Download Chronic granulomatous disease: Pathogenesis, clinical

Chronic granulomatous disease: Pathogenesis, clinical
manifestations, and diagnosis
Authors
Sergio D Rosenzweig, MD
Steven M Holland, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Elizabeth TePas, MD, MS
Disclosures
Last literature review version 19.2: mayo 2011 | This topic last updated:
junio 15, 2011 (More)
INTRODUCTION — Chronic granulomatous disease (CGD) is a genetically
heterogeneous condition characterized by recurrent life-threatening bacterial and
fungal infections and granuloma formation. CGD is caused by defects in the
phagocyte NADPH oxidase (phox). These genetic defects result in the inability of
phagocytes (neutrophils, monocytes, and macrophages) to destroy certain
microbes. The diagnosis is made by neutrophil function testing and then the exact
defect is determined by genotyping.
Infections are generally caused by catalase-positive microorganisms (most bacterial
and all fungal pathogens are catalase-positive). The frequent sites of infection are
lung, skin, lymph nodes, and liver. The formation of granulomata is especially
problematic in the gastrointestinal and genitourinary tracts. Other inflammatory
manifestations are seen as well.
This topic will review the pathogenesis, clinical manifestations, and diagnosis of
CGD. The treatment and prognosis of CGD, as well as an overview of primary
disorders of phagocyte function, are discussed separately. (See "Chronic
granulomatous disease: Treatment and prognosis" and "Primary disorders of
phagocytic function: An overview".)
PATHOGENESIS — Phagocytes utilize NADPH oxidase to generate reactive species
of oxygen. CGD arises from mutations that result in the loss or functional
inactivation of one of the subunits of the NADPH oxidase complex.
The fully assembled NADPH oxidase is a five-protein complex. In the basal state, it
exists as two components [1]:

The membrane-bound heterodimer, called cytochrome b-245 or cytochrome
b588, that is composed of gp91phox and p22phox and is embedded in the
walls of secondary granules

Proteins in the cytosol (p47phox, p67phox, and p40phox)
All of these proteins are necessary for the proper generation of superoxide.
Activation and assembly of the functional oxidase also requires the participation of
Rac2, a small GTP-binding protein, and Rap1, a small GTPase.
Activation of NADPH oxidase — The cytosolic components p47phox and p67phox
are phosphorylated and bind tightly together after cellular activation is initiated by
phagocytosis of microbes. In association with p40phox and Rac2, these proteins
combine with the cytochrome complex (gp91phox and p22phox) to form the intact
NADPH oxidase. An electron is then taken from NADPH and donated to molecular
oxygen, leading to the formation of superoxide. This is converted to hydrogen
peroxide by superoxide dismutase. In the final step, hydrogen peroxide is
converted to hypochlorous acid, or bleach, in the presence of myeloperoxidase and
chlorine in the neutrophil phagosome (figure 1) [1].
Respiratory burst — The rapid consumption of oxygen and production of
superoxide and its metabolites is referred to as the respiratory burst. Phagocyte
production of reactive oxygen species leads to the activation of granule proteases,
including elastase and cathepsin G. These proteases are responsible for the
destruction of ingested (phagocytosed) microorganisms. Thus, superoxide acts as
an intracellular activating molecule and not as a direct microbicidal molecule, as
was previously thought [2].
Genetic defects — Mutations in all five genes (gp91phox, p47phox, p22phox,
p67phox, and p40phox) that make up the NADPH oxidase complex account for all
of the known cases of CGD. There are one X-linked and four autosomal recessive
forms of CGD.

The gene for gp91phox is encoded by CYBB, located at Xp21.1. Defects in
this gene cause X-linked CGD (MIM 306400), which account for about 65 to
70 percent of cases.

The second membrane component, p22phox, is encoded by CYBA, located
at chromosome 16q24. Defects in this gene cause an autosomal recessive
CGD (MIM 233690), which account for less than 5 percent of cases [3].

The cytosolic factor p47phox is encoded by NCF1, located at 7q11.23 (MIM
233700). Defects in this gene account for about 25 percent of cases.

The cytosolic factor, p67phox, is encoded by NCF2, located at chromosome
1q25 (MIM 233710). Defects in NCF2 account for less than 5 percent of
cases [4-8].

