Хроническая гранулематозная болезнь

Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis

Authors:: Christa S Zerbe, MD, MS; Beatriz E Marciano, MD; Steven M Holland, MD
Section Editor:: Jordan S Orange, MD, PhD
Deputy Editor:: Elizabeth TePas, MD, MS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2020. | This topic last updated: Jul 22, 2019.

INTRODUCTIONChronic 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 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which constitutes the phagocyte 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 for superoxide production (nitroblue tetrazolium reduction or dihydrorhodamine [DHR] 123 flow cytometry assay). The exact molecular defect is determined by genotyping.

Infections in patients with CGD are generally caused by catalase-positive microorganisms (most bacterial and all fungal pathogens are catalase positive), but catalase is neither necessary nor sufficient for pathogenicity in CGD. The frequent sites of infection are lung, skin, lymph nodes, and liver. Inflammatory complications such as the formation of granulomata are especially problematic in the lungs and the gastrointestinal and genitourinary tracts. Colitis associated with CGD occurs in 30 to 40 percent of all patients with CGD regardless of residual superoxide production and genotype [1].

This topic reviews 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 phagocyte number and/or function: An overview».)

EPIDEMIOLOGYThe frequency of CGD in the United States is approximately 1:200,000 live births [2]. The disease primarily affects males since over 50 percent of the mutations are X linked. Rates are almost identical across ethnic and racial groups, with approximately one-third of the X-linked mutations occurring de novo. However, in cultures in which consanguineous marriage is common, the autosomal-recessive forms of CGD are more common than X-linked forms, and overall incidence rates may be higher [3].

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 years. In several series, the median age at diagnosis was 2.5 to 3 years of age [4-8]. A growing number of patients are diagnosed in later childhood or adulthood due in part to recognition of milder cases of autosomal-recessive CGD, as well as delayed diagnosis in some patients. Diagnosis may also be delayed because of newer 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 the most common autosomal-recessive form, p47phox deficiency [2].

PATHOGENESISPhagocytes use nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate reactive species of oxygen. CGD arises from mutations that result in the loss or functional inactivation of one of the six proteins required to make the NADPH oxidase complex. All of these proteins are necessary for the proper generation of superoxide. (See ‘Genetic defects’ below.)

The fully assembled NADPH oxidase is a five-protein complex. In the basal state, it exists as two components [9]:

●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)

The assembly of the cytochrome is dependent upon a sixth protein that stabilizes the other five in the membrane of the endoplasmic reticulum. This protein is called essential for reactive oxygen species (EROS), encoded by cytochrome b-245 chaperone 1 (CYBC1). The absence of this protein can also cause CGD [10].

Activation and assembly of the functional oxidase also requires the participation of Rac2, a small guanosine triphosphate (GTP)-binding protein, and Rap1, a small GTPase.

Neutrophil priming — Neutrophils exist in one of three states: quiescent, activated, or primed. Primed neutrophils are poised to undergo an exaggerated respiratory burst or secretory response when specific receptors are triggered. (See ‘Respiratory burst’ below.)

Three main types of agonists are capable of priming neutrophils:

●Inflammatory mediators that are chemotactic

●Serum immunoglobulin and complement

●Inflammatory cytokines and growth factors such as tumor necrosis factor (TNF) alpha, lipopolysaccharide (LPS), peptidoglycan, granulocyte monocyte colony-stimulating factor (GM-CSF), granulocyte colony stimulation factor (G-CSF), substance P, orthovanadate, and interleukin (IL) 1

Priming may be achieved rapidly, over a few minutes, or more slowly, over 30 minutes, depending upon the nature of the stimulus. The primed state is transient, lasting up to several hours.

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 membrane-bound cytochrome complex (gp91phox and p22phox) to form the intact nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (figure 1) [9].

The source of reducing equivalents for the respiratory burst oxidase and the glutathione detoxification pathway is NADPH [11-15]. This compound is replenished from NADP by glucose-6-phosphate dehydrogenase (G6PD) through the hexose monophosphate shunt.

Respiratory burst — After the NADPH oxidase has formed, an electron is then taken from NADPH and donated to molecular oxygen, leading to the formation of superoxide. This is converted to hydrogen peroxide spontaneously or enzymatically by superoxide dismutase. In the final step, hydrogen peroxide reacts with superoxide anion, forming a highly reactive hydroxyl radical that is converted to hypochlorous acid in the presence of myeloperoxidase and chlorine in the neutrophil phagosome (figure 1). 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 (ROS) leads to potassium and proton influx into the phagolysosome, leading to 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 in addition to a direct microbicidal molecule as previously thought [16]. This model also explains why patients with myeloperoxidase deficiency (MPO) do not develop the same infections as patients with CGD.

Innate immune receptors — Foreign material, such as bacteria, fungi, and parasites, display molecules that are not seen in higher organisms. Termed pathogen-associated molecular patterns (PAMPs), these molecular components of microorganisms are recognized by receptors globally referred to as pattern recognition receptors that include Toll-like receptors (TLRs). Patients with CGD, compared with the general population of patients with bacterial pneumonia, express lower levels of several neutrophil receptors, including TLRs (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 [17].

