- Review
- Open Access
Chronic granulomatous disease: a review of the infectious and inflammatory complications
https://doi.org/10.1186/1476-7961-9-10
© Song et al; licensee BioMed Central Ltd. 2011
- Received: 22 December 2010
- Accepted: 31 May 2011
- Published: 31 May 2011
Abstract
Chronic Granulomatous Disease is the most commonly encountered immunodeficiency involving the phagocyte, and is characterized by repeated infections with bacterial and fungal pathogens, as well as the formation of granulomas in tissue. The disease is the result of a disorder of the NADPH oxidase system, culminating in an inability of the phagocyte to generate superoxide, leading to the defective killing of pathogenic organisms. This can lead to infections with Staphylococcus aureus, Psedomonas species, Nocardia species, and fungi (such as Aspergillus species and Candida albicans). Involvement of vital or large organs can contribute to morbidity and/or mortality in the affected patients. Major advances have occurred in the diagnosis and treatment of this disease, with the potential for gene therapy or stem cell transplantation looming on the horizon.
Keywords
- Visceral Leishmaniasis
- Chronic Granulomatous Disease
- Mannose Binding Lectin
- Gastric Outlet Obstruction
- Acalculous Cholecystitis
Introduction
Host Immune Defense Mechanisms
Non-Specific | Specific |
---|---|
Barriers | Humoral* (Antibodies) |
Skin | Cellular* (Lymphocytes) |
Secretions (mucous, tears, saliva) | |
Mucociliary clearance | |
Peristalsis | |
Phagocytes | |
Complement | |
CRP and others | |
Cytokines | |
Pathogen recognition receptors* |
Innate and Adaptive Immunity
Feature | Innate | Adaptive |
---|---|---|
Action Time | Early (hours) | Late (days) |
Cells | Macrophage, DC, PMN, NK cells | B and T cells |
Receptors | TLR: Fixed in genome | Gene rearrangement BCRA, TCR |
Recognition | Conserved molecules/PAMP | Wide Variety |
Evolution | Conserved | Only vertebrates |
Distribution of Common Immunodeficiencies. Primary immune deficiencies can involve either the adaptive (T- and B-lymphocyte deficiencies) or the innate (phagocyte, complement or other defects) immune response (Figure 1). Of these, defects in phagocyte function constitute only about 18%, with the larger portion of the defects seen in the B cell/antibody and/or T cell components of immunity.
Defects Leading to Immunodeficiency Disease. The various defects are summarized in Figure 2, which describe the potential sequence of events, starting from T- and B cell interactions and antibody synthesis to the involvement of phagocyte and complement components of the innate immune response. Explanation for the various aspects of the immune response is provided at the bottom of the figure (components 1-8); Components 5 and 6 deal with phagocytic/neutrophil defects.
Pathogen Patterns in Immune Deficiency
Pathogen Type | T-cell Defect | B-cell Defect | Phagocyte Defect | Complement Defect |
---|---|---|---|---|
Bacteria | Bacterial sepsis | Pneumococcus, | Staphylococcus | Neisseria |
Haemophilus | Pseudomonas | Pyogenic bacteria | ||
M. catarrhalis | ||||
Virus | CMV, EBV, VZ | CEMA | --- | --- |
Fungi | Candida/PCP | PCP | Candida, Aspergillus | --- |
Parasite | --- | Giardia | --- | --- |
Acid Fast | AFB | --- | Nocardia | --- |
Disorders of the Phagocyte Resulting in Immune Deficiency
• Chronic granulomatous disease (CGD) |
• Neutrophil adhesion defects (such as the leukocyte adhesion deficiency syndromes), |
• Chediak-Higashi syndrome |
• Griscelli syndrome |
• Kostmann's syndrome |
• WHIM syndrome (disorder characterized by myelokathexis) |
• Mannose binding lectin deficiency (MBL deficiency) |
• Enzymatic defects within phagocytes- deficiencies of: |
○ Glucose-6-phosphate dehydrogenase (G6PD) |
○ Glutathione reductase, glutathione synthetase |
○ Myeloperoxidase |
The following sections discuss the immunobiology of phagocytes, the defects in CGD and the resulting clinical spectrum observed.
Normal Phagocyte Physiology
Role of Macrophages in Host Defenses. Macrophages are generated from bone marrow precursor cells in the presence of stem cell hematopoietic factors (such as granulocyte-macrophage colony stimulating factor/GM-CSF and macrophage colony stimulating factor/M-CSF). The activation of macrophages (in the presence of specific receptors and T lymphocytes as shown in the figure- CD40/CD40L, CD28/B7, interleukin-interleukin receptor etc) results in functional consequences such as microbicidal activity directed especially towards intracellular pathogens and aided by the expression of peroxides and superoxide radicals. These processes are defective in CGD (see text). Other secretory effects of macrophages result in the production of a plethora of mediators that assist in immunity (these are shown in the figure and include complement, enzymes, interleukins, interferons and growth factors).
The NADPH Oxidase System. The assembly of the various subunits of NADPH oxidase is shown in the figure, while the molecular genetics, rough prevalence, inheritance pattern and chromosomal localization of CGD subtypes are shown in the bottom of the figure. There are several components of NADPH oxidase: of these the cytochrome-b558 heterodimer is located in the membrane and consists of the gp91phox and p22phox units, while three cytosolic components exist- including the p67phox , p47phox and a p40phox. Following cellular activation, the soluble cytosolic components, p67phox , p47phox , and a p40phox , move to the membrane and bind to components of the cytochrome-b558 heterodimer. This is also accompanied by the binding of the GTPase protein, Rac, culminating by unclear mechanisms in flavocytochrome activation. This catalyzes the transfer of electrons from NADPH to oxygen, resulting in the formation of superoxide in the extracellular compartment (phagolysosome). Subsequent reactions via superoxide dismutase (SOD), catalase or myeloperoxidase (MPO), occurring in the phagolysome, can result in formation of H2O2, H2O or HOCl- respectively.
Mechanisms Involved in CGD
CGD represents a heterogeneous group of disorders characterized by defective generation of a respiratory burst in human phagocytes (neutrophils, mononuclear cells, macrophages, and eosinophils). The resultant defect is an inability to generate superoxide and hence an inability to contain certain infectious pathogens. The disease manifests as repeated, severe bacterial and fungal infections resulting in the formation of inflammatory granulomas. The earliest report of the disease was in 1954 by Janeway and colleagues [1]. Landing and Shirkey [2] subsequently described a patient with recurrent infection and associated histiocyte infiltration. A few years later, Bridges and Good reported on a fatal granulomatous disorder in boys and described this as a "new syndrome" [3]. Since these early descriptions, a rather amazing and accelerated understanding of the disease and its molecular genetics have developed in the last 5 decades [4]. Several research groups reported on defective oxidative burst as a possible mechanism of the disease [5–8]. In 1966, Holmes and colleagues recognized an abnormality of phagocyte function in the disease [9], while in 1967 Quie and coworkers demonstrated defective in vitro killing of bacteria by phagocytes obtained from patients with CGD [10]. In that same year, Baehner and Nathan described defective reduction of nitroblue tetrazolium by phagocytes from patients with CGD during phagocytosis, and postulated this as a diagnostic test [11]. This was a seminal paper that led to the critical test used to screen for the disease for decades [12]. This has now been replaced by a flow cytometric assay for the oxidative burst. In 1968, Baehner and Karnovsky demonstrated a deficiency of reduced nicotinamide-adenine dinucleotide oxidase in patients with CGD [13]. This was followed by the demonstration of defective superoxide generation from the phagocytes of patients with CGD by Curnette et al., [14] and confirmation of defective NADPH oxidase expression in the disease by Hohn and Lehrer [15]. In 1986, Baehner reported on the gene localization for X-linked CGD to xp21 [16, 17]. Subsequently, defects in several components of the NADPH oxidase complex, including the gp91phox, p22 phox[18], p67phox[18], and p47phox[19] were described by various researchers.
The presumed mechanism of CGD and the associated defects in NADPH oxidase system are shown in Figure 4. The assembly of the various subunits of NADPH oxidase is shown in the figure, while the molecular genetics, rough prevalence, inheritance pattern, and chromosomal localization are shown in the bottom of the figure. There are several components of NADPH oxidase: of these the cytochrome-b558 heterodimer is located in the membrane and consists of the gp91phox and p22phox units [4, 20, 21], while three cytosolic components exist- including the p67phox , p47phox , and a p40phox. Following cellular activation, the soluble cytosolic components, p67phox, p47phox, and a p40phox, move to the membrane and bind to components of the cytochrome-b558 heterodimer. This is also accompanied by the binding of the GTPase protein, Rac, culminating by unclear mechanisms in flavocytochrome activation. This catalyzes the transfer of electrons from NADPH to oxygen, resulting in the formation of superoxide in the extracellular component as shown in Figure 4. Subsequent reactions via superoxide dismutase (SOD), catalase or myeloperoxidase (MPO), occurring in the phagolysome, can result in formation of H2O2, H2O, or HOCl- respectively. Recent data suggest that the formation of superoxides and reactive oxygen species is not the end-all of these reactions, as such mediators may also set off subsequent activation of granule proteins such as cathepsin G and elastase, leading to further elaboration of the immune-inflammatory response, all of which are therefore likely to be defective in CGD.
