Although sulfamethoxazole is not known to increase the risk of birth defects in humans, it is typically administered in conjunction with trimethoprim. Data regarding teratogenicity of itraconazole are limited.

Genetic counseling.

CGD associated with a pathogenic variant in CYBB is inherited in an X-linked manner. CGD associated with biallelic pathogenic variants in CYBA, NCF1, NCF2, or NCF4 is inherited in an autosomal recessive manner.

• X-linked CGD. If the mother of an affected male is heterozygous for a CYBB pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and will usually not be affected with typical CGD but may have other manifestations including discoid lupus erythematosus and aphthous ulcers.
• AR-CGD. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Molecular genetic carrier testing and prenatal testing for pregnancies at increased risk is possible if the pathogenic variant(s) in a family are known. (Other carrier and prenatal testing options may be available if the pathogenic variant[s] in the family are not known.)

Suggestive Findings

Chronic granulomatous disease (CGD) should be suspected in individuals (usually children) with the following clinical features and laboratory testing:

Establishing the Diagnosis

The diagnosis of CGD is established in a proband with identification of pathogenic variant(s) in one of five genes that encode the subunits of phagocyte NADPH oxidase (see Table 1).

• CYBA, NCF1, NCF2, and NCF4 are the genes in which biallelic pathogenic variants cause autosomal recessive chronic granulomatous disease (AR-CGD).
• CYBB is the gene in which a hemizygous pathogenic variant causes X-linked chronic granulomatous disease (X-linked CGD).

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

• Serial single-gene testing. Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Of note:
  • Early-onset, more severe infections and male gender suggest X-linked CGD, and CYBB testing may be considered first.
  • Later-onset, milder course, female gender, and consanguinity suggest autosomal recessive CGD.
  • The c.75_76delGT deletion is a common pathogenic variant in NCF1 (see Table 1); however, NCF1-related CDG is not clinically distinguishable from other autosomal recessive forms.
• A multigene panel that includes CYBA, NCF1, NCF2, NCF4, CYBB, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of CGD.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Chronic granulomatous disease (CGD) is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory response resulting in granuloma formation and other inflammatory disorders such as colitis.

CGD may present anytime from infancy to late adulthood; however, the vast majority of affected individuals are diagnosed before age five years. The median age of diagnosis was 2.5 to three years in several series [Jones et al 2008, Martire et al 2008]. More recently, increased numbers of affected individuals have been diagnosed in adolescence or adulthood. This delay in diagnosis may be attributed to the following:

• Effective treatment of CGD-related infections with antimicrobials not available in the past
• Recognition of milder cases of autosomal recessive (AR) CGD that may have gone undiagnosed without currently available tests and/or awareness of milder disease manifestations
• Overall improvement in food handling and sanitation

Infections and granulomatous lesions are usually the first manifestations of CGD, with the most frequent sites being the lung, lymph nodes, liver, and skin. The types of infection seen most often include pneumonia, abscess, adenitis, osteomyelitis, and cellulitis. Other pulmonary complications include empyema and hilar adenopathy. The most common sites for abscesses are the perianal and perirectal areas as well as the liver.

Although the frequency of infections in persons with CGD has decreased with the routine administration of antibacterial and antifungal prophylaxis, infections still occur at a frequency of 0.3/year.

In North America, the majority of infections in CGD are caused by Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia species, and Aspergillus species [Marciano et al 2015] (Table 2). In other parts of the world, important causes of infection are Salmonella, bacille Calmette-Guérin (BCG), and tuberculosis [Winkelstein et al 2000, van den Berg et al 2009].

Genotype-Phenotype Correlations

Historically, it has been recognized that pathogenic variants in CYBB (the cause of X-linked CGD) give rise to a more serious phenotype than pathogenic variants causing autosomal recessive (AR) forms of CGD. Compared to persons with AR-CGD, males with X-linked CGD are typically diagnosed earlier and have a significantly higher incidence of perirectal abscess, suppurative adenitis, gastric outlet obstruction, urinary obstruction, and higher mortality at a young age.