Neutrophil extracellular traps — Neutrophils can continue to participate in antimicrobial activity even after they undergo apoptosis. During neutrophil cell death, the nuclei swell, chromatin dissolves, and large strands of decondensed DNA extrude from the cell, carrying with them proteins from cytosol, granules, and histones from the nuclei themselves [18,19]. These neutrophil extracellular traps (NETs) entangle and may contribute to the extracellular killing of bacteria and fungi [19,20]. NET formation is probably enhanced by hydrogen peroxide, and therefore patients with CGD do not form normal NETs [20,21].

Enhanced inflammation — Several different mechanisms may be involved in the enhanced inflammation seen in patients with CGD.

Inflammatory mediators — Defective production of ROS leads to increased expression of nuclear factor (NF)-kappa-B-regulated inflammatory genes [22]. Higher levels of inflammatory mediators are expressed in monocytes from patients with X-linked CGD without acute infection compared with controls. A similar increase in transcription of anti-inflammatory mediators is not seen.

Inflammasome activation — ROS dampen inflammasome activation in healthy individuals. This inhibition is impaired in patients with CGD [23-25].

Efferocytosis — Efferocytosis is the process by which apoptotic inflammatory cells are recognized and removed by phagocytes. Impaired efferocytosis has been demonstrated in macrophages in a mouse model of CGD [26] and in monocyte-derived macrophages from patients with CGD [27]. Defects in efferocytosis are suspected to contribute to the granulomatous inflammation seen in CGD. Treatment with pioglitazone restores efferocytosis, but it remains to be seen whether this therapy can alter the immune and inflammatory defects seen in CGD in vivo [28].

GENETIC DEFECTSMutations in the genes for the six proteins (gp91phox, p47phox, p22phox, p67phox, p40phox, and essential for reactive oxygen species [EROS]) that are required to make the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex account for all of the known cases of CGD. There are one X-linked and five autosomal-recessive forms of CGD [2]:

●The gene for gp91phox is encoded by cytochrome b-245, beta subunit (CYBB), located at Xp21.1. Defects in this gene cause X-linked CGD (MIM #306400), which accounts for approximately 65 to 70 percent of cases in the United States and Europe [29]. Missense or splicing mutations may be associated with some low levels of residual superoxide production. Patients with these mutations generally have better survival than those with nonsense or deletion mutations that leave no residual superoxide production [30].

●The second membrane component, p22phox, is encoded by cytochrome b-245, alpha subunit (CYBA), located at chromosome 16q24. Defects in this gene cause an autosomal-recessive CGD (MIM #233690), which accounts for less than 5 percent of cases [29].

●The cytosolic factor p47phox is encoded by neutrophil cytosolic factor 1 (NCF1), located at 7q11.23 (MIM #233700). Defects in this gene account for approximately 25 percent of North American cases. Approximately 80 percent of p47phox deficiency is due to a GT (guanine-thymine) deletion in exon 2 that is associated with residual superoxide production [31].

●The cytosolic factor, p67phox, is encoded by neutrophil cytosolic factor 2 (NCF2), located at chromosome 1q25 (MIM #233710). Defects in NCF2 account for less than 5 percent of cases [32].

●The cytosolic factor, p40phox, is encoded by neutrophil cytosolic factor 4 (NCF4), located at 22a13.1 (MIM #601488). Recessive defects in NCF4 cause a mildly impaired respiratory burst activity (may appear normal on standard neutrophil dihydrorhodamine 123 [DHR] testing) but severe inflammatory bowel disease (IBD) [33,34].

●The assembly of the cytochrome complex occurs in the endoplasmic reticulum and is dependent upon EROS (encoded by cytochrome b-245 chaperone 1 [CYBC1]). A handful of patients with CGD due to autosomal-recessive mutations in CYBC1 (MIM #618334) have been identified [10].

Neutrophil immunodeficiency syndrome, a syndrome with some overlap with CGD in terms of superoxide production but also with distinct neutrophil chemotaxis defects and T cell dysfunction, is caused by a dominant-negative mutation in the Ras-related C3 botulinum toxin substrate 2 (RAC2) gene. Patients with dominant-negative mutations in RAC2 may have impaired superoxide production, impaired chemotaxis and adhesion, low T cell receptor excision circles (TRECs), severe bacterial infections, and poor wound healing [35,36]. In contrast, dominant activating RAC2 mutations cause excessive superoxide production with impaired neutrophil migration and severe T and B cell lymphopenia [37].

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 (minority) mutations. The superscripts ⁺, ^—, and ⁰ have been used to indicate normal, decreased, or absent protein levels, respectively [9].

A macrophage-specific defect in gp91phox expression appears to predispose more to localized Bacillus Calmette-Guérin (BCG) infection and tuberculosis (TB) than the other infections typically seen in CGD [38]. (See «Mendelian susceptibility to mycobacterial diseases: Specific defects».)

CLINICAL MANIFESTATIONSPatients with CGD usually present with recurrent or severe infections caused by bacteria or fungi. Other presenting features include growth failure, abnormal wound healing, diarrhea, and granulomatous dermatitis. Patients with CGD may have hepatomegaly, splenomegaly, or lymphadenitis [39] on physical examination.