Molecular subtypes and Genetics of CGD
X-linked CGD (XL-CGD) arises due to mutations in the gp91phox gene and is responsible for 65-70% of the clinical cases in the United States [17, 22–24]. This gene is termed CYBB and spans a 30 kb region in the Xp21.1 region (Figure 4). Deletions, frameshift, missense, nonsense, and splice site mutations have been described in this gene. When larger X-chromosomal deletions including the XK gene occur, this may result in a so-called "Contiguous gene syndrome". This may result in associations of the Kell phenotype/Mcleod syndrome with X-linked chronic granulomatous disease (CGD; OMIM 306400), Duchenne muscular dystrophy (DMD; OMIM 310200), and X-linked retinitis pigmentosa (RP3; OMIM 300389)[25, 26].
Autosomal recessive CGD (AR-CGD), seen in the remaining 35% cases, arise due to mutations of the other components of the NADH oxidase (except p40phox and Rac which are yet to be associated with any CGD phenotype) [22]: these include- p22phox , p67phox and p47phox . Of these, the dominant mutations observed is of the p22phox gene which accounts for almost 25% cases. The chromosomal location, MIM number, inheritance, and frequency are shown in Figure 4. These phenotypes can be referred to as the X-CGD and as the A22/A47/A67 CGD. Of these subtypes, A47 patients appear to have a less severe course. Nevertheless, extreme heterogeneity may be seen in the manifestations of this disease. Perhaps concomitant immune defects such as those of IgA deficiency or mannose binding lectin mutations (MBL) might be responsible for some of the observed heterogeneity in severity and/or disease progression. These aspects need further study.
Clinical Features
Patients with CGD usually present in infancy or childhood with repeated, severe bacterial and/or fungal infections. However, delayed diagnosis in adulthood is also possible as is occurrence in females. The disease is relatively uncommon, affecting about 1/250,000 individuals. The most common manifestations include infection, granulomatous disease, inflammation, and failure to thrive (nutritional effects of chronic infection and inflammation). The disease is heterogeneous in its manifestations, related to the subtypes, and severity of the associated macrophage defect [22]. In the majority of patients, the production of superoxides is undetetectable and the manifestations are therefore early and predictable to a great extent. In others, low level respiratory burst activity may delay manifestations or diagnosis into early adulthood [27–30]. Most patients present with infectious illness, which include sinopulmonary disease, abscesses, or lymphadenitis. Other manifestations are related more to inflammatory consequences and/or structural disease and resultant organ dysfunction.
The following sections will discuss the clinical aspects of CGD (X-linked disease and the autosomal recessive disease counterparts), the Kell-deletion/Mcleod syndrome, association with MBL deficiency and other deficiencies and rare clinical manifestations of the carrier state.
Clinical Aspects
Infectious Consequences of CGD
Type | Organ System | Manifestations | Etiology | Diagnosis |
---|---|---|---|---|
Infectious | ||||
Blood stream | Sepsis | B Cepacia Pseudomonas Serratia Staphylococcus Salmonella | Blood cultures Echocardiogram | |
Pulmonary | Pneumonia | Aspergillus Nocardia Serratia Pseudomonas Staphylococcus Klebsiella Candida Others | Radiolology Cultures Biopsy | |
Cutaneous | Impetigo Abscess | Staphylococcus Klebsiella Aspergillus/Candida Serratia | Aspirate cultures Biopsy | |
Lymph node | Adenitis Adenopathy | Candida/Nocardia Aspergillus Serratia/Klebsiella | Fine needle aspirate Cultures Biopsy | |
Liver | Abscess | Staphylococcus Streptococcus Aspergillus/Nocardia Serratia | Ultrasound or CT Aspirate Biopsy | |
Bone | Osteomyelitis | Serratia, Aspegillus Staphylococcus Pseudomonas/Nocardia | Bone scan CT/Biopsy | |
GI Tract | Perirectal abscess Fistulae | Enterobacteriaceae Staphylococcus | Biopsy Cultures | |
Urinary | Pyelonephritis | Enterobacteriaceae | Cultures IVP/CT etc | |
CNS | Meningitis Brain abscess | Candida, Haemophilus Aspergillus Staphylococcus | LP, cultures CT/MRI Biopsy |
Inflammatory and Structural Complications of CGD
Frequency | Complication |
---|---|
>50%/Frequent | Lymphadenopathy |
Hepatosplenomegaly | |
Anemia | |
Hyperglobulinemia and APR Failure to thrive, underweight | |
Failure to thrive, underweight | |
≤50% | Diarrhea |
Gingivitis | |
Hydronephrosis | |
Gastric outlet obstruction | |
Granulomatous ileocolitis | |
Stomatitis | |
Granulomatous cystitis | |
Pulmonary fibrosis | |
Esophagitis | |
Glomerulonephritis | |
Chorioretinitis | |
Discoid lupus |
Differences between United States and European Data
Feature | US | European |
---|---|---|
Number (n) | 368 (259 XL/81 AR-CGD) | 429 (67% XL- and 33% AR-CGD) |
Pneumonia | 79% | 66% |
Suppurative adenitis | 53% | 50% |
Subcutaneous abscess | 52% | 53% |
Liver abscess | 27% | 32% |
Osteomyelitis | 25% | NA |
Sepsis | 18% | NA |
Gastric outlet obstruction | 15% | NA |
Urinary tract obstruction | 10% | NA |
Colitis/GI tract | 17% | 48% |
Mortality | 18% | NA |
Differences between the XL and AR forms of CGD*
Feature | XL CGD | AR CGD |
---|---|---|
Family history of lupus | 10% | 3% |
Age at diagnosis | 3.01 years | 7.81 years |
Perirectal abscess | 17% | 7% |
Suppurative adenitis | 59% | 32% |
Bacteremia and/or fungemia | 21% | 10% |
Gastric outlet obstruction | 19% | 5% |
Urinary obstruction | 11% | 3% |
Mortality (over 10 year observation) | 21.2% | 8.6% |
Sinopulmonary Complications
Pneumonia as stated earlier is often the most common complication of the disease. Infections with catalase-positive organisms are the rule. In many cases, no organism is cultured even though the patients are often treated with and respond to antimicrobials directed against bacteria or fungi. The diagnosis of pulmonary involvement is most often made clinically, complemented by radiology (chest roentgenography, computerized tomography or MRI), biopsy, and cultures. Airway obstruction that sometimes complicates infection/granulomatous disease is best diagnosed by pulmonary function tests and by bronchoscopy. Recurrent pneumonia, lung abscess, effusions and empyema thoracis, mediastinal adenopathy, and necrotizing nodular disease may be seen [30]. The common pathogens include Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, and Aspergillus spp. In the series reported by Winkelstein et al., pneumonia accounted for 79% of the infectious complications of CGD [30]. Genetically, variant alleles of mannose binding lectin (MBL) were associated with autoimmune disease and may predispose to some pulmonary complications [39]. Chest wall invasion by pathogens has also been described [40] and may be due to necrotizing infections by fungi such as Aspergillus[41]. Pulmonary infections have also been described due to Pneumocystis carinii[42–44], Cryptococcus neoformans[45], Aspergillus[41, 46–50], visceral Leishmaniasis[51], suppurative pathogens [52], Pseudomonas cepacia[53, 54], [55], Legionella[56, 57], Nocardia[58–61], Mycoplasma pneumoniae[62], Sarcinosporon inkin-a skin fungus [63], Tuberculosis [64], Trichosporon pullulans[65, 66], Tularemia[67], Q Fever [68], Acremonium kiliense[69], Botryomycosis[70], Chrysosporium zonatum[71], Burkholderia (Pseudomonas) gladioli[72], fulminant mulch/filamentous fungi [73], Respiratory Syncitial Virus [74], and Francisella philomiragia (formerly Yersinia philomiragia) [75]. Certain pneumonic variants have also been described in CGD, including crystalline, nodular, and eosinophilic pneumonias [76, 77].
Ocular Complications
Blepharokeratoconjunctivitis, marginal keratitis, and choroido-retinal scars have all been described in CGD [78, 79]. A case of congenital arteriovenous hemangioma, presumably related to defective phagocyte function and hemosiderin removal, was described in a patient with CGD [80].