Genotype-phenotype correlations in the X-linked gene CYBB (encoding gp91^phox) include the following:

• All nonsense variants or deletions of CYBB in males are highly deleterious and associated with poorer outcomes.
• Pathogenic missense variants that occur in the CYBB region encoding amino acids 1-309 are associated with residual superoxide production at a level sufficient for good overall survival. Exceptions are pathogenic variants in the nucleotides encoding histidine at residue 222, which do not support production of residual superoxide and, therefore, are more deleterious.
• CYBB regions encoding amino acid residues 310 and beyond affect the FAD- and NADPH-binding domains that are essential for superoxide function. Even when pathogenic variants in this region allow protein expression, the proteins are nonfunctional and associated with poorer overall outcomes in affected males. Therefore, protein expression is neither reliable nor useful as a predictor of residual superoxide production [Kuhns et al 2010].
• The phenotype caused by pathogenic variants in CYBB associated with residual superoxide production is characterized by better survival than with CYBB variants that cause no residual superoxide production.
• Of note, the occurrence of inflammatory bowel disease in CGD is not correlated with superoxide production or mortality [Bender et al 2009, Kuhns et al 2010].
• Kuhns et al [2010] detemined that the level of residual neutrophil superoxide production influences morbidity and survival rates in persons with CGD. The production of reactive oxygen intermediates (ROI) was measured using the cytochrome c reduction assay (see Research testing) and the DHR test (see Diagnosis, Laboratory testing). Protein expression was determined using the immunoblot test for the NADPH complex proteins (see Research testing). Persons with modest ROI production have less severe illness and higher long-term survival than those with little ROI production.
• ROI production may be predicted by the specific pathogenic variant type and gene:
  • Lower ROI production is associated with decreased survival and was observed in persons with deletions and nonsense, frameshift, and some splice variants.
  • Higher ROI production and increased survival were observed in persons with CYBB pathogenic missense variants between amino acids 1 and 309 (with the exception of histidine 222) or pathogenic variants in NCF1 [Kuhns et al 2010].

Complete CYBA pathogenic variants lead to absent protein expression and thereby disable the formation of the cytochrome complex. These variants therefore behave like the most deleterious of the CYBB pathogenic variants.

Nomenclature

When first characterized, chronic granulomatous disease was called "fatal granulomatous disease of childhood" [Bridges et al 1959].

Prevalence

The retrospectively and voluntarily reported prevalence of CGD is approximately 1:200,000 live births in the United States [Winkelstein et al 2000].

Prevalence rates in other countries vary somewhat based on social, religious, and cultural factors that influence birth rates and frequency of consanguinity [Wolach et al 2008, Fattahi et al 2011].

• Sweden: 1:450,000 [Ahlin et al 1995]
• Japan: 1:300,000 [Hasui & Japa 1999]
• United Kingdom: 1:133,000 [Jones et al 2008]
• Israel [Wolach et al 2008]
  • Arabs: 1:111,000
  • Jews: 1:218,000
• Italy: 1:1,000,000 [Martire et al 2008]
• Greece: 2.2:100,000 [Raptaki et al 2013]

Importantly, in regions with high rates of consanguineous marriages, the prevalence of recessive forms of CGD exceeds that of X-linked CGD.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with chronic granulomatous disease (CGD), evaluation should include the following:

• Consultation with a clinical geneticist and/or genetic counselor
• Tests looking for evidence of infection, such as C reactive protein (CRP) and erythrocyte sedimentation rate (ESR), which are sensitive but nonspecific markers of inflammation
• Complete blood count (CBC). Anemia is common either due to anemia of chronic disease or iron deficiency anemia. Poor iron absorption is common in CGD-related colitis.
• Albumin. Hypoalbuminemia is found in 70% of persons with GI involvement and in 25% of persons without GI manifestations [Marciano et al 2004].
• Endoscopy and colonoscopy if signs and symptoms of colitis are present
• Imaging as it pertains to specific symptoms for diagnosis and management of infection. Because CGD can affect almost every organ system, different imaging modalities can be used depending on the site affected. Because of its relative ease and sensitivity, CT scan is often used; however, ultrasound and MRI can be used instead in many instances. Positron emission tomography (PET) using fluorine-18-fluoro-2-deoxy-D-glucose (FDG) uptake can help discriminate active from resolved infection. High FDG uptake is consistent with active inflammation [Güngör et al 2001].