Infections — Patients with CGD typically experience repeated 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. Lower residual superoxide production is associated with a higher risk of severe infections and a higher mortality, but it does not affect the rates of CGD-related colitis [40].

Bacterial infections in CGD tend to be symptomatic and are typically associated with fever, pleuritic chest pain, and inflammatory marker (eg, C-reactive protein [CRP]) elevation but only mildly elevated leukocyte counts [41]. In contrast, fungal infections are typically associated with little to no fever and lower leukocytosis and are therefore more difficult to recognize clinically. Fungal infections are often detected either at asymptomatic stages on routine screening for infections [42] 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 [43].

Sites of infection — The most common sites of infection are the lung, skin, lymph nodes, and liver [2].

The types of serious infections most often seen (in descending order of frequency) include [40,44]:

●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. In a series of adults with CGD, over one-third with invasive pulmonary fungal infections were asymptomatic [45].

The most common sites for abscesses are perianal/perirectal and the liver. Gingivitis, stomatitis, gastroenteritis, and otitis are also common [2,4-7,9].

Organisms — In general, the organisms that infect patients with CGD are catalase producing. 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 CGD phagocytes could use the hydrogen peroxide produced by catalase-negative microbes to generate reactive oxidants, thereby bypassing the intrinsic CGD defect. However, the majority of pathogens in general 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 genes 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 severe infections in North America are due to five organisms (estimated incidence of severe infections in 268 patients followed at a single center over a 40-year period is shown) [40]:

●Aspergillus species (2.6 cases per 100 patient-years)

●S. aureus (1.44 per 100 patient-years)

●Burkholderia (Pseudomonas) cepacia complex (1.06 per 100 patient-years)

●Serratia marcescens (0.98 per 100 patient-years)

●Nocardia species (0.81 per 100 patient-years)

Another series of 27 patients followed at a different center in North America from 1985 to 2013 found that the most common causes of severe infections, in order of frequency, were S. aureus, Serratia, Klebsiella, Aspergillus, and Burkholderia [44].

Outside of North America, Salmonella and Bacillus Calmette-Guérin (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 and Klebsiella oxytoca, Mycobacterium tuberculosis, nontuberculous mycobacteria, Proteus species, Actinomyces [46], methylotrophic bacteria [47], and Leishmania species [4,6,7].

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 [2]. Severe, resistant facial acne and painful inflammation of the nares are common infectious skin manifestations of S. aureus infection. Other bacteria and fungi are now the more common causes of lung and bone infections in patients with CGD. (See «Chronic granulomatous disease: Treatment and prognosis», section on ‘Antibacterial prophylaxis’.)

B. 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, as well as hemophagocytic lymphohistiocytosis (HLH) [48-52]. 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 [50].

Infants often present with Serratia marcescens bone and soft tissue infections [43]. S. marcescens infections still occur in older children and adults with CGD, but the pattern of presentation is different [53]. 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 [2,54]. A high incidence of tuberculosis (TB) was observed in CGD patients living in areas endemic for TB [55,56]. Draining skin lesions at sites of BCG vaccination are seen in CGD patients, although these infections do not usually disseminate, as occurs in infants with severe combined immunodeficiency (SCID). However, dissemination of BCG may be strain dependent since numerous cases of disseminated BCG in CGD have been reported in particular countries where different strains are found [57].

Granulibacter bethesdensis is an environmental organism that can cause fever, weight loss, and necrotizing pyogranulomatous lymphadenitis [58,59]. Fatal bacteremia has been reported as well [60].

Bacteremia is uncommon, but, when it occurs, it is usually due to the following organisms:

●B. cepacia complex [49,61-63]

●S. marcescens, which is also a common cause of bacterial osteomyelitis [43]

●Chromobacterium violaceum, a gram-negative rod found in brackish water, especially in the Southeastern United States [64,65]

Infection with catalase-negative organisms is uncommon, but severe chronic recurrent actinomycosis has been reported [46]. 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 [66].

Fungal infections — Fungal infections remain the leading causes of mortality in CGD [2], even though the rate of fungal infections is lower than bacterial infections. The frequency of, and mortality from, fungal infections has been markedly reduced since the advent of itraconazole prophylaxis and the use of voriconazole and posaconazole for treatment of filamentous fungal infections (eg, Aspergillus). However, fungal infections continue to occur, even in those on azole antifungal prophylaxis [45]. (See «Chronic granulomatous disease: Treatment and prognosis», section on ‘Antifungal prophylaxis’.)

The fungal organisms that break through azole prophylaxis are usually resistant and require more aggressive diagnosis and therapy. A major recognition has been that the organisms frequently determined morphologically to be Aspergillus fumigatus are, in fact, non-fumigatus Aspergillus species, which is best determined by molecular speciation. Many of these organisms are more virulent in CGD than A. fumigatus and require combination antifungal therapy and may require surgical management [67,68]. Similarly, morphologic diagnosis can be misleading for organisms often thought to be Paecilomyces variotii, which are in fact the more treatment-refractory Geosmithia argillacea [69,70].