Neurological Complications
Patients with CGD can develop several neurological complications. Brain abscess has been well described in patients with CGD. Various pathogens have been associated with brain abscess development including Scedosporium prolificans[81], Alternaria infectoria[82], Salmonella enterica subspecies houtenae[83], and Aspergillus[84, 85]. Other complications associated with CGD include white matter disease [86], CNS granulomatous disease [87] and leptomeningeal, and focal brain infiltration by pigmented, lipid-laden macrophages [88]. Several reports of fungal brain infection [89], Aspergillus abscess resembling a brain tumor [90], spinal cord infection by Aspergillus[91] and fungal granuloma of the brain have been described [92]. Meningitis due to Streptococcus[93] and Candida[94] has also been reported on.
Hepatobiliary and GI Complications
A plethora of GI tract complications occur in CGD. As stated earlier, variant alleles of mannose binding lectin (MBL) were associated with autoimmune disease while polymorphisms of myeloperoxidase and Fc γ RIII were associated more with gastrointestinal complications in patients with CGD [39]. As summarized by Barton et al., GI tract disorders can present from the mouth to the anus, and can be characterized by ulcers, abscesses, fistulae, strictures, and obstructive symptoms [95]. Inflammatory granulomatous colitis can also lead to obstructive disease, diarrhea, malabsorption, or other manifestations [95]. Appendicitis, perirectal abscess, salmonella enteritis, and acalculous cholecystitis have been described, some requiring surgical intervention [96, 97].
Gastric outlet obstruction is a recognized complication [98–102]. A case of gastric outlet obstruction due to diffuse gastric infiltration has also been described [103]. There have been reports of nonsurgical resolution of gastric outlet obstruction following the use of glucocorticoids and antibiotics [104]. Liver involvement in the form of hepatic granuloma or multiple hepatic abscesses can complicate management [105–112].
Hepatic involvement by Staphylococcus aureus and Pseudomonas cepacia can manifest as granuloma or abscess formation [113]. A rare case of ascites has been described in CGD [114] and non-cirrhotic portal hypertension was reported to have prognostic significance [115]. In one study of 194 patients from the NIH, elevated liver enzymes (mainly transaminitis) were documented in >75%, liver abscess in 35%, hepatomegaly in 34%, and splenomegaly in over 50% cases [116]. Liver histology demonstrated granuloma in 75% and lobular hepatitis in 90%. Venopathy of the portal vein was observed in 80% and was associated with splenomegaly [116]. Ament and Ochs commented on the occurrence of several gastrointestinal manifestations in patients with CGD [117, 118]- including granulomata on biopsy, malabsorption syndromes, and B12-deficiency. Interferon gamma therapy, careful use of glucocorticoids and liver transplantation have improved outcomes in some patients with liver involvement [119, 120]. Chronic infection, nausea, vomiting, and malabsorption can lead to weight loss and/or failure to thrive in patients with CGD [70, 95, 121–123]. Catch up growth tends to occur and many patients attain predicted heights by late adolescence [124].
Renal and Gentourinary Complications
Granulomatous involvement and/or infectious complications can result in major genitourinary complications in patients with CGD. Use of glucocorticoids and antimicrobials has resulted in remission of obstructive pathology in some patients, thereby avoiding surgery. Frifeit and coworkers described chronic glomerulonephritis in a 12 year old male with CGD [125]. This culminated in terminal uremia and fatal pulmonary Aspergillosis and Pseudomonas septicemia. Diffuse infiltration of renal and other tissues by pigment-containing macrophages may also result in pathology in CGD [126]. Renal Aspergilloses resulting in renal abscess formation has also been described [127] as well as xantogranulomatous pyelonephritis and renal amyloidosis [128, 129]. In the latter case, renal amyloidosis resulting in nephritic syndrome occurred in a patient with CGD post-renal transplantation [129]. In one series, 23/60 patients (38%) with CGD demonstrated urological disease [130], including bladder granulomas, urethral strictures, recurrent urinary tract infections, and renal dysfunction. The judicious use of glucocorticoids and interferon gamma has had a beneficial effect on several of these conditions of either the genitourinary or gastrointestinal systems.
Other Complications
Dermatological manifestations in patients with CGD include atopic dermatitis-like disease but with systemic or deep seated infections [131], facial granulomata [132] and discoid lupus, and seborrheic dermatitis-like disease [133]. Vesicular and granulomatous of fungal skin lesions have been observed in small reports [134]. Altered skin Rebuck window responses in patients with CGD have been recorded [135]. Several skeletal complications related mainly to infections have been described in patients with CGD. Osteomyelitis secondary to invasive Aspergillus or Burkholderia gladioli[136–140] may occur. Osteomyelitis may involve either the long bones or even the spine [137, 139]. Dactylitis may complicate CGD [141]. Multifocal osteomyelitis secondary to Paecilomyces varioti has also been reported [142] as has sacral osteomyelitis secondary to Basidiomycetous fungi such as Inonotus tropicalis[143]. Gill et al., reported on a favorable response to Interferon gamma in osteomyelitis complicating CGD [144]. Occasionally recombinant hematopoietic growth factors (rhG-CSF), long term antimicrobials, and surgery may be required in the management of these complex patients [140, 145].
Inflammatory Responses in CGD
Table 6 lists the inflammatory and structural changes observed in CGD. Some of these changes may truly represent infectious complications, but as stated earlier, many such tissues fail to grow any identifiable pathogens in culture. These changes may also represent the exuberant inflammatory response seen in the disease. Whether these changes represent an overwhelming response to infection by other intact components of the immune response (such as T cells and B cells) and manifested by hyperglobulinemia and elevated acute phase reactants, a failure of the compensatory "anti-inflammatory response" [146], a diminished production of specific regulatory products such as PGE2[147] or activation of nuclear factor kappaB, the ubiquitous transcription fact [148] is unclear. This in addition to the poor superoxide radical response [149, 150], failure of phagocytosis and the enhanced cytokine responses [151] may be responsible for the observed inflammatory pathologies listed in Table 6. At least in a murine model, the failure of an immune-modulatory effect of superoxide radicals was associated with exuberant inflammatory responses and TH17-mediated pathology and arthritis [152]. The development of animal models of CGD to study this "hyperinflammation" further will improve our understanding of the immune dysregulation seen in the disease [153, 154]. Granuloma formation is often accompanied by inflammatory, obstructive, or functional impairments of organ systems, such as the GI tract or the GU system [155].
Other Aspects of CGD
In some patients with CGD, the deletion in the Xp21 can extend to other "contiguous" genes resulting in an association of the disease with lack of Kell blood antigens (Mcleod phenotype), Retinitis Pigmentosa, and Duchenne Muscular Dystrophy [156–159]. This could complicate blood transfusion. There have been reports of successful granulocyte transfusions in patients with the Mcleod Phenotype, complicated only by mild hemolysis [160].
Female carriers have manifested some symptoms, such as dermatitis, stomatitis, and discoid lupus-like disease [161–165]. CGD-like infections can sometimes present in female carriers, and these patients demonstrate both normal and CGD-neutrophils with functional mosaicism[166]. In one report of 15 carriers of the CGD gene, five patients had both stomatitis and discoid SLE-like lesions and five patients had stomatitis alone, while the remaining five patients were relatively asymptomatic [167]. Martin-Villa and co-workers also described more frequent autoantibodies among carriers of the CGD gene compared to non-carrier relatives, probably related to random X-chromosome inactivation [168].
Concomitant immune deficiencies may complicate CGD and contribute to infectious complications. In patients with documented CGD, variant alleles of mannose binding lectin (MBL) were associated with autoimmune disease and may predispose to some pulmonary complications [39]. There have been several reports of IgA deficiency in patients with CGD [55, 169, 170]. Further studies of humoral immune response and MBL deficiency in patients with CGD are essential to further understand these immune interactions and predisposition to autoimmunity and infectious disease.