The cytosolic factor, p40phox, is encoded by NCF4, located at 22a13.1 (MIM
601488). Defects in NCF4 have been described causing severe inflammatory
bowel disease in a single child with mildly impaired respiratory burst activity
[9].
Neutrophil immunodeficiency syndrome, a syndrome similar to CGD, is caused by a
mutation in the RAC2 gene. Two patients with dominant negative mutations in
RAC2 have been identified, the first presented with severe bacterial infections and
poor wound healing. This patient's neutrophils exhibited decreased superoxide
production, as well as impaired chemotaxis and adhesion [10]. The second case
was identified by newborn screening and transplanted before disease
manifestations were seen [11].
The large majority of the identified mutations in the phagocyte oxidase (phox)
proteins result in complete or nearly complete absence of the protein. A normal
amount of a nonfunctioning or hypofunctioning protein results from the other
mutations. The superscripts +, -, and 0 are used to indicate normal, decreased, or
absent protein levels, respectively [1].
A macrophage-specific defect in gp91phox appears to predispose more to
mycobacterial disease than the other infections typically seen in CGD [12] (see
"Mendelian susceptibility to mycobacterial diseases (MSMD)").
Innate immune receptors — Patients with CGD, compared to the general
population of patients with bacterial pneumonia, express lower levels of several
neutrophil receptors, including Toll-like receptors (TLR5 and TLR9), complement
receptors (CD11b, CD18, and CD35), and a chemokine receptor (CXCR1). In
contrast, patients with pneumonia who do not have CGD generally have higher than
normal expression levels of these proteins. Decreased expression results in
impaired neutrophil activation (TLR5), phagocytosis (CD11b/CD18), and
chemotaxis (CXCR1). Levels of expression of TLR5 and CD18 may correlate with
CGD disease severity [13].
Enhanced inflammation — Several different mechanisms may be involved in the
enhanced inflammation seen in patients with CGD.
Tryptophan catabolism — A hyperinflammatory phenotype is associated with
dysfunction of a superoxide-dependent step in tryptophan catabolism along the
kynurenine pathway in a mouse model of CGD [14]. However, this abnormality is
not present in human CGD patients [15].
Inflammatory mediators — Defective production of reactive oxygen species leads
to increased expression of NF-kappaB-regulated inflammatory genes [16]. Higher
levels of inflammatory mediators are expressed in monocytes from patients with Xlinked CGD without acute infection compared with controls. A similar increase in
transcription of anti-inflammatory mediators is not seen.
Efferocytosis — Efferocytosis is the process by which apoptotic inflammatory cells
are recognized and removed by phagocytes. In a mouse model of CGD,
efferocytosis by macrophages is suppressed [17].
EPIDEMIOLOGY — The frequency of CGD in the United States is approximately
1:200,000 live births [4]. The disease primarily affects males, as most mutations
are X-linked. Rates are almost identical across ethnic and racial groups, with about
one-third of the X-linked mutations occurring de novo. However, the autosomal
recessive forms of CGD are more common and overall incidence rates may be
higher in cultures in which consanguineous marriage is common [18].
CGD may present at any time from infancy to late adulthood, but the majority of
patients are diagnosed as toddlers and children before the age of five. In several
series, the median age at diagnosis was 2.5 to 3 years of age [19-22]. More
recently, a growing number of patients are diagnosed in later childhood or
adulthood. This is due in part to recognition of milder cases of autosomal recessive
CGD, as well as delayed diagnosis in some patients. Diagnosis may be delayed
because of potent antimicrobials that inadvertently treat many CGD-associated
infections, postponing diagnosis until more severe infections indicate CGD as the
underlying cause. X-linked CGD tends to have an earlier onset and be more severe
than p47phox deficiency [4].
CLINICAL PRESENTATION — Patients with CGD may present with growth failure,
abnormal wound healing, diarrhea, or infected dermatitis. They may have
hepatomegaly, splenomegaly, or lymphadenitis on physical examination. A history
of recurrent or unusually severe infections, particularly those caused by pathogens
commonly associated with CGD, should prompt testing for this disorder. (See
'Infections' below.)
X-linked carriers — The X-linked carrier state for gp91phox is not entirely silent.
In affected women, lyonization (ie, the inactivation of one or the other X
chromosome in every cell) leads to two populations of phagocytes: one with normal
respiratory burst function, the other with impaired respiratory burst activity [23].
Therefore, X-linked CGD carriers display a characteristic mosaic pattern on
respiratory burst testing of individual peripheral blood cells microscopically or by
flow cytometry.
As few as 10 percent of cells having normal respiratory burst activity is sufficient to
prevent most severe bacterial and fungal infections. Thus, most female carriers of
X-linked gp91phox CGD mutations are not compromised in their ability to handle
infectious challenges. However, carriers with less than 10 percent of normal oxidase
activity due to skewed X-chromosome lyonization may present with the phenotype
of mild to severe CGD [24-27]. Females may have other manifestations of
heterozygous carriage of X-linked CGD mutations, including discoid lupus
erythematosus, aphthous ulcers, and photosensitivity [28,29].
INFECTIONS — Patients with CGD typically experience recurrent infections caused
by bacterial and fungal pathogens. However, CGD patients may exhibit few clinical
signs and symptoms, despite the presence of significant infection. Response to viral
infections is normal in patients with CGD.
Bacterial infections in CGD tend to be symptomatic and are associated with fever
and mildly elevated leukocyte counts [30]. In contrast, fungal infections are
associated with less fever and lower leukocytosis and are therefore more difficult to
diagnose. Fungal infections are often detected either at asymptomatic stages on
routine screening for infections [31] or at an advanced stage. As an example,
patients with fungal osteomyelitis may not be diagnosed until later stages of
disease, when they have multiorgan involvement [32].
Sites of infection — The most common sites of infection are lung, skin, lymph
nodes, and liver [33].
The types of infections most often seen (in descending order of frequency) include:

Pneumonia

Abscesses (skin, tissue, organs)

Suppurative adenitis

Osteomyelitis

Bacteremia/fungemia

Superficial skin infections (cellulitis/impetigo)
Pneumonia is the most common pulmonary infection, but patients may also have
lung abscesses, empyema, and hilar lymphadenopathy. In contrast to what occurs
in neutropenic patients, fungal pneumonias do not generally cavitate in CGD,
whereas Nocardia infections do.
The most common sites for abscesses are perianal/perirectal and the liver.
Gingivitis, stomatitis, gastroenteritis, and otitis are also common [1,4,19-22].
Organisms — In general, the organisms that infect patients with CGD are
catalase-producing and include Staphylococcus aureus and Aspergillus species.
Catalase is an enzyme that inactivates the hydrogen peroxide normally produced by
some bacteria and fungi during growth. Although most microorganisms produce
hydrogen peroxide, some do not. It was thought that host phagocytes could use the
hydrogen peroxide produced by catalase-negative microbes to generate reactive
oxidants. However, the majority of pathogens are catalase-positive, and only a few
cause infections in CGD, suggesting that catalase production alone is insufficient for
pathogenicity. Furthermore, targeted deletion of the catalase gene in Aspergillus
nidulans and Staphylococcus aureus did not affect virulence in animal models of
CGD, indicating that microbial catalase is not a significant virulence factor for CGD
infections.
The overwhelming majority of infections in North America are due to five
organisms:

Staphylococcus aureus

Burkholderia (Pseudomonas) cepacia

Serratia marcescens

Nocardia

Aspergillus
Outside of North America, Salmonella and BCG are frequent infections and should
suggest the diagnosis. Other organisms isolated less frequently include
Streptococcus species, Neisseria meningitidis, Acinetobacter junii, Candida species,
Klebsiella pneumoniae, Mycobacterium tuberculosis, nontuberculous mycobacteria,
Proteus species, and Leishmania species [19,21,22].
Bacterial infections — The frequency of bacterial infections in CGD has decreased
since trimethoprim-sulfamethoxazole prophylaxis became routine in the 1980s.
Most lung, skin, and bone infections were staphylococcal in the preprophylaxis era.
On prophylaxis staphylococcal infections are essentially confined to the liver, lymph
nodes, and skin [4]. Severe, resistant facial acne and painful inflammation of the
nares are common infectious skin manifestations of S. aureus infection.
Burkholderia cepacia complex, which is a common cause of pneumonia with
primarily endobronchial disease in patients with cystic fibrosis (CF), can cause
pneumonia with nodular infiltrates in patients with CGD [34-36]. Patients with CGD
are prone to recurrent pulmonary infection with different strains of Burkholderia,
unlike patients with CF who tend to have chronic infection with the same strain
[36].
Infants often present with Serratia marcescens bone and soft tissue infections [32].
S. marcescens infections still occur in older children and adults with CGD, but the
pattern of presentation is different [37]. Osteomyelitis is rare, but disseminated
abscesses and skin infections with large, poorly healing ulcers are common.
Mycobacterial infections accounted for almost 6 percent of pneumonias in American
CGD surveys in 2000 and 2007 [4,38]. A high incidence of tuberculosis was
observed in CGD patients living in areas endemic for TB [39,40]. Draining skin
lesions at sites of BCG vaccination are seen in CGD patients, although these
infections rarely disseminate. However, dissemination of BCG may be straindependent, since numerous cases of disseminated BCG have been reported in
particular countries where different strains are found [41].
Granulibacter bethesdensis is an environmental organism that can cause fever,
weight loss, and necrotizing pyogranulomatous lymphadenitis [42,43]. Fatal
bacteremia has been reported as well [44].
Bacteremia is uncommon, but when it occurs, is usually due to the following
organisms:

Burkholderia cepacia complex [35,45-47]

