Chronic Granulomatous Disease

Clinical features

• Growth retardation in childhood
• Infections of lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis), especially spontaneously occurring severe or recurrent bacterial infections. Microbiologic confirmation of the cause of infection helps confirm the likelihood of CGD, since the spectrum of infection in CGD is distinct and narrow (see Table 2).
• Granuloma formation, especially genitourinary (bladder) and gastrointestinal (often pyloric initially, and later esophageal, jejunal, ileal, cecal, rectal, and perirectal)
• Colitis, manifesting as frequent stooling and fistulae or fissures. This may be the sole finding in some individuals.
• Abnormal wound healing caused by excessive granulation, which may cause the wound to dehisce and gape, leading to healing by secondary intention

Laboratory testing

Clinical tests that rely on direct measurement of neutrophil superoxide production via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex to establish the diagnosis of CGD include the following:

Dihydrorhodamine (DHR) test uses flow cytometry to measure the oxidation of dihydrorhodamine 123 to rhodamine 123 in phorbol myrisate acetate (PMA)-stimulated neutrophils, a marker for cellular NADPH oxidase activity [Vowells et al 1996]. In this test the generation of hydrogen peroxide oxidizes the dye, leading to the emission of fluorescence. Mean fluorescence intensity of the activated cells correlates directly with (and thus serves as a reliable surrogate for) superoxide production [Kuhns et al 2010].

The DHR test can distinguish the following forms of CGD:

• Complete forms (i.e., those with absent to greatly diminished production of superoxide) commonly observed in males with X-linked CGD
• Hypomorphic (variant) forms of CGD characterized by reduced protein expression/function and residual superoxide production (observed in autosomal recessive CGD and protein-positive X-linked CGD)
• Mosaic forms (i.e., those with two discrete populations of phagocytes: some oxidase-positive and some oxidase-negative) commonly observed in female carriers of X-linked CGD
  Note: Although the pattern of oxidase-positive and oxidase-negative phagocytes can suggest X-linked inheritance of CGD or autosomal recessive inheritance of CGD, the results are not definitive in establishing the mode of inheritance.

Although the DHR is superior to other tests for CGD, it is not always clinically available to ordering clinicians, and the nitroblue tetrazolium (NBT) test is ordered in its place.

Nitroblue tetrazolium (NBT) test, the oldest and most recognized diagnostic test for CGD, relies on light microscopy to provide a mostly qualitative determination of phagocyte NADPH oxidase activity. When stimulated in vitro, normal phagocytes produce superoxide that reduces yellow NBT to blue/black formazan, forming a precipitate in cells [Baehner & Nathan 1967]. The NBT test is typically performed on a microscope slide, which is read manually to distinguish reducing (blue-black) from non-reducing (unstained) cells:

• Neutrophils in unaffected non-carriers. More than 95% of cells produce superoxide that reduces NBT to formazan.
• Neutrophils in individuals with CGD. Production of superoxide is absent or greatly diminished.
• Female carriers of X-linked CGD (who have two populations of leukocytes). Superoxide is typically produced in 20%-80% of cells [Elloumi & Holland 2014] (range: 0.001%-97%).
  Note: Because the NBT test is semi-quantitative and evaluates only a limited number of cells, it may be falsely interpreted as normal in: (1) female carriers of X-linked CGD, especially those with skewed (non-random) X-chromosome inactivation (see Carriers of X-Linked CGD); and (2) persons with hypomorphic (variant) forms of CGD characterized by partial protein expression/function and residual superoxide production (observed in autosomal recessive CGD and protein-positive X-linked CGD).