Diagnosis and Treatment
Approach to Diagnosis of CGD
Clinical information |
1. Severe, recurrent pulmonary and hepatic infections including abscess formation |
2. Specific etiologic pathogens such as B. cepacia, Nocardia, Aspergillus etc |
3. Granulomatous lesions of the GI tract or the GU system |
Laboratory abnormalities |
1. Anemia |
2. Polyclonal hyperglobulinemia |
3. Elevated acute phase reactants such as ESR or CRP |
4. Normal studies of T and B lymphocyte immunity |
Diagnostic test |
1. NBT test (no longer used) |
2. DHR |
Molecular tests |
1. Immunoblotting or flow cytometry |
2. Molecular techniques including gene sequencing and mutational analyses for subtype |
Treatment of Chronic Granulomatous Disease
Prophylaxis of Infection | |
Antibacterial therapy | Trimethoprim-sulfamethoxazole (TMP-SMX) 5 mg/kg/day (based upon the TMP component, maximum dose 320 mg P.O in two divided daily doses) [187] |
Antifungal therapy | Itraconazole 5 mg/kg [85] (maximum dose 200 mg orally daily) |
Immunomodulatory therapy | Interferon-gamma (IFN-γ) [85, 137] 50 μg/m2 (subcutaneous) three times a week 1.5 μg/Kg (subcutaneous) three times a week for children <0.5 m2 |
Management of Infection | |
Empirical treatment | TMP-SMX/Fluoroquinolone/Antifungal (Voriconazole) |
• Burkholderia, Serratia species: TMP-SMX | |
• Nocardia species: TMP-SMX and/or Cabapenem | |
• Staphylococcus aureus:TMP-SMX or Vancomycin | |
• Fungal infection: Antifungal agent ±Steroid | |
Liver abscess | |
Granulocyte Transfusion | |
Definitive treatment | |
Stem cell transplant | HLA identical sibling umbilical cord stem cell transplantation (UCSCT) after myeloablative conditioning (Stem cell transplantation from a HLA-identical donor may, at present, be the only proven curative approach to CGD) [185–187] |
Gene therapy |
Declarations
Authors’ Affiliations
References
- Janeway CA: Hypergammaglobulinemia associated with severe, recurrent and chronic non-specific infection. Am J Dis Child. 1954, 88: 388-392.Google Scholar
- Landing BH, Shirkey HS: A syndrome of recurrent infection and infiltration of viscera by pigmented lipid histiocytes. Pediatrics. 1957, 20: 431-438.PubMedGoogle Scholar
- Bridges RA, Berendes H, Good RA: A fatal granulomatous disease of childhood; the clinical, pathological, and laboratory features of a new syndrome. AMA J Dis Child. 1959, 97: 387-408.PubMedView ArticleGoogle Scholar
- Seger RA: Advances in the diagnosis and treatment of chronic granulomatous disease. Curr Opin Hematol. 2010.Google Scholar
- Editorial: Microbial killing by neutrophils. Lancet. 1976, 1: 1393-1394.Google Scholar
- Phagocytic defects II: Abnormalities of the respiratory burst. Hematol Oncol Clin North Am. 1988, 2: 185-336.Google Scholar
- Babior BM: The respiratory burst oxidase. Hematol Oncol Clin North Am. 1988, 2: 201-212.PubMedGoogle Scholar
- Borregaard N: Activation of phagocytes. Eur J Clin Invest. 1985, 15: 240-241. 10.1111/j.1365-2362.1985.tb00176.xPubMedView ArticleGoogle Scholar
- Holmes B: Fatal granulomatous disease of childhood. An inborn abnormality of phagocytic function. Lancet. 1966, 1: 1225-1228.PubMedView ArticleGoogle Scholar
- Quie PG: In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. J Clin Invest. 1967, 46: 668-679. 10.1172/JCI105568PubMed CentralPubMedView ArticleGoogle Scholar
- Baehner RL, Nathan DG: Leukocyte oxidase: defective activity in chronic granulomatous disease. Science. 1967, 155: 835-836. 10.1126/science.155.3764.835PubMedView ArticleGoogle Scholar
- Baehner RL, Nathan DG: Quantitative nitroblue tetrazolium test in chronic granulomatous disease. N Engl J Med. 1968, 278: 971-976. 10.1056/NEJM196805022781801PubMedView ArticleGoogle Scholar
- Baehner RL, Karnovsky ML: Deficiency of reduced nicotinamide-adenine dinucleotide oxidase in chronic granulomatous disease. Science. 1968, 162: 1277-1279. 10.1126/science.162.3859.1277PubMedView ArticleGoogle Scholar
- Curnutte JT, Whitten DM, Babior BM: Defective superoxide production by granulocytes from patients with chronic granulomatous disease. N Engl J Med. 1974, 290: 593-597. 10.1056/NEJM197403142901104PubMedView ArticleGoogle Scholar
- Hohn DC, Lehrer RI: NADPH oxidase deficiency in X-linked chronic granulomatous disease. J Clin Invest. 1975, 55: 707-713. 10.1172/JCI107980PubMed CentralPubMedView ArticleGoogle Scholar
- Segal AW: Absence of both cytochrome b-245 subunits from neutrophils in X-linked chronic granulomatous disease. Nature. 1987, 326: 88-91. 10.1038/326088a0PubMedView ArticleGoogle Scholar
- Baehner RL: Chronic granulomatous disease of childhood: clinical, pathological, biochemical, molecular, and genetic aspects of the disease. Pediatr Pathol. 1990, 10: 143-153. 10.3109/15513819009067103PubMedView ArticleGoogle Scholar
- Umei T, Takeshige K, Minakami S: NADPH-binding component of the superoxide-generating oxidase in unstimulated neutrophils and the neutrophils from the patients with chronic granulomatous disease. Biochem J. 1987, 243: 467-472.PubMed CentralPubMedView ArticleGoogle Scholar
- Curnutte JT, Kuver R, Scott PJ: Activation of neutrophil NADPH oxidase in a cell-free system. Partial purification of components and characterization of the activation process. J Biol Chem. 1987, 262: 5563-5569.PubMedGoogle Scholar
- Bjorgvinsdottir H, Zhen L, Dinauer MC: Cloning of murine gp91phox cDNA and functional expression in a human X-linked chronic granulomatous disease cell line. Blood. 1996, 87: 2005-2010.PubMedGoogle Scholar
- Casimir C: Identification of the defective NADPH-oxidase component in chronic granulomatous disease: a study of 57 European families. Eur J Clin Invest. 1992, 22: 403-406. 10.1111/j.1365-2362.1992.tb01481.xPubMedView ArticleGoogle Scholar
- Curnutte JT: Chronic granulomatous disease: the solving of a clinical riddle at the molecular level. Clin Immunol Immunopathol. 1993, 67: S2-15. 10.1006/clin.1993.1078PubMedView ArticleGoogle Scholar
- Roos D: The genetic basis of chronic granulomatous disease. Immunol Rev. 1994, 138: 121-157. 10.1111/j.1600-065X.1994.tb00850.xPubMedView ArticleGoogle Scholar
- Kinnon C, Levinsky R: The molecular basis of X-linked immunodeficiency disease. J Inherit Metab Dis. 1992, 15: 674-682. 10.1007/BF01799623PubMedView ArticleGoogle Scholar
- Bertelson CJ: Localization of the McLeod locus (XK) within Xp21 by deletion analysis. Am J Hum Genet. 1988, 42: 703-711.PubMed CentralPubMedGoogle Scholar
- Brown J: Analysis of three deletion breakpoints in Xp21.1 and the further localization of RP3. Genomics. 1996, 37: 200-210. 10.1006/geno.1996.0543PubMedView ArticleGoogle Scholar
- Al-Khuwaitir TS: Chronic granulomatous disease with recurrent hepatic abscesses in an adult. Saudi Med J. 2007, 28: 1593-1596.PubMedGoogle Scholar
- Aliabadi H, Gonzalez R, Quie PG: Urinary tract disorders in patients with chronic granulomatous disease. N Engl J Med. 1989, 321: 706-708. 10.1056/NEJM198909143211102PubMedView ArticleGoogle Scholar
- Becker CE, Graddick SL, Roy TM: Patterns of chronic granulomatous disease. J Ky Med Assoc. 1993, 91: 447-450.PubMedGoogle Scholar
- Winkelstein JA: Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000, 79: 155-169. 10.1097/00005792-200005000-00003.View ArticleGoogle Scholar
- Antachopoulos C, Walsh TJ, Roilides E: Fungal infections in primary immunodeficiencies. Eur J Pediatr. 2007, 166: 1099-1117. 10.1007/s00431-007-0527-7PubMedView ArticleGoogle Scholar
- Alsultan A: Chronic granulomatous disease presenting with disseminated intracranial aspergillosis. Pediatr Blood Cancer. 2006, 47: 107-110. 10.1002/pbc.20426PubMedView ArticleGoogle Scholar
- Ahlin A: Prevalence, genetics and clinical presentation of chronic granulomatous disease in Sweden. Acta Paediatr. 1995, 84: 1386-1394. 10.1111/j.1651-2227.1995.tb13575.xPubMedView ArticleGoogle Scholar