Treatment of Manifestations

Serious infections may occur at any time in persons with CGD. Infections that are asymptomatic or minimally symptomatic may be identified at initial presentation. Significant rises in CRP or ESR should prompt evaluation for infection. Imaging is important in detecting and understanding the severity of infections. CT or MRI should be followed closely until resolution of infections.

A definitive microbiologic diagnosis is essential to proper treatment of infections. Biopsies to identify the pathogen should be pursued prior to initiation of antimicrobial therapy unless infections are life threatening. Often obtaining an appropriate sample for diagnosis requires fine needle aspiration or percutaneous drainage of an abscess.

Initially antibiotics and antifungals are often used empirically, with more selective use after the pathogen is identified. Newer azole drugs (voriconazole, posaconazole, isovuconazole) have expanded therapeutic options for fungal infections in CGD. Long courses of antimicrobials are often needed for adequate treatment. For example, those who do develop fungal infections on itraconazole prophylaxis develop them at an older age and may require longer duration of therapy.

The primary prophylaxis used to prevent bacterial and fungal infections also has good activity against yeasts. However, if invasive yeast infections occur, organism-specific antimicrobials are warranted.

Percutaneous drainage itself can be therapeutic, especially for liver or other intra-abdominal abscesses. Lymphadenitis and liver abscesses often require excisional surgery [Feld et al 2008]. Staphylococcal liver abscesses can be effectively treated without surgery using a combination of drainage of liquid pus (if present), intravenous antimicrobials, and moderate dose corticosteroids (1 mg/kg/day tapered over 1-2 months) [Leiding et al 2012].

Colitis. Treatment of colitis in CGD can be difficult.

Corticosteroids are usually effective but have long-term complications including growth retardation, osteoporosis, and increased risk of infection. The authors' current practice is to initiate therapy for proven colitis with prednisone 1 mg/kg/day for one to two weeks followed by a slow taper to 0.1-0.25 mg/kg/day over one to two months [Holland 2010].

Metronidazole to reduce bowel flora, salicylic acid derivatives, 6-mercaptopurine, and mesalamine are also useful in treatment of CGD colitis.

In CGD, the use of TNF-alpha inhibitors, specifically infliximab, a chimeric (mouse/human) monoclonal antibody to TNF alpha, is successful in closing fistulae but leads to increased frequency of severe infections with typical CGD pathogens or death. A report of infliximab in five persons with CGD found severe infections in all five and death in two. Of note, none of the five developed mycobacterial infections, as has been reported with use of infliximab in other conditions [Uzel et al 2010].

Successful bone marrow transplantation appears to cure CGD and the related colitis [Kang et al 2011].

Corticosteroid treatment of heightened inflammatory response. Simultaneous administration of antimicrobials and corticosteroids can help resolve the infections and extensive areas of inflammation that can occur with chronic colitis [Marciano et al 2004], granulomatous cystitis [Kontras et al 1971], pulmonary infections with Nocardia [Freeman et al 2011], and staphylococcal liver abscesses [Leiding et al 2012].

Successful treatment of mulch pneumonitis, the exuberant inflammatory response following inhalation of mulch or other organic matter, requires the simultaneous administration of antifungals and corticosteroids [Siddiqui et al 2007].

Aggressive treatment of the syndrome of secondary hemophagocytic lymphohistiocytosis (HLH) in CGD with antimicrobials, IVIg, and steroids can lead to clinical improvement and remission [Parekh et al 2011]. Because the HLH-like syndrome in CGD represents a reaction to bacterial or fungal infection, these infections must be aggressively treated if patients receive immunosuppression for HLH. Although the merit of immunosuppression in the setting of infection-triggered HLH in CGD is unclear, treatment of the infection is essential.