Fungal infections typically begin in the lung after inhalation of spores or hyphae. Fungal spores are common in the air in general, but specific exposures are problematic for patients with CGD, such as gardening, yard work, lawn mowing, leaf raking, and mulching. Fungal pneumonia may spread locally to ribs and spine or metastatically to brain. Aspergillus nidulans, an organism that infects patients with CGD almost exclusively, causes a significantly higher rate of osteomyelitis and mortality than other fungi [42,71,72]. Penicillium piceum is a relatively nonpathogenic fungus that can produce lung nodules and osteomyelitis in CGD [73]. In contrast, zygomycosis is rare in patients with CGD and is typically associated with iatrogenic immune suppression [74]. Histoplasmosis and coccidioidomycosis have not been reported in patients with CGD.

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 [75].

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 [76]. Other tissues and organs, such as the retina, liver, lungs, and bone, may also be affected by granulomata [77]. The reasons for granuloma formation in CGD are unknown, but CGD cells fail to degrade chemotactic and inflammatory signals normally and fail to degrade apoptotic cells normally, which may lead to persistent and exuberant inflammation.

Gastrointestinal — Gastrointestinal 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 gastrointestinal manifestations [1]. All patients with confirmed inflammatory bowel disease (IBD) complained of abdominal pain. Diarrhea was reported in 39 percent and nausea and vomiting in 24 percent. Thirty-five percent had gastrointestinal obstruction (gastric, esophageal, duodenal, and other). Bowel strictures and fistulae are present in a significant number of patients. Upper gastrointestinal tract inflammatory disease is common, although typically not as severe as colonic disease [78].

Sixty-five percent of the patients in one series with gastrointestinal involvement had either granulomatous or ulcerative colonic lesions [1]. Crohn disease and ulcerative colitis were diagnosed in only 20 percent of those with inflammatory bowel lesions. The CGD genotype appears to accentuate the standard genetic risks associated with IBD [79]. The granulomata in CGD IBD were characterized by sharply defined histiocyte aggregates with surrounding lymphocytic inflammation, unlike the poorly formed granulomata seen in Crohn disease. However, when staining for the macrophage marker CD68 was done, CGD bowel disease had much lower levels of staining than either normal patients or patients with Crohn disease who did not have CGD [80]. This appears to be related to CD68 expression since other markers of macrophage number are similar between Crohn disease and CGD. While IBD is common in CGD, the rate of CGD in general IBD is not clear; it may account for approximately 1 percent of cases. Genome-wide association studies (GWAS) in patients with early-onset IBD have repeatedly identified the genes involved in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [81].

It is important to keep CGD granulomatous colitis in mind since patients with CGD have a much worse (and sometimes fatal) outcome with tumor necrosis factor (TNF) alpha inhibition (eg, infliximab) than do typical patients with Crohn disease [82]. (See «Clinical presentation and diagnosis of inflammatory bowel disease in children» and «Overview of the management of Crohn disease in children and adolescents» and «Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors» and «Chronic granulomatous disease: Treatment and prognosis», section on ‘Therapy for inflammatory manifestations’.)

Hepatic — Liver abnormalities are frequently identified. In a CGD cohort of 194 patients, liver enzymes were elevated in 73 percent, with persistent elevations of alkaline phosphatase seen in 25 percent. Drug-induced hepatitis was reported in 15 percent. 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 had a portal venopathy that was often associated with splenomegaly. 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 [83].

Genitourinary — Urologic disorders are fairly common. 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 [84]. Colitis associated with CGD can also result in fistula formation causing urogenital tract dysfunction [85]. 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 patients with X-linked CGD due to mutations in the gene for gp91phox [86] and are also detected in some gp91phox female carriers. These lesions are mostly asymptomatic retinal scars associated with pigment clumping. Some of these lesions contain bacterial DNA (detected by polymerase chain reaction [PCR]) [87]. The clinical meaning of this finding is unclear, but it may reflect remote seeding. However, these lesions do not progress despite aggressive immunosuppression in some cases, suggesting that they are not sites of active infection. Keratitis has also been reported [4]. (See ‘X-linked carriers’ below.)

Pulmonary — Chronic respiratory disease due to recurrent pulmonary infections is common, particularly in adults [4,45,76]. Findings on chest computed tomography (CT) include bronchiectasis, obliterative bronchiolitis, and chronic fibrosis [4,76]. (See «Pulmonary complications of primary immunodeficiencies», section on ‘Chronic granulomatous disease’.)

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 within 1 to 10 days after inhalation of large burdens of fungal spores and hyphae, such as those found in mulch, hay, peat moss, or dirt [88]. This syndrome is important to recognize since it is best treated with simultaneous administration of glucocorticoids and antifungals.

Potentially noninfectious respiratory events (defined as a radiologic pulmonary opacity that often has an inflammatory pattern and is not proven to be caused by an infection) are common in adults with CGD, occurring in 28 percent of adults in one series [45]. Approximately two-thirds of these patients presented with respiratory symptoms, and most received treatment with immunomodulatory therapies, such as systemic glucocorticoids with or after treatment for infections.

Oral — Recurrent aphthous ulceration is common in CGD and especially common in X-linked carriers. Other oral manifestations may include periodontitis, gingivitis, and gingival hypertrophy [4,89-92].

Skin — Noninfectious skin manifestations of CGD include photosensitivity, discoid lupus, granulomatous lesions, and vasculitis [4].