- Kobayashi S: 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: 1389-1394. 10.1007/s00431-008-0680-7PubMedView ArticleGoogle Scholar
- Jones LB: Special article: chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry. Clin Exp Immunol. 2008, 152: 211-218. 10.1111/j.1365-2249.2008.03644.xPubMed CentralPubMedView ArticleGoogle Scholar
- Liese J: Long-term follow-up and outcome of 39 patients with chronic granulomatous disease. J Pediatr. 2000, 137: 687-693. 10.1067/mpd.2000.109112PubMedView ArticleGoogle Scholar
- Liese JG: Chronic granulomatous disease in adults. Lancet. 1996, 347: 220-223. 10.1016/S0140-6736(96)90403-1PubMedView ArticleGoogle Scholar
- van den Berg JM: Chronic granulomatous disease: the European experience. PLoS One. 2009, 4: e5234. 10.1371/journal.pone.0005234PubMed CentralPubMedView ArticleGoogle Scholar
- Foster CB: Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease. J Clin Invest. 1998, 102: 2146-2155. 10.1172/JCI5084PubMed CentralPubMedView ArticleGoogle Scholar
- Kawashima A: Pulmonary Aspergillus chest wall involvement in chronic granulomatous disease: CT and MRI findings. Skeletal Radiol. 1991, 20: 487-493.PubMedGoogle Scholar
- Altman AR: Thoracic wall invasion secondary to pulmonary aspergillosis: a complication of chronic granulomatous disease of childhood. AJR Am J Roentgenol. 1977, 129: 140-142.PubMedView ArticleGoogle Scholar
- Adinoff AD: Chronic granulomatous disease and Pneumocystis carinii pneumonia. Pediatrics. 1982, 69: 133-134.PubMedGoogle Scholar
- Markus MR: Chronic granulomatous disease and Pneumocystis carinii pneumonia. S Afr Med J. 1983, 63: 350.PubMedGoogle Scholar
- Pedersen FK: Refractory Pneumocystis carinii infection in chronic granulomatous disease: successful treatment with granulocytes. Pediatrics. 1979, 64: 935-938.PubMedGoogle Scholar
- Allen DM, Chng HH: Disseminated Mycobacterium flavescens in a probable case of chronic granulomatous disease. J Infect. 1993, 26: 83-86. 10.1016/0163-4453(93)97000-NPubMedView ArticleGoogle Scholar
- Chudwin DS: Aspergillus pneumonia in chronic granulomatous disease: recurrence and long-term outcome. Acta Paediatr Scand. 1982, 71: 915-917. 10.1111/j.1651-2227.1982.tb09548.xPubMedView ArticleGoogle Scholar
- Chusid MJ, Sty JR, Wells RG: Pulmonary aspergillosis appearing as chronic nodular disease in chronic granulomatous disease. Pediatr Radiol. 1988, 18: 232-234. 10.1007/BF02390402PubMedView ArticleGoogle Scholar
- Conrad DJ: Microgranulomatous aspergillosis after shoveling wood chips: report of a fatal outcome in a patient with chronic granulomatous disease. Am J Ind Med. 1992, 22: 411-418. 10.1002/ajim.4700220313PubMedView ArticleGoogle Scholar
- Kelly JK: Fatal Aspergillus pneumonia in chronic granulomatous disease. Am J Clin Pathol. 1986, 86: 235-240.PubMedGoogle Scholar
- Kosut JS, Kamani NR, Jantausch BA: One-month-old infant with multilobar round pneumonias. Pediatr Infect Dis J. 2006, 25: 95-97. 10.1097/01.inf.0000195717.40250.8bPubMedView ArticleGoogle Scholar
- Asensi V: Visceral leishmaniasis and other severe infections in an adult patient with p47-phox-deficient chronic granulomatous disease. Infection. 2000, 28: 171-174. 10.1007/s150100050074PubMedView ArticleGoogle Scholar
- Carnide EG: Clinical and laboratory aspects of chronic granulomatous disease in description of eighteen patients. Pediatr Allergy Immunol. 2005, 16: 5-9. 10.1111/j.1399-3038.2005.00225.xPubMedView ArticleGoogle Scholar
- Clegg HW, Ephros M, Newburger PE: Pseudomonas cepacia pneumonia in chronic granulomatous disease. Pediatr Infect Dis. 1986, 5: 111.PubMedGoogle Scholar
- O'Neil KM: Pseudomonas cepacia: an emerging pathogen in chronic granulomatous disease. J Pediatr. 1986, 108: 940-942. 10.1016/S0022-3476(86)80934-9PubMedView ArticleGoogle Scholar
- Sieber OF Jr, Fulginiti VA: Pseudomonas cepacia pneumonia in a child with chronic granulomatous disease and selective IgA deficiency. Acta Paediatr Scand. 1976, 65: 519-520. 10.1111/j.1651-2227.1976.tb04924.xPubMedView ArticleGoogle Scholar
- Ephros M: Legionella gormanii pneumonia in a child with chronic granulomatous disease. Pediatr Infect Dis J. 1989, 8: 726-727. 10.1097/00006454-198910000-00014PubMedView ArticleGoogle Scholar
- Peerless AG: Legionella pneumonia in chronic granulomatous disease. J Pediatr. 1985, 106: 783-785. 10.1016/S0022-3476(85)80355-3PubMedView ArticleGoogle Scholar
- McNeil MM: Disseminated Nocardia transvalensis infection: an unusual opportunistic pathogen in severely immunocompromised patients. J Infect Dis. 1992, 165: 175-178. 10.1093/infdis/165.1.175PubMedView ArticleGoogle Scholar
- Johnston HC: Nocardia pneumonia in a neonate with chronic granulomatous disease. Pediatr Infect Dis J. 1989, 8: 526-528. 10.1097/00006454-198908000-00011PubMedView ArticleGoogle Scholar
- Jonsson S: Recurrent Nocardia pneumonia in an adult with chronic granulomatous disease. Am Rev Respir Dis. 1986, 133: 932-934.PubMedView ArticleGoogle Scholar
- Shetty AK, Arvin AM, Gutierrez KM: Nocardia farcinica pneumonia in chronic granulomatous disease. Pediatrics. 1999, 104: 961-964. 10.1542/peds.104.4.961PubMedView ArticleGoogle Scholar
- Kato M: [Mycoplasma pneumoniae pneumonia in patients with chronic granulomatous disease]. Kansenshogaku Zasshi. 1983, 57: 823-827.PubMedView ArticleGoogle Scholar
- Kenney RT: Invasive infection with Sarcinosporon inkin in a patient with chronic granulomatous disease. Am J Clin Pathol. 1990, 94: 344-350.PubMedGoogle Scholar
- Lee PP: 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: 224-230. 10.1097/INF.0b013e31815b494cPubMedView ArticleGoogle Scholar
- Lestini BJ, Church JA: Trichosporon pullulans as a complication of chronic granulomatous disease in a patient undergoing immunosuppressive therapy for inflammatory bowel disease. Pediatr Infect Dis J. 2006, 25: 87-89. 10.1097/01.inf.0000195641.69380.a0PubMedView ArticleGoogle Scholar
- Moylett EH, Chinen J, Shearer WT: Trichosporon pullulans infection in 2 patients with chronic granulomatous disease: an emerging pathogen and review of the literature. J Allergy Clin Immunol. 2003, 111: 1370-1374. 10.1067/mai.2003.1522PubMedView ArticleGoogle Scholar
- Maranan MC: Pneumonic tularemia in a patient with chronic granulomatous disease. Clin Infect Dis. 1997, 25: 630-633. 10.1086/513777PubMedView ArticleGoogle Scholar
- Meis JF: Rapidly fatal Q-fever pneumonia in a patient with chronic granulomatous disease. Infection. 1992, 20: 287-289. 10.1007/BF01710798PubMedView ArticleGoogle Scholar
- Pastorino AC: Acremonium kiliense infection in a child with chronic granulomatous disease. Braz J Infect Dis. 2005, 9: 529-534. 10.1590/S1413-86702005000600014PubMedView ArticleGoogle Scholar
- Paz HL: Primary pulmonary botryomycosis. A manifestation of chronic granulomatous disease. Chest. 1992, 101: 1160-1162. 10.1378/chest.101.4.1160PubMedView ArticleGoogle Scholar
- Roilides E: Disseminated infection due to Chrysosporium zonatum in a patient with chronic granulomatous disease and review of non-Aspergillus fungal infections in patients with this disease. J Clin Microbiol. 1999, 37: 18-25.PubMed CentralPubMedGoogle Scholar
- Ross JP: Severe Burkholderia (Pseudomonas) gladioli infection in chronic granulomatous disease: report of two successfully treated cases. Clin Infect Dis. 1995, 21: 1291-1293. 10.1093/clinids/21.5.1291PubMedView ArticleGoogle Scholar
- Siddiqui S: Fulminant mulch pneumonitis: an emergency presentation of chronic granulomatous disease. Clin Infect Dis. 2007, 45: 673-681. 10.1086/520985PubMedView ArticleGoogle Scholar
- Uzel G: Respiratory syncytial virus infection in patients with phagocyte defects. Pediatrics. 2000, 106: 835-837. 10.1542/peds.106.4.835PubMedView ArticleGoogle Scholar