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Special Consideration in a Male with Suspected CGD and Other Medical Issues

Large deletions in Xp21.1 have been reported in some with X-CGD. Other genes that lie in close proximity to CYBB at Xp21.1 include the following [Peng et al 2007] (see Note):

• XK, encoding the Kx blood group (telomeric) associated with McLeod neuroacanthocytosis syndrome (deletion of XK). This is a multisystem disorder with central nervous system (CNS), neuromuscular, and hematologic manifestations in males. CNS manifestations are a neurodegenerative basal ganglia disease including (1) movement disorder, (2) cognitive impairment, and (3) psychiatric symptoms. Neuromuscular manifestations include a (mostly subclinical) sensorimotor axonopathy and clinically relevant muscle weakness or atrophy. The hematologic manifestations are red blood cell acanthocytosis, compensated hemolysis, and the McLeod blood group phenotype resulting from absent expression of the Kx erythrocyte antigen and reduced expression of the Kell blood group antigens. The Kell blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in newborns of Kell-negative mothers. Heterozygous females have mosaicism for the Kell system blood group antigens and RBC acanthocytosis but lack CNS and neuromuscular manifestations.
• RPGR, encoding retinitis pigmentosa GTPase regulator (telomeric) associated with RPGR-related retinitis pigmentosa
• DMD, encoding the protein dystrophin (telomeric) associated with Duchenne muscular dystrophy
• OTC, encoding ornithine transcarbamylase (centromeric) associated with ornithine transcarbamylase deficiency (OTC) leading to urea cycle defects
• Note: Concurrent deletion of XK with CYBB is the most common; deletion of all five genes is exceedingly rare.

Therefore:

• Patients with suspected X-CGD and clinical manifestations of McLeod syndrome, retinitis pigmentosa, Duchenne muscular dystrophy, and/or ornithine transcarbamylase deficiency should have a chromosome microarray analysis (CMA).
• If a large deletion is found within CYBB, a CMA may be indicated.

Bacterial Infections

Widespread prophylaxis has limited staphylococcal infections primarily to the skin, lymph nodes, liver, and (rarely) lung [Marciano et al 2015].

Burkholderia cepacia complex infection is common in patients with CGD and can occasionally cause sepsis.

Outside of CGD, Nocardia infections occur predominantly in the setting of high-dose corticosteroids.

Mycobacterial diseases in CGD are mostly limited to regional and disseminated BCG infections and tuberculosis. Persons with CGD are less susceptible to nontuberculous infections than persons with defects in T cell or interferon gamma/IL-12 pathways: in persons with CGD, BCG infection may cause severe localized disease such as draining skin lesions at sites of BCG vaccination [Lee et al 2008], whereas in persons with severe combined immunodeficiency or defects in the IFN-gamma receptor pathway, BCG infection typically causes disseminated disease.

Uncommon bacterial infections that are virtually pathognomonic for CGD include:

• Granulibacter bethesdensis, which causes necrotizing lymphadenitis, sepsis, and meningitis [Greenberg et al 2006];
• Chromobacterium violaceum, which is found in brackish waters such as the Gulf of Mexico and causes sepsis [Sirinavin et al 2005];
• Francisella philomiragia, which is also found in brackish waters such as the Chesapeake Bay and is a cause of sepsis [Mailman & Schmidt 2005].

Bacteremia is relatively uncommon except with certain gram-negative organisms.

Fungal Infections

Invasive fungal infections, which have the highest prevalence in CGD among all primary immunodeficiencies, remain the leading cause of mortality in CGD. They occur most commonly in the first two decades of life and can be a first presentation of disease [Marciano et al 2015]; about 30% of individuals with CGD will develop fungal infections [Beauté et al 2011, Marciano et al 2015].

Fungal infections are typically acquired through inhalation of spores or hyphae resulting in pneumonia that can spread locally to the ribs and spine or metastatically to the brain. Presentation may be insidious with symptoms that are absent or manifest as failure to thrive and malaise. Other common presenting signs and symptoms include cough, fever, and chest pain.

Aspergillus species are the most common cause of invasive fungal infections, typically in the lung.

• Aspergillus fumigatus is the most common of the Aspergillus species to cause infection in CGD. Although angioinvasion is common in neutropenic settings, it does not occur in CGD.
• Aspergillus nidulans infection is almost exclusive to CGD and causes more severe and refractory disease with local and distant spread [Segal et al 1998, Beauté et al 2011].

Paecilomyces lilacinus and Paecilomyces variotti cause pneumonia and osteomyelitis in CGD almost exclusively.