Autoimmune — Autoimmune disorders are more common in CGD, affecting up to 5 percent of patients [2]. Both discoid and systemic lupus erythematosus (SLE) have been described and occur with at least the same frequency in X-linked CGD female carriers as in patients [93,94]. Immune thrombocytopenia (ITP) and juvenile idiopathic arthritis (JIA) are also more frequent in CGD than in the general population [2]. Other reported autoimmune diseases in patients with CGD include fibrotic pulmonary disease, immunoglobulin A (IgA) nephropathy, antiphospholipid syndrome, and recurrent pericardial effusion [95].

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 [4]. Thirty-five percent required nasogastric and/or parenteral nutritional supplementation. In another small series of 23 patients, approximately 20 percent were below the 10^th percentile for height and weight [5]. Growth often improves in late adolescence [96], and many patients with CGD attain their expected growth potential by adulthood. Hematopoietic cell transplantation appears to correct most cases of growth retardation regardless of the cause [97].

McLeod syndrome — The Kell metallo-endopeptidase (KEL) gene locus on chromosome 7q33 encodes the Kell blood group proteins, of which there are more than 25 antigens. The Kell blood group system is formed by two disulfide-linked proteins, Kell and Kx, which is encoded by X-linked Kx blood group (XK), telomeric to CYBB on chromosome Xp21. Patients with deletions in the X chromosome may have deletions in portions of both CYBB and XK (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, Kell(-). This may result in anemia, elevated creatine phosphokinase, and late-onset peripheral and central nervous system manifestations. (See «Causes of spiculated cells (echinocytes and acanthocytes) and target cells», section on ‘Blood group abnormalities’ and «Neuroacanthocytosis», section on ‘Mcleod syndrome’ and «Red blood cell antigens and antibodies», section on ‘Kell blood group system’.)

Special care has to be taken when transfusing patients with X-linked CGD/McLeod syndrome to avoid Kell(+) transfusions into these Kell(-) patients [98,99]. 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.

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 (positive dihydrorhodamine [DHR] 123 test) and the other with impaired respiratory burst activity [100]. Therefore, X-linked CGD carriers display a characteristic mosaic pattern on respiratory burst testing of individual peripheral blood cells seen microscopically (nitroblue tetrazolium [NBT] test) or by flow cytometry (DHR test). (See ‘Neutrophil function tests’ below.)

As few as 20 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 infections. However, carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD [101-104]. In a large series of X-linked carriers, those with <20 percent DHR+ cells had serious infectious complications, while all carriers, regardless of percent DHR+ cells, had increased rates of inflammatory and autoimmune complications [105]. In addition, progressive skewing of X-chromosome inactivation with age in previously healthy carriers of gp91phox null mutations can lead to late-onset manifestations of CGD [106]. Females may have other manifestations of heterozygous carriage of X-linked CGD mutations, including discoid lupus erythematosus, aphthous ulcers, chorioretinal lesions, and photosensitivity [107,108], which are not dependent upon the degree of lyonization but appear to correlate with lyonization per se.

LABORATORY FINDINGSCertain abnormalities in routine laboratory tests are associated with the disease, although these are not required for diagnosis:

●Hypergammaglobulinemia, possibly due to chronic inflammation

●Low numbers of circulating memory B cells [109]

●CD4 T cell lymphocytopenia, which may be marked, but does not correlate with infection risk nor predispose to T cell pathogens [110]

●Anemia of chronic disease

●Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), usually in the presence of infection

●Hypoalbuminemia, found in 70 percent of patients with gastrointestinal involvement and 25 percent without gastrointestinal manifestations [1]

DIAGNOSISPatients suspected of having CGD should initially undergo neutrophil-function testing. Positive findings should be confirmed by genotyping. It is important to appreciate that the p47phox mutation is due to a pseudogene conversion and so may not be detectable by standard sequencing. In these cases, an immunoblot or gene dose determination may be needed to confirm p47phox deficiency.

A history of recurrent and/or unusually severe infections, particularly abscesses and infections caused by the pathogens commonly associated with CGD, should prompt functional or genetic screening. Neonatal or early postnatal screening of potentially affected children is essential with a family history of CGD. (See ‘Infections’ above.)

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 (DHR) 123 oxidation test.

Most 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 [111,112]. Other tests can also provide reliable diagnosis of CGD but either cannot distinguish carrier status or require significant operator experience.

Dihydrorhodamine 123 test — In this test, the nonfluorescent rhodamine derivative, DHR, is taken up by phagocytes and oxidized to a green fluorescent compound by products of the nicotinamide adenine dinucleotide phosphate (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 [30]. (See ‘Genetic testing’ below.)

Other conditions that affect the neutrophil respiratory burst, giving abnormal DHR test results but normal measures of extracellular superoxide production (eg, cytochrome c reduction or NBT tests), include myeloperoxidase deficiency and the syndrome of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) [113,114]. The DHR test can also be used to determine chimerism status following hematopoietic cell transplantation [115]. Several reference laboratories in the United States and around the world offer these assays.

Nitroblue tetrazolium test — The oldest laboratory test for CGD is the 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.