- Wenger JD: Infection caused by Francisella philomiragia (formerly Yersinia philomiragia). A newly recognized human pathogen. Ann Intern Med. 1989, 110: 888-892.PubMedView ArticleGoogle Scholar
- Trawick D: Eosinophilic pneumonia as a presentation of occult chronic granulomatous disease. Eur Respir J. 1997, 10: 2166-2170. 10.1183/09031936.97.10092166PubMedView ArticleGoogle Scholar
- Narchi H, Gammoh S: Multiple nodular pneumonitis in a three-week-old female infant. Pediatr Infect Dis J. 1999, 18: 471-486.PubMedView ArticleGoogle Scholar
- Palestine AG: Ocular findings in patients with neutrophil dysfunction. Am J Ophthalmol. 1983, 95: 598-604.PubMedView ArticleGoogle Scholar
- Djalilian AR: Keratitis caused by Candida glabrata in a patient with chronic granulomatous disease. Am J Ophthalmol. 2001, 132: 782-783. 10.1016/S0002-9394(01)01091-1PubMedView ArticleGoogle Scholar
- Andersen SR: Vascular lesion (arteriovenous aneurysm or haemangioma) of the orbit in a case of chronic granulomatous disease. Ophthalmologica. 1976, 173: 145-151. 10.1159/000307875PubMedView ArticleGoogle Scholar
- Bhat SV: Scedosporium prolificans brain abscess in a patient with chronic granulomatous disease: successful combination therapy with voriconazole and terbinafine. Scand J Infect Dis. 2007, 39: 87-90. 10.1080/00365540600786564PubMedView ArticleGoogle Scholar
- Hipolito E: Alternaria infectoria brain abscess in a child with chronic granulomatous disease. Eur J Clin Microbiol Infect Dis. 2009, 28: 377-380. 10.1007/s10096-008-0623-2PubMedView ArticleGoogle Scholar
- Ma JS: Brain abscess caused by Salmonella enterica subspecies houtenae in a patient with chronic granulomatous disease. J Microbiol Immunol Infect. 2003, 36: 282-284.PubMedGoogle Scholar
- Narita M: A case of chronic granulomatous disease in which the patient survived a recurrence of suspected Aspergillus brain abscess. Kansenshogaku Zasshi. 1999, 73: 783-786.PubMedView ArticleGoogle Scholar
- Saulsbury FT: Successful treatment of aspergillus brain abscess with itraconazole and interferon-gamma in a patient with chronic granulomatous disease. Clin Infect Dis. 2001, 32: E137-E139. 10.1086/320158PubMedView ArticleGoogle Scholar
- Hadfield MG: Brain lesions in chronic granulomatous disease. Acta Neuropathol. 1991, 81: 467-470. 10.1007/BF00293469PubMedView ArticleGoogle Scholar
- Walker DH, Okiye G: Chronic granulomatous disease involving the central nervous system. Pediatr Pathol. 1983, 1: 159-167. 10.3109/15513818309040653PubMedView ArticleGoogle Scholar
- Riggs JE: Pigmented, lipid-laden histiocytes in the central nervous system in chronic granulomatous disease of childhood. J Child Neurol. 1989, 4: 61-63. 10.1177/088307388900400111PubMedView ArticleGoogle Scholar
- Leto TL: Cloning of a 67-kD neutrophil oxidase factor with similarity to a noncatalytic region of p60c-src. Science. 1990, 248: 727-730. 10.1126/science.1692159PubMedView ArticleGoogle Scholar
- Patiroglu T: Atypical presentation of chronic granulomatous disease in an adolescent boy with frontal lobe located Aspergillus abscess mimicking intracranial tumor. Childs Nerv Syst. 2010, 26: 149-154. 10.1007/s00381-009-1003-7PubMedView ArticleGoogle Scholar
- Bukhari E, Alrabiaah A: First case of extensive spinal cord infection with Aspergillus nidulans in a child with chronic granulomatous disease. J Infect Dev Ctries. 2009, 3: 321-323.PubMedGoogle Scholar
- Turgut M: Fungal granuloma of the brain caused by Aspergillus in an adolescent boy with chronic granulomatous disease. Childs Nerv Syst. 2010, 26: 733-734. 10.1007/s00381-010-1149-3PubMedView ArticleGoogle Scholar
- Garel D: [Streptococcus group B tardive meningitis revealing chronic septic granulomatosis]. Ann Pediatr (Paris). 1989, 36: 35-37.Google Scholar
- Fleischmann J, Church JA, Lehrer RI: Primary Candida meningitis and chronic granulomatous disease. Am J Med Sci. 1986, 291: 334-341. 10.1097/00000441-198605000-00009PubMedView ArticleGoogle Scholar
- Barton LL: Gastrointestinal complications of chronic granulomatous disease: case report and literature review. Clin Pediatr (Phila). 1998, 37: 231-236. 10.1177/000992289803700403.View ArticleGoogle Scholar
- Mulholland MW, Delaney JP, Simmons RL: Gastrointestinal complications of chronic granulomatous disease: surgical implications. Surgery. 1983, 94: 569-575.PubMedGoogle Scholar
- Huang A, Abbasakoor F, Vaizey CJ: Gastrointestinal manifestations of chronic granulomatous disease. Colorectal Dis. 2006, 8: 637-644. 10.1111/j.1463-1318.2006.01030.xPubMedView ArticleGoogle Scholar
- Saul RA: Gastric outlet obstruction in chronic granulomatous disease. J Pediatr. 1989, 114: 505.PubMedView ArticleGoogle Scholar
- Born M, Willinek WA, Hassan C: [Gastric outlet obstruction in chronic granulomatous disease]. Z Gastroenterol. 2002, 40: 511-516. 10.1055/s-2002-32799PubMedView ArticleGoogle Scholar
- Dickerman JD, Colletti RB, Tampas JP: Gastric outlet obstruction in chronic granulomatous disease of childhood. Am J Dis Child. 1986, 140: 567-570.PubMedGoogle Scholar
- Johnson FE: Gastric outlet obstruction due to X-linked chronic granulomatous disease. Surgery. 1975, 78: 217-223.PubMedGoogle Scholar
- Varma VA: Chronic granulomatous disease of childhood presenting as gastric outlet obstruction. Am J Surg Pathol. 1982, 6: 673-676. 10.1097/00000478-198210000-00009PubMedView ArticleGoogle Scholar
- Hartenberg MA, Kodroff MB: Chronic granulomatous disease of childhood. Probable diffuse gastric involvement. Pediatr Radiol. 1984, 14: 57-58. 10.1007/BF02386736PubMedView ArticleGoogle Scholar
- Danziger RN: Outpatient management with oral corticosteroid therapy for obstructive conditions in chronic granulomatous disease. J Pediatr. 1993, 122: 303-305. 10.1016/S0022-3476(06)80138-1PubMedView ArticleGoogle Scholar
- Caksen H: Recurrent multiple hepatic abscesses, hepatic calcification and congenital hearing loss in a child with chronic granulomatous disease. Acta Paediatr Taiwan. 2004, 45: 249-252.PubMedGoogle Scholar
- Berlin CM Jr: Hepatic granulomata. Presenting with prolonged fever. Resolution with anti-inflammatory treatment. Clin Pediatr (Phila). 1990, 29: 339-342. 10.1177/000992289002900610.View ArticleGoogle Scholar
- Chen LE: Cut it out: Managing hepatic abscesses in patients with chronic granulomatous disease. J Pediatr Surg. 2003, 38: 709-713. 10.1016/jpsu.2003.50189PubMedView ArticleGoogle Scholar
- Fehon R: Two-year-old boy with cervical and liver abscesses. J Paediatr Child Health. 2008, 44: 670-672. 10.1111/j.1440-1754.2008.01398.xPubMedView ArticleGoogle Scholar
- Garel LA: Liver involvement in chronic granulomatous disease: the role of ultrasound in diagnosis and treatment. Radiology. 1984, 153: 117-121.PubMedView ArticleGoogle Scholar
- Grund KE, Klotter HJ, Lemmel EM: Chronic granulomatosis as a rare cause of recurrent liver abscess. Med Welt. 1982, 33: 202-203.PubMedGoogle Scholar
- Larsen LR, Raffensperger J: Liver abscess. J Pediatr Surg. 1979, 14: 329-331. 10.1016/S0022-3468(79)80493-5PubMedView ArticleGoogle Scholar
- Marchetti F: A 7-month-old boy with liver abscesses. J Pediatr Gastroenterol Nutr. 2010, 50: 117. 10.1097/MPG.0b013e3181c615b1PubMedView ArticleGoogle Scholar
- Nakhleh RE, Glock M, Snover DC: Hepatic pathology of chronic granulomatous disease of childhood. Arch Pathol Lab Med. 1992, 116: 71-75.PubMedGoogle Scholar
- Castro M: Ascites as an unusual manifestation of chronic granulomatous disease in childhood. Pediatr Med Chir. 1992, 14: 317-319.PubMedGoogle Scholar
- Feld JJ: Hepatic involvement and portal hypertension predict mortality in chronic granulomatous disease. Gastroenterology. 2008, 134: 1917-1926. 10.1053/j.gastro.2008.02.081PubMed CentralPubMedView ArticleGoogle Scholar
- Hussain N: Hepatic abnormalities in patients with chronic granulomatous disease. Hepatology. 2007, 45: 675-683. 10.1002/hep.21524PubMedView ArticleGoogle Scholar