S. marcescens, which is also a common cause of bacterial osteomyelitis [32]

Chromobacterium violaceum, a gram negative rod found in brackish water,
especially in the southeastern United States [48]
Infection with catalase-negative organisms is uncommon, but severe chronic
recurrent Actinomycosis has been reported [49]. All patients in one series
presented with a prolonged history of fever and clinical signs of infection without an
obvious focus. Sites of infection were cervicofacial, hepatic, and/or pulmonary.
Fungal infections — Fungal infections were previously the leading causes of
mortality in CGD [4], even though the rate of fungal infections is lower than
bacterial infections. Fungal infections typically begin in the lung after inhalation of
spores or hyphae. The resulting pneumonia may spread locally to ribs and spine or
metastatically to brain. The frequency and mortality of fungal infections have been
markedly reduced since the advent of itraconazole prophylaxis and the use of
voriconazole and posaconazole for treatment of filamentous fungal infections (eg,
Aspergillus).
Bony involvement by fungi typically occurs by direct extension from the lung.
Aspergillus nidulans, an organism that infects CGD patients almost exclusively,
causes a significantly higher rate of osteomyelitis and mortality than other fungi
[31,50]. Penicillium piceum is a relatively non-pathogenic fungus that can produce
lung nodules and osteomyelitis in CGD [51]. In contrast, infections with
Zygomycosis are rare in patients with CGD and are typically associated with
iatrogenic immune suppression [52].
INFLAMMATORY AND OTHER MANIFESTATIONS — Patients with CGD are also
prone to granulomata of various organs, growth retardation, chronic pulmonary
disease, and autoimmune disorders. In contrast to many other immunodeficiencies,
CGD is probably not associated with an increased incidence of neoplasia, although
several cancers have been identified in patients with CGD [53].
Granulomata — Patients with CGD are prone to the formation of granulomata.
These can affect any hollow viscus, but are especially problematic in the
gastrointestinal and genitourinary tracts [33]. Other tissues and organs, such as
the retina, liver, lungs, and bone, may also be affected by granulomata [54]. The
reasons for granuloma formation in CGD are unknown. CGD cells fail to degrade
chemotactic and inflammatory signals normally and this may lead to persistent and
exuberant inflammation.
Gastrointestinal — Gastrointestinal (GI) manifestations of CGD include abdominal
pain, diarrhea, colitis, proctitis, strictures, fistulae, and obstruction. In a series of
140 CGD patients, 43 percent of X-linked and 11 percent of autosomal recessive
CGD patients had GI manifestations [55]. All patients with confirmed inflammatory
bowel disease complained of abdominal pain. Diarrhea was reported in 39 percent
and nausea and vomiting in 24 percent. Thirty-five percent had GI obstruction
(gastric, esophageal, duodenal, and other).
Sixty-five percent of the patients in this series with GI involvement had either
granulomatous or ulcerative colonic lesions [55]. Crohn's disease and ulcerative
colitis were diagnosed in only 20 percent of those with inflammatory bowel lesions.
The granulomata in CGD IBD were characterized by sharply defined histiocyte
aggregates with surrounding lymphocytic inflammation, unlike the poorly formed
granulomata seen in Crohn's disease.
Hepatic — Liver abnormalities were frequently identified in a CGD cohort of 194
patients: liver enzymes were elevated in 73 percent, 25 percent had persistent
elevations of alkaline phosphatase, and drug-induced hepatitis was reported in 15
percent [56]. In patients with abnormal liver enzymes who underwent liver biopsy,
histology revealed granulomata in 75 percent and lobular hepatitis in 90 percent.
Eighty percent of patients in the series above had a portal venopathy that was
often associated with splenomegaly [56]. Liver abscesses and hepatomegaly were
each seen in one-third of cases. Portal hypertension was an important risk factor
for mortality and was strongly suggested by a decreasing platelet count over time
[57].
Genitourinary — In a series of 60 CGD patients, approximately 40 percent of
patients had urologic manifestations, including ureteral and urethral strictures,
urinary tract infections, altered renal function, and bladder granulomata [58]. All
patients with urologic strictures had defects of the membrane component of the
NADPH oxidase (gp91phox or p22phox).
Ophthalmic — Chorioretinal lesions are described in up to one quarter of X-linked
CGD patients [59]. These lesions are mostly asymptomatic retinal scars associated
with pigment clumping. These same lesions can be detected in gp91phox female
carriers. Keratitis has also been reported [19].
Pulmonary — Chronic respiratory disease due to recurrent pulmonary infections is
common. Findings on chest CT include bronchiectasis, obliterative bronchiolitis, and
chronic fibrosis [19,33]. A clinical entity specific to CGD is mulch pneumonitis, so-
called because patients with CGD can develop a characteristic syndrome of
dyspnea, hypoxia, and fever leading to respiratory failure and death after inhalation
of large burdens of fungal spores and hyphae, such as those found in mulch, hay,
peat moss, or dirt [60]. This syndrome is important to recognize since it is best
treated with simultaneous administration of glucocorticoids and antifungals.
Oral disease — Oral manifestations of CGD include gingivitis, stomatitis, aphthous
ulcerations, and gingival hypertrophy [19].
Skin — Non-infectious skin manifestations of CGD include photosensitivity,
granulomatous lesions, and vasculitis [19].
Autoimmune disease — Autoimmune disorders are more common in CGD. Both
discoid and systemic lupus erythematosus have been described, and occur with at
least the same frequency in X-linked CGD female carriers [61,62]. Idiopathic
thrombocytopenic purpura and juvenile idiopathic arthritis are also more frequent in
CGD than in the general population [4]. Other reported autoimmune diseases in
patients with CGD include autoimmune pulmonary disease, IgA nephropathy,
antiphospholipid syndrome, and recurrent pericardial effusion [63].
Growth retardation — Patients with CGD commonly experience growth
retardation. Failure to thrive is a frequent presenting symptom in young children. In
one series of 94 patients, approximately 75 percent were below the population
mean for height and weight at the time of diagnosis [19]. Thirty-five percent
required nasogastric and/or parenteral nutritional supplementation. In another
small series of 23 patients, approximately 20 percent were below the 10th
percentile for height and weight [20]. Growth often improves in late adolescence
[64]; many CGD patients attain their expected growth potential by adulthood.
McLeod syndrome — The gene coding for the Kell blood cell antigen system (XK)
maps to Xp21, immediately adjacent to CYBB, the gene for gp91phox. Patients with
deletions in the X-chromosome may delete portions of both genes (contiguous gene
disorder) and thereby present with X-linked CGD and McLeod syndrome. McLeod
syndrome causes acanthocytosis and low or absent expression of the erythrocyte
blood group Kell antigens, eg, Kell(-). This may result in anemia, elevated
creatine phosphokinase, and late-onset peripheral and central nervous system
manifestations. (See "A primer of red blood cell antigens and antibodies", section
on 'McLeod phenotype' and "Spiculated cells (echinocytes and acanthocytes) and
target cells", section on 'Blood group abnormalities'.)
Special care has to be taken when transfusing X-linked CGD patients to avoid
Kell(+) transfusions into these Kell(-) patients [65,66]. All X-linked CGD patients
should be tested for Kell antigens. Those who test negative should have this noted
on their medical record and wear medical identification jewelry stating that they
must be given Kell(-) blood if they require a transfusion.
DIAGNOSIS — Patients suspected of having CGD should initially undergo
neutrophil function testing. Positive findings should be confirmed by additional
testing, such as immunoblot, followed by genotyping.
A history of recurrent and/or unusually severe infections, particularly abscesses and
infections caused by the pathogens commonly associated with CGD, should prompt
neutrophil function testing. Neonatal or early postnatal screening of potentially
affected children is indicated if there is a family history of CGD. (See
'Infections' above.)
Typical presenting clinical features include splenomegaly, hepatomegaly, growth
retardation, diarrhea, and abnormal wound healing with dehiscence, but these are
neither necessary nor sufficient for the diagnosis.
Certain abnormalities in routine laboratory tests are associated with the disease,
although these are not required for diagnosis:

Hypergammaglobulinemia, possibly due to chronic inflammation

Anemia of chronic disease

Elevated erythrocyte sedimentation rate and C reactive protein, usually in
the presence of infection