Genetic testing — The clinical history usually suggests autosomal-recessive or X-linked disease, based on sex, consanguinity, age at presentation, and severity. A diagnosis of CGD based on abnormal neutrophil function should be followed by genetic testing. Sequencing of the patient’s phagocyte oxidase (phox) genes to determine the exact molecular defect is recommended. Genetic testing is available through specialized commercial laboratories and selected tertiary referral centers. The most common p47phox defect can be difficult to identify genetically as it is caused by pseudogene conversion and may be missed in typical sequencing studies. For these cases, immunoblotting or flow cytometry can show absence of protein. An amplification of the various pseudogenes can also be performed to prove loss of the functional allele.

Genetic testing is increasingly important in the risk profiling of 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 usually lead to complete loss of DHR activity, more severe CGD, and diminished survival [30]. Thus, gene sequencing can be used without further functional studies to predict relative mortality risk and counsel regarding bone marrow transplantation or gene therapy.

Prenatal diagnosis — If the precise mutation of a family member with CGD is known, then chorionic villus or amniotic fluid 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 test.

DIFFERENTIAL DIAGNOSISThe 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 (CF)

●Hyperimmunoglobulin E syndrome

●Glucose-6-phosphate dehydrogenase (G6PD) deficiency

●Glutathione synthetase (GS) deficiency

●Crohn disease (in patients with inflammation limited to the rectum)

Patients with CF may develop B. cepacia complex infections. However, the infections in patients with CF 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».)

Patients with hyperimmunoglobulin E syndrome develop staphylococcal infections and may develop Aspergillus infections in the lung. However, the Aspergillus infections occur only in the setting of pre-existing lung cysts, which are not common in patients with CGD. Also, hyperimmunoglobulin E patients have characteristic facies and markedly elevated immunoglobulin E (IgE) levels, whereas CGD patients do not. (See «Autosomal dominant hyperimmunoglobulin E syndrome».)

G6PD deficiency and GS deficiency affect the neutrophil respiratory burst and increase susceptibility to bacterial infections [116-118]. 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 intellectual disability. These disorders are reviewed separately. (See «Myeloperoxidase deficiency and other enzymatic WBC defects causing immunodeficiency».)

Patients with Crohn disease have inflammatory bowel symptoms similar to those in CGD colitis. However, Crohn disease is not associated with severe infections, as is CGD. While Crohn disease can involve any part of the gastrointestinal tract and may have extraintestinal manifestations, CGD colitis is more often rectal and perirectal and is not associated with extraintestinal manifestations. Histopathologically, CGD bowel biopsies have lipid-laden macrophages, which are not characteristic of Crohn disease.

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 [119]. This effect is not diagnostically significant.

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See «Society guideline links: Primary immunodeficiencies».)

INFORMATION FOR PATIENTSUpToDate offers two types of patient education materials, «The Basics» and «Beyond the Basics.» The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on «patient info» and the keyword(s) of interest.)

●Basics topic (see «Patient education: Chronic granulomatous disease (The Basics)»)

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 years. (See ‘Introduction’ above.)

●CGD is caused by defects in phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which comprises the phagocyte oxidase (phox). This enzyme complex is responsible for the phagocyte respiratory burst. (See ‘Pathogenesis’ above.)

●Mutations in the genes for all six proteins (gp91phox, p47phox, p22phox, p67phox, p40phox, and essential for reactive oxygen species [EROS]) that make up the NADPH oxidase complex account for all of the known cases of CGD. Most mutations in North America are X linked (gp91phox deficiency). (See ‘Genetic defects’ 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 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.)

●Female carriers generally do not have an increased rate of infections, but they are more predisposed to certain inflammatory manifestations associated with CGD. However, females can develop typical CGD infections when oxidase activity drops to <20 percent of normal due to skewed X-chromosome lyonization. (See ‘X-linked carriers’ above.)

●A neutrophil function test, dihydrorhodamine (DHR) 123, is the initial diagnostic test performed. A significantly abnormal finding should be confirmed by genotyping. Those with severe X-linked mutations are at higher risk for infection and mortality and may be candidates for hematopoietic cell transplantation. (See ‘Diagnosis’ above and «Chronic granulomatous disease: Treatment and prognosis», section on ‘Hematopoietic cell transplantation’.)

ACKNOWLEDGMENTThe editorial staff at UpToDate would like to acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

The editorial staff at UpToDate would also like to acknowledge Sergio D Rosenzweig, MD, who contributed as an author to earlier versions of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

Topic 3925 Version 26.0

GRAPHICS

NADPH oxidase activation

Glucose-6-phosphate dehydrogenase is required for the production of NADPH, an essential component of the NADPH oxidase system (1). The phagocyte NADPH oxidase system generates O^— ₂ by transferring e^— from NADPH to O₂ (2). Superoxide is metabolized to H₂O₂ by superoxide dismutase (3). Hydrogen peroxide can follow different metabolic pathways inside the cell. Myeloperoxidase can convert it into HOCl (4), which is involved in the oxygen-dependent killing of microorganisms in combination with other reactive oxygen species (5). Alternatively, hydrogen peroxide can be degraded to H₂O and O₂, thereby avoiding deleterious effect on the cell (6). Hydrogen peroxide can also diffuse outside the cell and can augment other defective cells (7).