Mucormycosis has been reported in CGD but appears to occur only in the setting of significant immunosuppression [Vinh et al 2009].

The overall frequency and mortality of invasive fungal infections have been significantly reduced with the use of itraconazole as antifungal prophylaxis and the use of other azoles (voriconazole and posaconazole) as therapy. However, when they occur, fungal infections develop at an older age and may require longer duration of therapy. Fungal infections cause more mortality than other infections in CGD [Marciano et al 2015]. An increased frequency of infection with Aspergillus nidulans and other opportunistic fungi may be associated with itraconazole prophylaxis [Blumental et al 2011].

Yeast infections are not nearly as common as bacterial and fungal infections in persons with CGD; mucocutaneous candidiasis is not encountered.

Note: The endemic dimorphic mold infections histoplasmosis, blastomycosis, and coccidioidomycosis do not occur in CGD [Holland 2010].

Inflammatory and Other Manifestations

Formation of granulomata and dysregulated inflammation in CGD contribute to morbidity and can cause multiple symptoms. The genitourinary and gastrointestinal tracts are most commonly affected.

• Genitourinary manifestations include bladder granulomata that are associated with ureteral obstruction and urinary tract infections. Other manifestations include pseudotumors of the bladder and eosinophilic cystitis.
• Gastrointestinal manifestations
  • Pyloric edema leads to functional gastric outlet obstruction and can be an initial presentation of CGD.
  • Esophageal, jejunal, ileal, cecal, rectal, and perirectal granulomata similar to those in Crohn disease have also been described. Symptomatic inflammatory bowel disease affects up to 50% of affected individuals and can be the presenting finding [Marciano et al 2004].
  • Other gastrointestinal symptoms indicative of CGD colitis include abdominal pain, diarrhea, strictures, and fistulae. Significant colitis leading to bowel obstruction, fistulae, and strictures can be an important cause of growth retardation [Marciano et al 2004].

Liver involvement is a significant cause of morbidity in CGD, with abscesses occurring in up to 35% of affected individuals. Liver abscesses have been difficult to cure without surgery and carry a significant risk for recurrence, but not relapse [Hussain et al 2007].

Other common liver abnormalities include liver enzyme elevation, persistent elevations in alkaline phosphatase, and drug-induced hepatitis.

High rates of portal venopathy are associated with splenomegaly and nodular regenerative hyperplasia. Portal hypertension and thrombocytopenia are associated with intrahepatic disease and important risk factors for mortality [Hussain et al 2007, Feld et al 2008].

Hyperinflammation is seen, especially in response to infectious agents. The exact etiology of dysregulated inflammation in CGD is unclear. Heightened inflammatory response has been described in chronic colitis [Marciano et al 2004], granulomatous cystitis [Kontras et al 1971], pulmonary infections with Nocardia [Freeman et al 2011], and staphylococcal liver abscesses [Yamazaki-Nakashimada et al 2006, Leiding et al 2012].

Fungi elicit an exuberant inflammatory response regardless of whether the fungi are alive or dead [Morgenstern et al 1997] as in "mulch pneumonitis," a syndrome caused by inhalation of aerosolized decayed organic matter (e.g., hay, dead leaves) [Siddiqui et al 2007]. Acute fulminant pneumonitis (similar to that seen in hypersensitivity pneumonitis) ensues.

Prolonged and dysregulated inflammation in CGD can overlap clinically with the syndrome of hemophagocytic lymphohistiocytosis (HLH). HLH is caused by an ineffective and unrestrained inflammatory response by T lymphocytes, NK cells, and macrophages leading to fever, hepatosplenomegaly, cytopenias, and hemophagocytosis in the bone marrow and other tissues. Persons with CGD can develop prolonged fever and most of the clinical features of HLH.

Growth retardation is common in CGD and failure to thrive can be a common presenting finding [Marciano et al 2004]. Growth failure can be compounded by colitis. Growth may improve in late adolescence and many affected individuals may attain appropriate adult height and weight, albeit on the lower end of the spectrum.

Chronic respiratory disease can result from recurrent infection. Bronchiectasis, obliterative bronchiolitis, and chronic fibrosis may occur but are not as common as in some other primary immunodeficiencies.