Granulocyte infusions. The value of granulocyte infusions has not been evaluated in prospective controlled trials; however, multiple case reports suggest its utility in treating serious bacterial and fungal infections [von Planta et al 1997, Ozsahin et al 1998, Bielorai et al 2000, Ikincioğullari et al 2005]. The principle is that a small number of normal phagocytes complement the oxidative defect in CGD phagocytes by supplying diffusible hydrogen peroxide. Transfused granulocytes have been recovered from sites of infection and appear to have normal respiratory burst activity and to traffic normally.

Granulocyte infusions are generally well tolerated; however, adverse effects include fever, development of leukoagglutinins, and rarely, pulmonary leukostasis. Alloimmunization is a major concern, as many patients with histories of severe infections may also be considered for hematopoietic stem cell transplantation (HSCT) [Heim et al 2011]. The possibility of CMV transmission is also a cause for caution.

Prevention of Primary Manifestations

Antibacterial prophylaxis. No randomized prospective clinical trials of antibacterial prophylaxis in persons with CGD have been performed; however, several retrospective studies suggest that trimethoprim-sulfamethoxazole (TMP-SMX) is effective in preventing bacterial infections. Lifelong daily antibacterial prophylaxis with oral TMP-SMX is recommended at 5 mg/kg up to 320 mg administered in two divided doses. Note: In liquid TMP-SMX the concentration of TMP is 40 mg / 5 mL and sulfamethoxazole 200 mg / 5 mL; the therapeutic dose of TMP-SMX is determined by the TMP component.

Alternatives to TMP-SMX for patients allergic to sulfonamides include trimethoprim as a single agent, dicloxacillin, cephalosporins, and fluroquinolones.

Antifungal prophylaxis. The use of azole antifungal drugs has markedly reduced the frequency and severity of fungal infections in CGD. Lifelong antifungal prophylaxis with itraconazole 5 mg/kg oral solution to a maximum of 200 mg once daily is recommended [Gallin et al 2003].

In a randomized trial, 39 patients were assigned to receive either placebo or itraconazole (100 mg/day in patients age 5-12 years; 200 mg/day in those age >13 years and weight >50 kg); only one person receiving itraconazole had a serious fungal infection compared to seven in the placebo group [Gallin et al 2003].

For those unable to tolerate itraconazole, posaconazole has been studied in the oncology setting and is likely to be effective in CGD as well [Segal et al 2005].

Of note, the primary prophylaxis used to prevent bacterial and fungal infections also has good activity against yeasts.

Immunomodulatory therapy. Interferon gamma (IFN-gamma) has become part of the prophylactic regimen in most centers in the United States; however, opinions differ on its use as primary prophylaxis and in the treatment of acute infections. The exact mechanism of IFN-gamma in CGD is not known, adding to the debate over its utility.

An international multicenter randomized prospective placebo-controlled trial showed a decrease in the rate of serious infections in the group receiving IFN-gamma (22%) versus placebo (46%) after a follow-up period of 8.9 months. This improvement was independent of age, CGD genotype, or concomitant use of other prophylactic antibiotics. Three prospective Phase IV trials showed decreased rates of infections ranging from 0.13 to 0.4 per patient year. However, one prospective study comparing treatment with TMP-SMX and itraconazole alone versus addition of IFN-gamma showed no difference in the rates of infection [Martire et al 2008].

Some practitioners use IFN-gamma only in the setting of acute infection, rather than as primary prophylaxis. The data for this are anecdotal and unimpressive. The authors typically discontinue IFN-gamma during acute infection, as its utility is unclear and the exacerbation of malaise and fever can confuse the clinical picture and alter decision-making [Holland 2010].