- Ament ME, Ochs HD, Davis SD: Structure and function of the gastrointestinal tract in primary immunodeficiency syndromes. A study of 39 patients. Medicine (Baltimore). 1973, 52: 227-248. 10.1097/00005792-197305000-00004.View ArticleGoogle Scholar
- Ament ME, Ochs HD: Gastrointestinal manifestations of chronic granulomatous disease. N Engl J Med. 1973, 288: 382-387. 10.1056/NEJM197302222880802PubMedView ArticleGoogle Scholar
- Hadzic N: Successful orthotopic liver transplantation for fulminant liver failure in a child with autosomal recessive chronic granulomatous disease. Transplantation. 1995, 60: 1185-1186. 10.1097/00007890-199511270-00023PubMedView ArticleGoogle Scholar
- Hague RA: Resolution of hepatic abscess after interferon gamma in chronic granulomatous disease. Arch Dis Child. 1993, 69: 443-445. 10.1136/adc.69.4.443PubMed CentralPubMedView ArticleGoogle Scholar
- Chin TW: Corticosteroids in treatment of obstructive lesions of chronic granulomatous disease. J Pediatr. 1987, 111: 349-352. 10.1016/S0022-3476(87)80452-3PubMedView ArticleGoogle Scholar
- Metin A: Gastric antral stricture in a patient with chronic granulomatous disease. Turk J Pediatr. 1999, 41: 369-373.PubMedGoogle Scholar
- Safe AF: Relapsing Salmonella enteritidis infection in a young adult male with chronic granulomatous disease. Postgrad Med J. 1991, 67: 198-201. 10.1136/pgmj.67.784.198PubMed CentralPubMedView ArticleGoogle Scholar
- Buescher ES, Gallin JI: Stature and weight in chronic granulomatous disease. J Pediatr. 1984, 104: 911-913. 10.1016/S0022-3476(84)80497-7PubMedView ArticleGoogle Scholar
- Frifelt JJ: Chronic granulomatous disease associated with chronic glomerulonephritis. Acta Paediatr Scand. 1985, 74: 152-157. 10.1111/j.1651-2227.1985.tb10940.xPubMedView ArticleGoogle Scholar
- Grossniklaus HE, Frank KE, Jacobs G: Chorioretinal lesions in chronic granulomatous disease of childhood. Clinicopathologic correlations. Retina. 1988, 8: 270-274. 10.1097/00006982-198808040-00009PubMedView ArticleGoogle Scholar
- Myerson DA, Rosenfield AT: Renal aspergillosis: a report of two cases. J Can Assoc Radiol. 1977, 28: 214-216.PubMedGoogle Scholar
- Johansen KS: Chronic granulomatous disease presenting as xanthogranulomatous pyelonephritis in late childhood. J Pediatr. 1982, 100: 98-100. 10.1016/S0022-3476(82)80246-1PubMedView ArticleGoogle Scholar
- Peces R, Ablanedo P, Seco M: [Amyloidosis associated with chronic granulomatous disease in a patient with a renal transplant and recurrent urinary tract infections]. Nefrologia. 2002, 22: 486-491.PubMedGoogle Scholar
- Walther MM: The urological manifestations of chronic granulomatous disease. J Urol. 1992, 147: 1314-1318.PubMedGoogle Scholar
- Jung K: Severe infectious complications in a girl suffering from atopic dermatitis were found to be due to chronic granulomatous disease. Acta Derm Venereol. 1993, 73: 433-436.PubMedGoogle Scholar
- Ahmed I: Clinicopathologic challenge. Childhood granulomatous peri-orificial dermatitis with extra-facial lesions. Int J Dermatol. 2007, 46: 143-145. 10.1111/j.1365-4632.2007.03089.xPubMedView ArticleGoogle Scholar
- Luis-Montoya P, Saez-de Ocariz MM, Vega-Memije ME: Chronic granulomatous disease: two members of a single family with different dermatologic manifestations. Skinmed. 2005, 4: 320-322. 10.1111/j.1540-9740.2005.03927.xPubMedView ArticleGoogle Scholar
- Dohil M: Cutaneous manifestations of chronic granulomatous disease. A report of four cases and review of the literature. J Am Acad Dermatol. 1997, 36: 899-907. 10.1016/S0190-9622(97)80269-1PubMedView ArticleGoogle Scholar
- Gallin JI, Buescher ES: Abnormal regulation of inflammatory skin responses in male patients with chronic granulomatous disease. Inflammation. 1983, 7: 227-232. 10.1007/BF00917259PubMedView ArticleGoogle Scholar
- Boyanton BL Jr: Burkholderia gladioli osteomyelitis in association with chronic granulomatous disease: case report and review. Pediatr Infect Dis J. 2005, 24: 837-839. 10.1097/01.inf.0000177285.44374.dcPubMedView ArticleGoogle Scholar
- Al-Tawfiq JA, Al-Abdely HM: Vertebral osteomyelitis due to Aspergillus fumigatus in a patient with chronic granulomatous disease successfully treated with antifungal agents and interferon-gamma. Med Mycol. 2010, 48: 537-541. 10.3109/13693780903325290PubMedView ArticleGoogle Scholar
- Dotis J, Roilides E: Osteomyelitis due to Aspergillus spp. in patients with chronic granulomatous disease: comparison of Aspergillus nidulans and Aspergillus fumigatus. Int J Infect Dis. 2004, 8: 103-110. 10.1016/j.ijid.2003.06.001PubMedView ArticleGoogle Scholar
- Dotis J: Femoral osteomyelitis due to Aspergillus nidulans in a patient with chronic granulomatous disease. Infection. 2003, 31: 121-124. 10.1007/s15010-002-2167-1PubMedView ArticleGoogle Scholar
- Hodiamont CJ: Multiple-azole-resistant Aspergillus fumigatus osteomyelitis in a patient with chronic granulomatous disease successfully treated with long-term oral posaconazole and surgery. Med Mycol. 2009, 47: 217-220. 10.1080/13693780802545600PubMedView ArticleGoogle Scholar
- Kozlowski K: Dactylitis secondary to chronic granulomatous disease (report of a case). Radiol Diagn (Berl). 1976, 17: 347-350.Google Scholar
- Cohen-Abbo A, Edwards KM: Multifocal osteomyelitis caused by Paecilomyces varioti in a patient with chronic granulomatous disease. Infection. 1995, 23: 55-57. 10.1007/BF01710060PubMedView ArticleGoogle Scholar
- Davis CM: Basidiomycetous fungal Inonotus tropicalis sacral osteomyelitis in X-linked chronic granulomatous disease. Pediatr Infect Dis J. 2007, 26: 655-656. 10.1097/INF.0b013e3180616cd0PubMedView ArticleGoogle Scholar
- Gill PJ: Chronic granulomatous disease presenting with osteomyelitis: favorable response to treatment with interferon-gamma. J Pediatr Orthop. 1992, 12: 398-400. 10.1097/01241398-199205000-00022PubMedView ArticleGoogle Scholar
- Isotani H: Treatment with rhG-CSF for osteomyelitis in a patient with p47-phox-deficient chronic granulomatous disease. Ann Hematol. 1997, 75: 243-246. 10.1007/s002770050351PubMedView ArticleGoogle Scholar
- Brown JR: Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD). J Leukoc Biol. 2003, 73: 591-599. 10.1189/jlb.1202599PubMedView ArticleGoogle Scholar
- Bonta IL, Adolfs MJ, Parnham MJ: Distribution and further studies on the activity of prostaglandin E in chronic granulomatous inflammation. Agents Actions Suppl. 1979, 121-132.Google Scholar
- Bylund J: Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS-independent activation of NF-kappa B. Eur J Immunol. 2007, 37: 1087-1096. 10.1002/eji.200636651PubMedView ArticleGoogle Scholar
- Carp H, Janoff A: Potential mediator of inflammation. Phagocyte-derived oxidants suppress the elastase-inhibitory capacity of alpha 1-proteinase inhibitor in vitro. J Clin Invest. 1980, 66: 987-995. 10.1172/JCI109968PubMed CentralPubMedView ArticleGoogle Scholar
- Hampton MB: Oxidant-mediated phosphatidylserine exposure and macrophage uptake of activated neutrophils: possible impairment in chronic granulomatous disease. J Leukoc Biol. 2002, 71: 775-781.PubMedGoogle Scholar
- Govan JR: The Burkholderia cepacia complex and cytokine induction: an inflammatory tale. Pediatr Res. 2003, 54: 294-296. 10.1203/01.PDR.0000076660.83194.ECPubMedView ArticleGoogle Scholar
- George-Chandy A: Th17 development and autoimmune arthritis in the absence of reactive oxygen species. Eur J Immunol. 2008, 38: 1118-1126. 10.1002/eji.200737348PubMedView ArticleGoogle Scholar
- Petersen JE: Enhanced cutaneous inflammatory reactions to Aspergillus fumigatus in a murine model of chronic granulomatous disease. J Invest Dermatol. 2002, 424-429.Google Scholar
- Schappi M: Branched fungal beta-glucan causes hyperinflammation and necrosis in phagocyte NADPH oxidase-deficient mice. J Pathol. 2008, 214: 434-444.PubMedView ArticleGoogle Scholar