Ophthalmic manifestations include chorioretinal lesions and granulomata with pigment clumping that are usually asymptomatic but often associated with recovery of bacterial DNA from retinal tissue samples [Wang et al 2013]. Inflammatory eye disease including keratitis and uveitis can occur as well.

Oral manifestations include gingivitis, stomatitis, aphthous ulceration, and gingival hypertrophy.

Noninfectious skin manifestations include photosensitivity, granulomatous lesions, vasculitis, and excessive inflammation at drainage and surgical wounds leading to dehiscence.

Autoimmune disorders are common. Autoimmune diseases reported in individuals with CGD include idiopathic thrombocytopenic purpura, juvenile idiopathic arthritis, autoimmune pulmonary disease, myasthenia gravis, IgA nephropathy, antiphospholipid syndrome, and recurrent pericardial effusion [Winkelstein et al 2000, De Ravin et al 2008].

Malignancies have been reported in CGD, and may be more common in autosomal recessive CGD than in X-linked CGD, raising the possibility that the increased incidence of malignancy is due to other cosegregating autosomal recessive traits [Aguilera et al 2009, Geramizadeh et al 2010, Lugo Reyes et al 2011].

The histopathologic patterns of malignancy have significant overlap with certain chronic inflammatory conditions. However, the largest series to date reported no malignancies [Winkelstein et al 2000, van den Berg et al 2009]. Smaller, more recent series corroborate a low overall incidence of malignancy [Köker et al 2013, Raptaki et al 2013, Baba et al 2014, Al-Zadjali et al 2015].

Survival in CGD has improved greatly, and is now approximately 90% at age ten years [Jones et al 2008, Martire et al 2008, Kuhns et al 2010, Marciano et al 2015]. Overall rates of survival are lower among those with X-linked CGD than those with autosomal recessive CGD.

Survival is influenced by several factors:

• Residual superoxide production, which correlates most directly with overall survival [Kuhns et al 2010] (see Genotype-Phenotype Correlations):
  • Persons with NCF1 pathogenic variants have relatively good overall survival (>80% beyond age 40 years), which is similar to the survival rate in persons with CYBB pathogenic missense variants associated with residual superoxide production.
  • Persons with CYBB pathogenic variants that result in no superoxide production have a survival of approximately 55% beyond age 40 years.
• Use of azoles for antifungal prophylaxis and therapy. Several series [Jones et al 2008, Kobayashi et al 2008, Martire et al 2008, Marciano et al 2015] report increased survival rates over the past 20 years:
  • 88%-97% at age 10 years
  • 73%-87% at age 20 years
  • 46%-55% at age 30 years
    Note: Patients diagnosed and treated before the use of azoles usually did not survive past age 30-40 years.
• Access to care and expertise of caregivers
• Post-infectious complications such as hepatic nodular regenerative hyperplasia and portal venopathy associated with liver abscess, which contribute to overall morbidity and mortality [Marciano et al 2004, Hussain et al 2007, Feld et al 2008]

Note: Inflammatory bowel disease does not influence mortality: overall survival rates of persons with CGD with and without colitis are similar [Marciano et al 2004, Kuhns et al 2010, Marciano et al 2015].

Hypomorphic (variant) CGD is characterized by partial protein expression/function and residual superoxide production (observed in autosomal recessive CGD and protein-positive X-linked CGD). Affected individuals typically have a milder course and come to clinical attention later in life than those with absent protein expression [Bender et al 2009].

Carriers of X-Linked CGD

Female carriers of a CYBB pathogenic variant are typically unaffected, as the amount of gp91^phox produced by their normal CYBB allele allows adequate superoxide production. However, some women are affected because they express primarily the CYBB disease-causing allele as the result of skewed (non-random) X-chromosome inactivation. These women may develop clinical evidence of CGD [Johnston 1985, Anderson-Cohen et al 2003]:

• The most common findings are cutaneous lesions resembling discoid lupus and recurrent aphthous stomatitis [Hafner et al 1992].
• In a prospective study of 19 women known to carry a CYBB pathogenic