NADPH: reduced form of nicotinamide adenine dinucleotide phosphate; NADP⁺: nicotinamide adenine dinucleotide phosphate; p47 phox: 47 kilodalton (KD) phagocyte oxidase; p67 phox: 67 kilodalton (KD) phagocyte oxidase; p40 phox: 40 kilodalton (KD) phagocyte oxidase; p22 phox: 22 kilodalton (KD) phagocyte oxidase; gp91 phox: 91 kilodalton (KD) glycoprotein oxidase; GTP: guanosine triphosphate; rap1: a small GTP hydrolase (GTPase); rac: GTPase-activating protein; H₂O₂: hydrogen peroxide; O₂: molecular oxygen; e^—: electron; O^— 2: superoxide anion; HOCl: hypocholorous acid.

Graphic 72548 Version 5.0

DHR test

DHR assay for CGD diagnosis. Unstimulated (left) and PMA-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 two populations seen: one is normally fluorescent, while the other is essentially the same as the unstimulated population.
In the patient with X-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.

DHR: dihydrorhodamine; PMA: phorbol myristate acetate; X-CGD: X-linked chronic granulomatous disease; gp91: 91 kiloDalton glycoprotein (an enzyme that is part of the phagocyte oxidase system); p47phox: 47 kiloDalton phagocyte oxidase protein; CGD: chronic granulomatous disease.

Tracings courtesy of Dr. Douglas B Kuhns, SAIC Frederick.

Graphic 68461 Version 3.0

Chronic granulomatous disease: Treatment and prognosis

Authors:: Beatriz E Marciano, MD; Christa S Zerbe, MD, MS; Steven M Holland, MD
Section Editor:: Jordan S Orange, MD, PhD
Deputy Editor:: Elizabeth TePas, MD, MS

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2020. | This topic last updated: Jun 23, 2020.

INTRODUCTIONChronic 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 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (phox). The cornerstones of CGD management are antimicrobial and immunomodulatory prophylaxis, early diagnosis and aggressive management of infectious complications, careful management of inflammatory complications, and consideration for hematopoietic stem cell repair or replacement.

CGD was initially termed «fatal granulomatous disease of childhood» because patients rarely survived past their first decade in the time before routine use of prophylactic antimicrobial agents. The average patient now survives at least 40 years. Overall, survival rates are better for females (autosomal recessive) than males (most often X linked), reflecting the greater severity of X-linked CGD.

The treatment and prognosis of CGD are reviewed here. The pathogenesis, clinical manifestations, and diagnosis of CGD, as well as an overview of primary disorders of phagocytic function, are discussed separately. (See «Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis» and «Primary disorders of phagocyte number and/or function: An overview».)

MANAGEMENTThe management of CGD focuses on aggressive diagnosis and treatment of infections. The reduction in mortality and morbidity seen over the past few decades is largely attributable to antimicrobial prophylaxis and rapid recognition and treatment of infections in these patients [1-4].

The cornerstones of CGD management are [5]:

●Lifelong antibacterial and antifungal prophylaxis

●Early diagnosis of infection

●Aggressive management of infectious complications

Antimicrobial prophylaxis — Antimicrobial prophylaxis in CGD patients relies on a combination of antibacterial and antifungal therapy with or without immunomodulatory therapy. The triad of therapies used in the United States is the following:

●Antibacterial – Trimethoprim-sulfamethoxazole (TMP-SMX or cotrimoxazole)

●Antifungal – Itraconazole

●Immunomodulatory – Interferon (IFN) gamma

This combination therapy dramatically reduces the rate of severe infections from one per patient-year to almost one every 10 patient-years [1-3,5,6]. IFN-gamma therapy is less commonly used outside of the United States. (See ‘Immunomodulatory therapy with interferon-gamma’ below.)

Antibacterial prophylaxis — Lifelong antibacterial prophylaxis is the standard of care for patients with CGD despite the lack of randomized trials examining this approach. There are several retrospective series that suggest that trimethoprim-sulfamethoxazole (TMP-SMX) is effective in preventing bacterial infections [1,7-9]. Lifelong antibacterial prophylaxis with TMP-SMX (5 mg/kg/day up to a maximum of 320 mg, based upon the trimethoprim [TMP] component, administered orally in two divided daily doses) is therefore suggested. Several centers use once-daily dosing to enhance treatment adherence. Alternatives for patients allergic to sulfonamide drugs include trimethoprim without sulfamethoxazole, beta-lactamase-stable penicillins (eg, dicloxacillin), cephalosporins, or fluoroquinolones.

In one of these series, 11 patients were followed both on and off of antibacterial prophylaxis. TMP-SMX lowered the incidence of bacterial infections from 15.8 per 100 patient-months to 6.9 per 100 patient-months in patients with X-linked CGD (n = 4) and from 7.1 to 2.4 per 100 patient-months in patients with autosomal-recessive CGD (n = 7) [1]. TMP-SMX prophylaxis did not result in an increase in fungal infections.