Hypoalbuminemia, found in 70 percent of patients with GI involvement and
25 percent without GI manifestations [55]
Neutrophil function tests — Diagnostic tests for CGD rely on various measures of
neutrophil superoxide production. These include direct measurement of superoxide
production, cytochrome c reduction assay, chemiluminescence, nitroblue
tetrazolium (NBT) reduction test, and dihydrorhodamine 123 (DHR) oxidation test.
We prefer the DHR test because of its objectivity, relative ease of use, ability to
distinguish between X-linked and autosomal forms of CGD, and the ability to detect
gp91phox carriers [67,68]. Other tests can provide reliable diagnosis of CGD, but
either cannot distinguish carrier status or require significant operator experience.
Dihydrorhodamine 123 (DHR) test — In this test, the non-fluorescent
rhodamine derivative, DHR, is taken up by phagocytes and oxidized to a green
fluorescent compound by products of the NADPH oxidase (figure 2). The sensitivity
and quantitative nature of this assay make it possible to differentiate oxidase
positive from oxidase negative phagocyte subpopulations in CGD carriers and
identify deficiencies in gp91phox and p47phox. DHR testing can also be quantitated
to allow for allocation of cellular response into more and less impaired subgroups.
The degree of residual superoxide production as measured by DHR testing provides
important prognostic information that dovetails with genetic information [69]. (See
'Genetic testing' below.)
Other conditions that affect the neutrophil respiratory burst include
myeloperoxidase deficiency and SAPHO (the syndrome of synovitis, acne,
pustulosis, hyperostosis, as osteitis), giving abnormal DHR test results but normal
measures of extracellular superoxide production (eg, cytochrome c reduction or
NBT tests) [70,71]. Several reference laboratories in the United States and around
the world offer these assays.
Nitroblue tetrazolium (NBT) test — The oldest and best-known laboratory test
for CGD is the nitroblue tetrazolium (NBT) test. This provides a simple and rapid
(but largely qualitative) determination of phagocyte NADPH oxidase activity.
Superoxide produced by normal peripheral blood neutrophils stimulated in vitro
reduces yellow NBT to dark blue/black formazan, which forms a precipitate in the
cells. Normal phagocyte oxidase activity will result in at least 95 percent positive
cells in this assay. X-linked carriers can be identified with this test. Test limitations
include a higher rate of false negative results and operator subjectivity.
Confirmatory tests — Techniques such as immunoblot can be used to confirm the
diagnosis of CGD. Failure to detect p47phox or p67phox proteins indicates
autosomal recessive mutations in the corresponding genes. The limitation of this
technique is that it cannot distinguish between the X-linked gp91phox defect and
the p22phox autosomal recessive defect, since expression of these two proteins on
the cell membrane is mutually dependent. If there is a deficiency of either one of
them, the other is also absent in immunoblot analysis [1].
Genetic testing — The clinical history usually suggests autosomal recessive or Xlinked disease, based on sex, consanguinity, age at presentation, and severity. A
diagnosis of CGD based on abnormal neutrophil function should be followed by a
confirmatory test to verify that the patient really does have CGD before genetic
counseling is provided. Sequencing of the patient's phagocyte oxidase (phox) genes
to determine the exact molecular defect is recommended but not necessary.
Genetic testing is available through specialized commercial laboratories and
selected tertiary referral centers (commercial laboratories in the United States
include: GeneDx in Maryland, Correlagen Diagnostics in Massachusetts, and ARUP
Laboratories in Utah; tertiary centers include: NIH in Bethesda, Great Ormand
Street Hospital in London, Necker Hospital in Paris, and Garrahan Hospital in
Buenos Aires).
Genetic testing is increasingly important in the risk profiling of X-linked CGD.
Mutations in the gene encoding gp91phox (CYBB) are usually either missense
(replacement of the correct amino acid with an incorrect one but preserving protein
synthesis) or nonsense (replacement of an amino acid with a stop codon leading to
protein truncation and usually abrogating protein synthesis). Nonsense mutations
generally lead to more severe CGD with diminished survival. Missense mutations
that are in amino acids 1 to 309 are associated with residual superoxide formation,
slight DHR positivity, and better survival. In contrast, mutations at amino acids 310
and beyond affect critical protein functional domains and lead to complete loss of
DHR activity, more severe CGD, and diminished survival [69].
Prenatal diagnosis — If the precise mutation of a family member with CGD is
known, then chorionic villus sampling can be performed to obtain a sample for
genotyping of the fetus. Another testing option is to sample fetal blood and perform
a DHR or NBT test.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of CGD mainly involves
disorders associated with recurrent and/or unusually severe infections, particularly
those caused by the pathogens commonly associated with the disease. (See
'Infections' above.) However, it is usually possible to differentiate between these
diseases and CGD when the entire clinical picture is examined. The differential
diagnosis may consider:

Cystic fibrosis

Hyper IgE syndrome

Glucose 6-phosphate dehydrogenase (G6PD) deficiency

Glutathione synthetase (GS) deficiency

Crohn's disease (in patients with inflammation limited to the rectum)
Cystic fibrosis patients may develop Burkholderia cepacia complex infections.
However, the infections in patients with cystic fibrosis are limited to the lung and
typically occur in the setting of significant bronchiectasis, which is not as common
in patients with CGD. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)
Hyper IgE syndrome patients develop staphylococcal infections and may develop
Aspergillus in the lung. However, the Aspergillus infections occur only in the setting
of preexisting lung cysts, which are not common in patients with CGD. Also, hyper
IgE patients have characteristic facies and markedly elevated IgE levels, whereas
CGD patients do not. (See "Hyperimmunoglobulin E syndrome".)
G6PD deficiency and GS deficiency affect the neutrophil respiratory burst and
increase susceptibility to bacterial infections [72-74]. G6PD deficiency is most often
associated with some degree of hemolytic anemia, whereas CGD is not. Severe GS
deficiency is also associated with hemolytic anemia, in addition to 5-oxoprolinuria,
acidosis, and mental retardation. These disorders are reviewed separately. (See
"Myeloperoxidase deficiency and other enzymatic WBC defects causing
immunodeficiency".)
In vitro the respiratory burst may also be inhibited by diverse pathogens, including
Legionella pneumophila, Toxoplasma gondii, Chlamydia, Entamoeba histolytica, and
Ehrlichia risticii. Human granulocytic ehrlichiosis infection depresses the respiratory
burst by downregulating gp91phox [75]. This effect is not diagnostically significant.
SUMMARY AND RECOMMENDATIONS

Chronic granulomatous disease (CGD) is a genetically heterogeneous
condition characterized by recurrent life-threatening bacterial and fungal
infections and granuloma formation. Most patients are diagnosed before the
age of five. (See 'Introduction' above.)

CGD is caused by defects in phagocyte NADPH oxidase (phox), the enzyme
complex responsible for the phagocyte respiratory burst. (See
'Pathogenesis' above.)

Mutations in all five genes (gp91phox, p47phox, p22phox, p67phox, and
p40phox) that make up the NADPH oxidase complex account for all of the
known cases of CGD. Most mutations are X-linked (gp91phox). (See 'Genetic
defects' above.)