- Casale AJ: Bilateral complete ureteral obstruction and renal insufficiency secondary to granulomatous disease. J Urol. 1989, 142: 812-814.PubMedGoogle Scholar
- Francke U: Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome. Am J Hum Genet. 1985, 37: 250-267.PubMed CentralPubMedGoogle Scholar
- Frey D: Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the Xk gene locus. Blood. 1988, 71: 252-255.PubMedGoogle Scholar
- Marsh WL, Uretsky SC, Douglas SD: Antigens of the Kell blood group system on neutrophils and monocytes: their relation to chronic granulomatous disease. J Pediatr. 1975, 87: 1117-1120. 10.1016/S0022-3476(75)80124-7PubMedView ArticleGoogle Scholar
- Ito K: Kell phenotypes in 15 Japanese patients with chronic granulomatous disease. Vox Sang. 1979, 37: 39-40. 10.1111/j.1423-0410.1979.tb02266.xPubMedView ArticleGoogle Scholar
- Brzica SM Jr: Chronic granulomatous disease and the Mcleod phenotype. Successful treatment of infection with granulocyte transfusions resulting in subsequent hemolytic transfusion reaction. Mayo Clin Proc. 1977, 52: 153-156.PubMedGoogle Scholar
- Brandrup F: Discoid lupus erythematosus-like lesions and stomatitis in female carriers of X-linked chronic granulomatous disease. Br J Dermatol. 1981, 104: 495-505. 10.1111/j.1365-2133.1981.tb08163.xPubMedView ArticleGoogle Scholar
- Garioch JJ: Dermatoses in five related female carriers of X-linked chronic granulomatous disease. Br J Dermatol. 1989, 121: 391-396. 10.1111/j.1365-2133.1989.tb01434.xPubMedView ArticleGoogle Scholar
- Humbert JR: Frequency of the carrier state for X-linked chronic granulomatous disease among females with lupus erythematosus. Clin Genet. 1976, 10: 16-20.PubMedView ArticleGoogle Scholar
- Rupec RA: Lupus erythematosus tumidus and chronic discoid lupus erythematosus in carriers of X-linked chronic granulomatous disease. Eur J Dermatol. 2000, 10: 184-189.PubMedGoogle Scholar
- Sillevis Smitt JH: Discoid lupus erythematosus-like lesions in carriers of X-linked chronic granulomatous disease. Br J Dermatol. 1990, 122: 643-650. 10.1111/j.1365-2133.1990.tb07286.xPubMedView ArticleGoogle Scholar
- Johnston RB III, Harbeck RJ, Johnston RB Jr: Recurrent severe infections in a girl with apparently variable expression of mosaicism for chronic granulomatous disease. J Pediatr. 1985, 106: 50-55. 10.1016/S0022-3476(85)80463-7PubMedView ArticleGoogle Scholar
- Kragballe K: Relation of monocyte and neutrophil oxidative metabolism to skin and oral lesions in carriers of chronic granulomatous disease. Clin Exp Immunol. 1981, 43: 390-398.PubMed CentralPubMedGoogle Scholar
- Martin-Villa JM: Higher incidence of autoantibodies in X-linked chronic granulomatous disease carriers: random X-chromosome inactivation may be related to autoimmunity. Autoimmunity. 1999, 31: 261-264.PubMedView ArticleGoogle Scholar
- Gerba WM: Chronic granulomatous disease and selective IgA deficiency. Am J Pediatr Hematol Oncol. 1982, 4: 155-160.PubMedGoogle Scholar
- Shamsian BS: Autosomal recessive chronic granulomatous disease, IgA deficiency and refractory autoimmune thrombocytopenia responding to Anti-CD20 monoclonal antibody. Iran J Allergy Asthma Immunol. 2008, 7: 181-184.PubMedGoogle Scholar
- [The NBT test in pediatrics]. Recenti Prog Med. 1976, 61: 219-231.Google Scholar
- Ayatollahi M, et al: A fast and easy nitroblue tetrazolium method for carrier screening and prenatal detection of chronic granulomatous disease. Arch Iran Med. 2006, 9: 335-338.PubMedGoogle Scholar
- Budny JL, Grotke NC, MacGillivray M: Nitroblue tetrazolium dye reduction: diagnostic value in children with febrile illnesses. N Y State J Med. 1976, 76: 877-881.PubMedGoogle Scholar
- Crockard AD: Diagnosis and carrier detection of chronic granulomatous disease in five families by flow cytometry. Int Arch Allergy Immunol. 1997, 114: 144-152. 10.1159/000237660PubMedView ArticleGoogle Scholar
- Elloumi HZ, Holland SM: Diagnostic assays for chronic granulomatous disease and other neutrophil disorders. Methods Mol Biol. 2007, 412: 505-523. 10.1007/978-1-59745-467-4_31PubMedView ArticleGoogle Scholar
- Emmendorffer A: A fast and easy method to determine the production of reactive oxygen intermediates by human and murine phagocytes using dihydrorhodamine J. Immunol Methods. 1990, 131: 269-275. 10.1016/0022-1759(90)90198-5.PubMedView ArticleGoogle Scholar
- Emmendorffer A: Evaluation of flow cytometric methods for diagnosis of chronic granulomatous disease variants under routine laboratory conditions. Cytometry. 1994, 18: 147-155. 10.1002/cyto.990180306PubMedView ArticleGoogle Scholar
- Epling CL: Neutrophil function screening in patients with chronic granulomatous disease by a flow cytometric method. Cytometry. 1992, 13: 615-620. 10.1002/cyto.990130609PubMedView ArticleGoogle Scholar
- Chien SC: Rapid prenatal diagnosis of X-linked chronic granulomatous disease using a denaturing high-performance liquid chromatography (DHPLC) system. Prenat Diagn. 2003, 23: 1092-1096. 10.1002/pd.761PubMedView ArticleGoogle Scholar
- Klaudel-Dreszler MA: Treosulfan-based conditioning regimen in a second matched unrelated peripheral blood stem cell transplantation for a pediatric patient with CGD and invasive aspergillosis, who experienced initial graft failure after RIC. Int J Hematol. 2009, 90: 571-575. 10.1007/s12185-009-0433-zPubMedView ArticleGoogle Scholar
- de BM: Prenatal diagnosis in a family with X-linked chronic granulomatous disease with the use of the polymerase chain reaction. Prenat Diagn. 1992, 12: 773-777. 10.1002/pd.1970120910View ArticleGoogle Scholar
- Johnston RB Jr: Clinical aspects of chronic granulomatous disease. Curr Opin Hematol. 2001, 8: 17-22. 10.1097/00062752-200101000-00004PubMedView ArticleGoogle Scholar
- lekst S: Surgery and granulocyte transfusions for life-threatening infections in chronic granulomatous disease. Helv Paediatr Acta. 1985, 40: 277-284.Google Scholar
- Lekstrom-Himes JA: Treatment with intralesional granulocyte instillations and interferon-gamma for a patient with chronic granulomatous disease and multiple hepatic abscesses. Clin Infect Dis. 1994, 19: 770-773. 10.1093/clinids/19.4.770PubMedView ArticleGoogle Scholar
- Del GI: Allogeneic stem cell transplant from HLA-identical sibling for chronic granulomatous disease and review of the literature. Ann Hematol. 2003, 82: 189-192.Google Scholar
- Bhattacharya A: Successful umbilical cord blood stem cell transplantation for chronic granulomatous disease. Bone Marrow Transplant. 2003, 31: 403-405. 10.1038/sj.bmt.1703863PubMedView ArticleGoogle Scholar
- Seger RA: Modern management of chronic granulomatous disease. Br J Haematol. 2008, 140: 255-266. 10.1111/j.1365-2141.2007.06880.xPubMedView ArticleGoogle Scholar
- Barese CN, Goebel WS, Dinauer MC: Gene therapy for chronic granulomatous disease. Expert Opin Biol Ther. 2004, 4: 1423-1434. 10.1517/14712598.4.9.1423PubMedView ArticleGoogle Scholar
- Gene therapy for X-linked chronic granulomatous disease. Haematologica. 2000, 85: 450.Google Scholar
- Becker S: Correction of respiratory burst activity in X-linked chronic granulomatous cells to therapeutically relevant levels after gene transfer into bone marrow CD34+ cells. Hum Gene Ther. 1998, %20;9: 1561-1570.View ArticleGoogle Scholar
- Bjorgvinsdottir H: Retroviral-mediated gene transfer of gp91phox into bone marrow cells rescues defect in host defense against Aspergillus fumigatus in murine X-linked chronic granulomatous disease. Blood. 1997, 89: 41-48.PubMedGoogle Scholar
- Blaese RM: What is the status of gene therapy for primary immunodeficiency?. Immunol Res. 2007, 38: 274-284. 10.1007/s12026-007-0009-zPubMedView ArticleGoogle Scholar
Copyright
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.