Administration by injection, cost, and lack of familiarity with cytokine therapy all affect the use of IFN-gamma in CGD. The authors use IFN-gamma in addition to antimicrobials as prophylaxis [Holland 2010]. Dosing is based on body surface area (BSA). For BSA >0.5/m² the dose is 50 μg/m² subcutaneously 3x/week; for BSA ≤0.5/m² the dose is 1.5 μg/kg subcutaneously 3x/week. Fever, myalgias, and malaise are the most common side effects but can be alleviated with concurrent administration of acetaminophen.

Hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT is the only known cure for CGD. Historically, HSCT has been associated with high morbidity and mortality and thus reluctantly offered. However, the use of non-myeloablative conditioning regimens has greatly decreased the risk of regimen-related toxicity as well as allowing for transplantation in the setting of active infection; recent reports place transplant survival at greater than 90% [Güngör et al 2014] with roughly equal survival among patients with matched related, matched unrelated, and umbilical cord blood donors.

The issue of which individuals with CGD should undergo HSCT remains complex. While transplant-related mortality rates have fallen dramatically and successful cure has risen, issues of long-term risk, sterility, graft-versus-host disease, donor matching, expense, center experience, availability, and insurance coverage all strongly influence family and physician choices regarding transplantation. Levels of residual superoxide production have correlated well with overall survival [Kuhns et al 2010]; that is, individuals with very low superoxide production had worse long-term survival than those with higher levels of residual superoxide production, suggesting that this latter group could benefit more from transplantation. However, even within this group some patients do relatively well for long periods.

Patients with CGD may experience behavioral, emotional, and learning difficulties as a consequence of chronic disease, recurrent hospitalization, and limitations of activity. Older children and adolescents are especially likely to be noncompliant with respect to prophylaxis and risk avoidance, increasing their risk for CGD-related complications. The inflammatory bowel disease present in up to 50% of persons with X-linked CGD may result in discomfort and growth impairment, and may require colostomy or colectomy. Overall quality of life is reduced in children with CGD, whereas patients with CGD who have undergone transplant report quality of life comparable to healthy children [Cole et al 2013]. Thus, with improved outcomes HSCT presents an increasingly reasonable alternative and the possibility of a normal life.

As HSCT becomes safer, more reliable, and more available it will likely be an early and initial choice for the management of CGD. Currently, many centers offer HSCT after the first life-threatening infection, but with advances in the technique, the availability of donors, especially for minority populations, and the availability of experienced centers, that equation and timing may change. Even without HSCT the majority of persons with CGD will live into adulthood. There is currently very little difference in overall survival over the first decades of life between medical and transplant management. However, the significant mortality in medical management begins to accrue after age 20 [Kuhns et al 2010]. Aggressive prophylaxis and infection management increase the likelihood of doing well.

The European Bone Marrow Transplantation (EBMT) Working Group 2011 statement [EBMT Working Group 2011] recommends allogeneic bone marrow transplantation for CGD in the case of unavailability of reliable specialist medical care, noncompliance with long-term antibiotic/antifungal prophylaxis, one or more life-threatening infections, severe granulomatous disease with progressive organ dysfunction (e.g., lung restriction), steroid-dependent granulomatous disease (e.g., colitis), or ongoing therapy-refractory infection (e.g., aspergillosis).

Surveillance

Regular follow-up visits can aid in early detection and treatment of asymptomatic or minimally symptomatic infections and noninfectious complications such as colitis, pulmonary granulomas, and pulmonary fibrosis [Roesler et al 2005].

• Laboratory examinations include CBC, chemistries, CRP, and ESR.
  • Significant rises in CRP or ESR should prompt evaluation for infection.
  • Presence of microcytic anemia and hypoalbuminemia may indicate development of colitis.
  • Monitor liver chemistries for transaminase and alkaline phosphatase elevation, especially drug-related hepatotoxicity.
• Although imaging is also important in detection of infectious and noninfectious manifestations, no specific guidelines address the intervals at which imaging should be used. CT or MRI should be followed closely to monitor progression of disease or until resolution of infections.

Frequent follow-up visits also provide the treating clinician opportunities to encourage compliance with prophylaxis and educate the patient and family about the disease.