Female carriers generally do not have an increased rate of infections, but
they are more predisposed to certain inflammatory manifestations
associated with CGD. However, highly lyonized females can develop typical
CGD infections. (See 'X-linked carriers' above.)

Patients with CGD typically experience recurrent infections caused by
bacterial and fungal pathogens. The frequent sites of infection are lung,
skin, lymph nodes, and liver. (See 'Infections' above.)

The overwhelming majority of infections in patients with CGD living in North
America are due to five organisms: Staphylococcus aureus, Burkholderia
(Pseudomonas) cepacia complex, Serratia marcescens, Nocardia, and
Aspergillus. (See 'Organisms' above.)

Patients with CGD are prone to the formation of granulomata that are
especially problematic in the gastrointestinal and genitourinary tracts. Colitis
is a common gastrointestinal manifestation. (See 'Inflammatory and other
manifestations' above.)

A neutrophil function test is the initial diagnostic test performed. A positive
finding should be confirmed by additional testing, such as immunoblot or
genotyping. (See 'Diagnosis' above.)
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REFERENCES
1.
Segal BH, Leto TL, Gallin JI, et al. Genetic, biochemical, and clinical features
of chronic granulomatous disease. Medicine (Baltimore) 2000; 79:170.
2.
Reeves EP, Lu H, Jacobs HL, et al. Killing activity of neutrophils is mediated
through activation of proteases by K+ flux. Nature 2002; 416:291.
3.
Teimourian S, Zomorodian E, Badalzadeh M, et al. Characterization of six
novel mutations in CYBA: the gene causing autosomal recessive chronic
granulomatous disease. Br J Haematol 2008; 141:848.
4.
Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous
disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000;
79:155.
5.
Roos D. X-CGDbase: a database of X-CGD-causing mutations. Immunol
Today 1996; 17:517.
6.
Roos D, de Boer M, Kuribayashi F, et al. Mutations in the X-linked and
autosomal recessive forms of chronic granulomatous disease. Blood 1996; 87:1663.
7.
Rae J, Newburger PE, Dinauer MC, et al. X-Linked chronic granulomatous
disease: mutations in the CYBB gene encoding the gp91-phox component of
respiratory-burst oxidase. Am J Hum Genet 1998; 62:1320.
8.
Ariga T, Furuta H, Cho K, Sakiyama Y. Genetic analysis of 13 families with
X-linked chronic granulomatous disease reveals a low proportion of sporadic
patients and a high proportion of sporadic carriers. Pediatr Res 1998; 44:85.
9.
Matute JD, Arias AA, Wright NA, et al. A new genetic subgroup of chronic
granulomatous disease with autosomal recessive mutations in p40 phox and
selective defects in neutrophil NADPH oxidase activity. Blood 2009; 114:3309.
10.
Kurkchubasche AG, Panepinto JA, Tracy TF Jr, et al. Clinical features of a
human Rac2 mutation: a complex neutrophil dysfunction disease. J Pediatr 2001;
139:141.
11.
Routes JM, Grossman WJ, Verbsky J, et al. Statewide newborn screening for
severe T-cell lymphopenia. JAMA 2009; 302:2465.
12.
Bustamante J, Arias AA, Vogt G, et al. Germline CYBB mutations that
selectively affect macrophages in kindreds with X-linked predisposition to
tuberculous mycobacterial disease. Nat Immunol 2011; 12:213.
13.
Hartl D, Lehmann N, Hoffmann F, et al. Dysregulation of innate immune
receptors on neutrophils in chronic granulomatous disease. J Allergy Clin Immunol
2008; 121:375.
14.
Romani L, Fallarino F, De Luca A, et al. Defective tryptophan catabolism
underlies inflammation in mouse chronic granulomatous disease. Nature 2008;
451:211.
15.
De Ravin SS, Zarember KA, Long-Priel D, et al. Tryptophan/kynurenine
metabolism in human leukocytes is independent of superoxide and is fully
maintained in chronic granulomatous disease. Blood 2010; 116:1755.
16.
Brown KL, Bylund J, MacDonald KL, et al. ROS-deficient monocytes have
aberrant gene expression that correlates with inflammatory disorders of chronic
granulomatous disease. Clin Immunol 2008; 129:90.
17.
Fernandez-Boyanapalli RF, Frasch SC, McPhillips K, et al. Impaired apoptotic
cell clearance in CGD due to altered macrophage programming is reversed by
phosphatidylserine-dependent production of IL-4. Blood 2009; 113:2047.
18.
Suliaman F, Amra N, Sheikh S, et al. Epidemiology of chronic granulomatous
disease of childhood in Eastern Province, Saudi Arabia. Pediatr Asthma Allergy
Immunol 2009; 22:21.
19.
Jones LB, McGrogan P, Flood TJ, et al. Special article: chronic granulomatous
disease in the United Kingdom and Ireland: a comprehensive national patient-based
registry. Clin Exp Immunol 2008; 152:211.
20.
Kobayashi S, Murayama S, Takanashi S, et al. Clinical features and
prognoses of 23 patients with chronic granulomatous disease followed for 21 years
by a single hospital in Japan. Eur J Pediatr 2008; 167:1389.
21.
Martire B, Rondelli R, Soresina A, et al. Clinical features, long-term follow-up
and outcome of a large cohort of patients with Chronic Granulomatous Disease: an
Italian multicenter study. Clin Immunol 2008; 126:155.
22.
Soler-Palacín P, Margareto C, Llobet P, et al. Chronic granulomatous disease
in pediatric patients: 25 years of experience. Allergol Immunopathol (Madr) 2007;
35:83.
23.
Repine JE, Clawson CC, White JG, Holmes B. Spectrum of function of
neutrophils from carriers of sex-linked chronic granulomatous disease. J Pediatr
1975; 87:901.
24.
Anderson-Cohen M, Holland SM, Kuhns DB, et al. Severe phenotype of
chronic granulomatous disease presenting in a female with a de novo mutation in
gp91-phox and a non familial, extremely skewed X chromosome inactivation. Clin
Immunol 2003; 109:308.
25.
Wolach B, Scharf Y, Gavrieli R, et al. Unusual late presentation of X-linked
chronic granulomatous disease in an adult female with a somatic mosaic for a novel
mutation in CYBB. Blood 2005; 105:61.
26.
Roesler J. Carriers of X-linked chronic granulomatous disease at risk. Clin
Immunol 2009; 130:233; author reply 234.
27.
Lewis EM, Singla M, Sergeant S, et al. X-linked chronic granulomatous
disease secondary to skewed X chromosome inactivation in a female with a novel
CYBB mutation and late presentation. Clin Immunol 2008; 129:372.
28.
Brandrup F, Koch C, Petri M, et al. Discoid lupus erythematosus-like lesions
and stomatitis in female carriers of X-linked chronic granulomatous disease. Br J
Dermatol 1981; 104:495.
29.
Kragballe K, Borregaard N, Brandrup F, et al. Relation of monocyte and
neutrophil oxidative metabolism to skin and oral lesions in carriers of chronic
granulomatous disease. Clin Exp Immunol 1981; 43:390.
30.
Dorman SE, Guide SV, Conville PS, et al. Nocardia infection in chronic
granulomatous disease. Clin Infect Dis 2002; 35:390.
31.
Segal BH, DeCarlo ES, Kwon-Chung KJ, et al. Aspergillus nidulans infection
in chronic granulomatous disease. Medicine (Baltimore) 1998; 77:345.
32.
Galluzzo ML, Hernandez C, Davila MT, et al. Clinical and histopathological
features and a unique spectrum of organisms significantly associated with chronic
granulomatous disease osteomyelitis during childhood. Clin Infect Dis 2008;
46:745.
33.
Towbin AJ, Chaves I. Chronic granulomatous disease. Pediatr Radiol 2010;
40:657.
34.
Ramanuja S, Wolf KM, Sadat MA, et al. Newly diagnosed chronic
granulomatous disease in a 53-year-old woman with Crohn disease. Ann Allergy
Asthma Immunol 2005; 95:204.
35.
O'Neil KM, Herman JH, Modlin JF, et al. Pseudomonas cepacia: an emerging
pathogen in chronic granulomatous disease. J Pediatr 1986; 108:940.
36.
Greenberg DE, Goldberg JB, Stock F, et al. Recurrent Burkholderia infection
in patients with chronic granulomatous disease: 11-year experience at a large
referral center. Clin Infect Dis 2009; 48:1577.
37.
Friend JC, Hilligoss DM, Marquesen M, et al. Skin ulcers and disseminated
abscesses are characteristic of Serratia marcescens infection in older patients with
chronic granulomatous disease. J Allergy Clin Immunol 2009; 124:164.
38.
Bustamante J, Aksu G, Vogt G, et al. BCG-osis and tuberculosis in a child
with chronic granulomatous disease. J Allergy Clin Immunol 2007; 120:32.
39.
Lau YL, Chan GC, Ha SY, et al. The role of phagocytic respiratory burst in
host defense against Mycobacterium tuberculosis. Clin Infect Dis 1998; 26:226.
40.
Lee PP, Chan KW, Jiang L, et al. Susceptibility to mycobacterial infections in
children with X-linked chronic granulomatous disease: a review of 17 patients living
in a region endemic for tuberculosis. Pediatr Infect Dis J 2008; 27:224.
41.
Rosenzweig S, personal communication, 2010.
42.
Greenberg DE, Ding L, Zelazny AM, et al. A novel bacterium associated with
lymphadenitis in a patient with chronic granulomatous disease. PLoS Pathog 2006;
2:e28.
43.
Greenberg DE, Shoffner AR, Zelazny AM, et al. Recurrent Granulibacter
bethesdensis infections and chronic granulomatous disease. Emerg Infect Dis 2010;
16:1341.
44.
López FC, de Luna FF, Delgado MC, et al. Granulibacter bethesdensis
isolated in a child patient with chronic granulomatous disease. J Infect 2008;
57:275.
45.
Sirinavin S, Techasaensiri C, Pakakasama S, et al. Hemophagocytic
syndrome and Burkholderia cepacia splenic microabscesses in a child with chronic
granulomatous disease. Pediatr Infect Dis J 2004; 23:882.
46.
Hisano M, Sugawara K, Tatsuzawa O, et al. Bacteria-associated
haemophagocytic syndrome and septic pulmonary embolism caused by
Burkholderia cepacia complex in a woman with chronic granulomatous disease. J
Med Microbiol 2007; 56:702.
47.
Lacy DE, Spencer DA, Goldstein A, et al. Chronic granulomatous disease
presenting in childhood with Pseudomonas cepacia septicaemia. J Infect 1993;
27:301.
48.
Macher AM, Casale TB, Fauci AS. Chronic granulomatous disease of
childhood and Chromobacterium violaceum infections in the southeastern United
States. Ann Intern Med 1982; 97:51.
49.
Reichenbach J, Lopatin U, Mahlaoui N, et al. Actinomyces in chronic
granulomatous disease: an emerging and unanticipated pathogen. Clin Infect Dis
2009; 49:1703.
50.
Sponseller PD, Malech HL, McCarthy EF Jr, et al. Skeletal involvement in
children who have chronic granulomatous disease. J Bone Joint Surg Am 1991;
73:37.
51.
Santos PE, Piontelli E, Shea YR, et al. Penicillium piceum infection: diagnosis
and successful treatment in chronic granulomatous disease. Med Mycol 2006;
44:749.
52.
Vinh DC, Freeman AF, Shea YR, et al. Mucormycosis in chronic
granulomatous disease: association with iatrogenic immunosuppression. J Allergy
Clin Immunol 2009; 123:1411.
53.
Lugo Reyes SO, Suarez F, Herbigneaux RM, et al. Hodgkin lymphoma in 2