Agents/Circumstances to Avoid

Exposures. Activities that expose the affected person to decayed organic matter (e.g., mulching, gardening, leaf raking, house demolition) are to be avoided as inhalation of fungal spores can result in fulminant pneumonitis leading to hypoxia and respiratory failure [Siddiqui et al 2007]. Therefore, the following should be avoided:

• Exposure to mulch
• Potting of plants or gardening
• Raking leaves or mowing lawns
• Swimming in stagnant water, brackish water, or ponds

BCG vaccination should be avoided (live viral vaccines are likely safe).

Transfusion considerations. Persons with CGD and McLeod neuroacanthocytosis syndrome lack red blood cell Kell antigens and thus should not receive blood transfusions that are Kell antigen positive.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

Evaluations can include the following:

• Molecular genetic testing if the pathogenic variant(s) in the family are known
• Routine DHR testing of peripheral blood, which will detect the CGD disease state (except for p40phox deficiency), if the pathogenic variant(s) in the family are not known

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The major concern during the pregnancy of a woman known to have CGD is continued use of prophylactic antimicrobials.

• Trimethoprim, a folic acid antagonist, is usually avoided in pregnancy
• Sulfamethoxazole is not known to increase the risk of birth defects in humans; however, it is typically administered in conjunction with trimethoprim for prophylaxis in affected non-pregnant women.
• Data regarding teratogenicity of itraconazole are limited. Although case reports of birth defects in infants born to women taking itraconazole during pregnancy have been published, this observation is not supported by larger case series. Given the lack of adequate data on the use of itraconazole during pregnancy, some practitioners suggest that it should be avoided during pregnancy until such data become available.

The authors' practice for women with CGD who are or are planning to become pregnant is to use antibacterial prophylaxis (e.g., penicillin- or cephalosporin-based therapies) for which more data on safety during pregnancy exist [Author, personal communication]. Although no antifungal prophylactic medications known to be completely safe during pregnancy are currently available, the risks and benefits of antifungal treatment must be weighed case by case. Interferon gamma is held during pregnancy and restarted after breastfeeding has ceased.

Therapies Under Investigation

Gene therapy. CGD is an attractive target for gene therapy: the disorder results from a single gene defect, neutrophil superoxide production can be reconstituted in vitro, and correction of neutrophil superoxide production need not be complete to provide complete protection, as exemplified by X-linked carriers. Although initially unsuccessful, more recent gene therapy efforts have been encouraging.

Early trials using retrovirus-based therapy were complicated by loss of engraftment. Most forms of CGD gene therapy seek to introduce a retroviral vector containing normal CYBB into mobilized CD34 stem cells. Ott et al [2006] reported successful early levels of gene-corrected oxidase-producing circulating neutrophils in two adults with X-linked CGD. While there was initial clinical benefit to both patients, over time gene silencing with loss of oxidase activity and myelodysplasia developed. Kang et al [2010] reported three individuals with X-linked CGD who underwent gene therapy: two had low-level correction of neutrophil superoxide production. One had resolution of infection with 1.1% of neutrophils regaining gp91^phox expression. The lack of an intrinsic survival advantage for gene-corrected CGD cells further complicated low rates of correction. All three individuals lost corrected gene expression over the course of several months.

Hematopoietic gene therapy in general and in CGD in particular has been complicated by the development of hematologic malignancies [Ott et al 2006, Stein et al 2010]. Two adults who were treated with retrovirus-based therapy developed monosomy 7 secondary to retroviral insertional activation of transcription of the oncogene MECOM (MDS and EVI1 complex locus).

Promising results with the use of lentiviral vectors in a murine X-linked CGD model have been obtained [Chiriaco et al 2014]. Recently an international study using a lentiviral vector encoding a chimeric myeloid promoter in patients with X-linked CGD has opened. As is true for many forms of hematopoietic stem cell gene therapy, the treatment of CGD will require some chemotherapeutic bone marrow conditioning to facilitate long-term corrected cell engraftment and persistence.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.