children with chronic granulomatous disease. J Allergy Clin Immunol 2011;
127:543.
54.
Rosenzweig SD. Inflammatory manifestations in chronic granulomatous
disease (CGD). J Clin Immunol 2008; 28 Suppl 1:S67.
55.
Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement
in chronic granulomatous disease. Pediatrics 2004; 114:462.
56.
Hussain N, Feld JJ, Kleiner DE, et al. Hepatic abnormalities in patients with
chronic granulomatous disease. Hepatology 2007; 45:675.
57.
Feld JJ, Hussain N, Wright EC, et al. Hepatic involvement and portal
hypertension predict mortality in chronic granulomatous disease. Gastroenterology
2008; 134:1917.
58.
Walther MM, Malech H, Berman A, et al. The urological manifestations of
chronic granulomatous disease. J Urol 1992; 147:1314.
59.
Goldblatt D, Butcher J, Thrasher AJ, Russell-Eggitt I. Chorioretinal lesions in
patients and carriers of chronic granulomatous disease. J Pediatr 1999; 134:780.
60.
Siddiqui S, Anderson VL, Hilligoss DM, et al. Fulminant mulch pneumonitis:
an emergency presentation of chronic granulomatous disease. Clin Infect Dis 2007;
45:673.
61.
Manzi S, Urbach AH, McCune AB, et al. Systemic lupus erythematosus in a
boy with chronic granulomatous disease: case report and review of the literature.
Arthritis Rheum 1991; 34:101.
62.
Cale CM, Morton L, Goldblatt D. Cutaneous and other lupus-like symptoms in
carriers of X-linked chronic granulomatous disease: incidence and autoimmune
serology. Clin Exp Immunol 2007; 148:79.
63.
De Ravin SS, Naumann N, Cowen EW, et al. Chronic granulomatous disease
as a risk factor for autoimmune disease. J Allergy Clin Immunol 2008; 122:1097.
64.
Buescher ES, Gallin JI. Stature and weight in chronic granulomatous
disease. J Pediatr 1984; 104:911.
65.
Marsh WL, Oyen R, Nichols ME, Allen FH Jr. Chronic granulomatous disease
and the Kell blood groups. Br J Haematol 1975; 29:247.
66.
Frey D, Mächler M, Seger R, et al. Gene deletion in a patient with chronic
granulomatous disease and McLeod syndrome: fine mapping of the Xk gene locus.
Blood 1988; 71:252.
67.
Vowells SJ, Sekhsaria S, Malech HL, et al. Flow cytometric analysis of the
granulocyte respiratory burst: a comparison study of fluorescent probes. J Immunol
Methods 1995; 178:89.
68.
Vowells SJ, Fleisher TA, Sekhsaria S, et al. Genotype-dependent variability
in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide
phosphate oxidase function in patients with chronic granulomatous disease. J
Pediatr 1996; 128:104.
69.
Kuhns DB, Alvord WG, Heller T, et al. Residual NADPH oxidase and survival
in chronic granulomatous disease. N Engl J Med 2010; 363:2600.
70.
Mauch L, Lun A, O'Gorman MR, et al. Chronic granulomatous disease (CGD)
and complete myeloperoxidase deficiency both yield strongly reduced
dihydrorhodamine 123 test signals but can be easily discerned in routine testing for
CGD. Clin Chem 2007; 53:890.
71.
Ferguson PJ, Lokuta MA, El-Shanti HI, et al. Neutrophil dysfunction in a
family with a SAPHO syndrome-like phenotype. Arthritis Rheum 2008; 58:3264.
72.
Roos D, van Zwieten R, Wijnen JT, et al. Molecular basis and enzymatic
properties of glucose 6-phosphate dehydrogenase volendam, leading to chronic
nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to
infections. Blood 1999; 94:2955.
73.
Whitin JC, Cohen HJ. Disorders of respiratory burst termination. Hematol
Oncol Clin North Am 1988; 2:289.
74.
Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patients
with glutathione synthetase deficiency. J Pediatr 2001; 139:79.
75.
Banerjee R, Anguita J, Roos D, Fikrig E. Cutting edge: infection by the agent
of human granulocytic ehrlichiosis prevents the respiratory burst by downregulating gp91phox. J Immunol 2000; 164:3946.
GRAPHICS
NADPH oxidase activation
Glucose-6-phosphate dehydrogenase is required for the production of nicotinamide
adenine dinucleotide phosphate (NADPH), an essential component of the NADPH
oxidase system (1). The phagocyte NADPH oxidase system generates superoxide
anion (O- 2) by transferring electrons from NADPH to molecular oxygen (O2) (2).
Superoxide is metabolized to hydrogen peroxide (H2O2) by superoxide dismutase
(3). Hydrogen peroxide can follow different metabolic pathways: myeloperoxidase
can convert it into hypochlorus acid (HOCl) (4), which in combination with other
reactive oxygen species is involved in the oxygen-dependent killing of
microorganisms (5). Hydrogen peroxide can also be degraded to H2O and O2,
thereby avoiding deleterious effect on the cell (6, 7, dashed lines).
DHR test
Dihydrorhodamine assay for CGD diagnosis. Unstimulated (left) and phorbol
myristate acetate stimulated (right) neutrophils are shown. Y axis is number of
events, X axis is fluorescence intensity shown on a log scale. In the normal (top
panels) there is a rightward shift seen with stimulation. In the X-linked CGD carrier
state (second row), there are 2 populations seen: one is normally fluorescent, while
the other is essentially the same as the unstimulated population. In the patient with
X-linked CGD (third row) there is no shift in fluorescence with stimulation. In the
patient with the autosomal recessive p47phox deficiency (fourth row), the
rightward shift seen with stimulation is abnormally broad and not very bright.
Tracings courtesy of Dr. Douglas B. Kuhns, SAIC Frederick.