Antifungal prophylaxis — The advent and evolution of the azole antifungal drugs have dramatically altered the clinical consequences of fungal infections in CGD. Lifelong antifungal prophylaxis is the standard of care for patients with CGD. Several observational series and a single randomized trial demonstrated that itraconazole is highly effective as antifungal prophylaxis in CGD, although fungal infections can still occur [2,10-14]. Itraconazole is the recommended therapy for lifelong antifungal prophylaxis. For children who cannot swallow pills, we administer 5 mg/kg oral solution once daily, maximum dose 200 mg. For patients able to swallow pills, we use the capsule strength closest to 5 mg/kg/day (100 mg or 200 mg capsule). Itraconazole-resistant fungal infections do occur, but most have been responsive to voriconazole or posaconazole [15,16].

In the randomized trial, 39 patients were assigned to receive either placebo or itraconazole (100 mg orally per day in patients aged 5 to 12 years; 200 mg orally per day in patients ≥13 years old or ≥50 kg) for one year [2]. Thereafter, they alternated between itraconazole and placebo annually. All patients were on antibacterial prophylaxis, and most received prophylactic IFN-gamma. Seven invasive fungal infections requiring systemic therapy were reported in patients while receiving placebo compared with only one serious fungal infection while on itraconazole. (This single patient was reported as noncompliant with the antifungal prophylaxis.)

In one series of 67 adult patients, 24 of 29 patients with invasive fungal respiratory infections were reported to be on itraconazole prophylaxis [14]. However, of the seven patients who had serum itraconazole levels measured, five had low levels.

Immunomodulatory therapy with interferon-gamma — Immunomodulatory therapy with IFN-gamma is part of the prophylactic regimen in some centers in the United States, although it has not been as widely adopted in other countries. Issues impacting the use of IFN-gamma in CGD patients around the world include the need for administration by injection, cost, and lack of general familiarity with cytokine therapies [11,12,17]. Additionally, it has been argued that CGD prognosis has improved significantly since the advent of routine antifungal prophylaxis with itraconazole, lessening the need for adjunctive, costly immunomodulatory therapy.

Despite these uncertainties, we suggest IFN-gamma (50 mcg/m² subcutaneously three times per week) as part of the prophylactic therapy for CGD, especially for those who have had more severe recurrent infections. For children less than 0.5 m², 1.5 mcg/kg subcutaneously three times weekly is the suggested dose. Fever and myalgias are the most common adverse events associated with IFN-gamma. These side effects are minimized by concomitant administration of acetaminophen and dosing of IFN-gamma before bedtime and usually ameliorate over time.

An international, multicenter, randomized trial examined prophylactic treatment with IFN-gamma [3]. One-hundred twenty-eight patients with CGD (median age 15 years, range 4 to 24 years old) received IFN-gamma 50 mcg/m² or placebo subcutaneously three times weekly for an average of 8.9 months. Forty-six percent of patients in the placebo group developed at least one serious infection during the follow-up period compared with 22 percent in the IFN-gamma group. Twelve months after randomization, 77±0.06 percent (mean ± standard error [SE]) of patients in the IFN-gamma group had not yet developed a serious infection, whereas only 30±0.11 percent of patients in the placebo group were free of serious infection. This improvement was independent of age, CGD genotype, or concomitant use of other prophylactic agents. However, there was no improvement in superoxide production by phagocytes in treated patients. In addition, no decrease in Aspergillus infections was demonstrated.

One major limitation of the randomized trial was that other experimental drugs, which included itraconazole at the time, were excluded. Results from earlier observational studies of prophylactic IFN-gamma therapy in which most patients were not on itraconazole are consistent with the randomized trial. Three prospective, open-label, phase-IV studies confirmed the decreased rate of serious infections, ranging from a rate of 0.13 to 0.4 per patient-year [6,18,19]. However, a prospective study comparing treatment with trimethoprim-sulfamethoxazole (TMP-SMX) and itraconazole with or without IFN-gamma found no change in the rate of severe infection (0.01 severe infections per patient-year in both groups) [20]. Thus, many studies suggest a benefit to prophylactic IFN-gamma in addition to TMP-SMX. However, it is not clear how much additional benefit, if any, prophylactic IFN-gamma provides beyond that of TMP-SMX combined with itraconazole.

The mechanism of IFN-gamma benefit in patients with CGD remains unclear. It is also unclear whether all patients with CGD benefit equally. Early studies indicated that there were some patients with permissive defects who were more responsive to IFN-gamma in vitro in terms of superoxide production. A subgroup of patients with X-linked CGD have IFN-gamma responsive splice-site defects [21,22]. In these patients, IFN-gamma therapy improved the ability to generate superoxide. Further study is needed to clarify whether there are additional subpopulations of patients who benefit from IFN-gamma therapy and other groups that do not. However, upregulation of superoxide through the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is unlikely be the critical mechanism of IFN-gamma action, since the previous studies showed efficacy in most subgroups and IFN-gamma had activity in a mouse model incapable of NADPH oxidase activity [3,23].

The use of IFN-gamma in the setting of acute infection is of uncertain value. Some experts use IFN-gamma only in the setting of infection rather than as prophylaxis, but the reasons for this are unclear [24]. We suggest discontinuing IFN-gamma in the setting of an acute infection since antimicrobials are of much greater value in this setting, and the addition of IFN-gamma often causes increases in temperature and malaise, obscuring clinical response.

Vaccination in CGD — Bacillus Calmette-Guérin (BCG) vaccination is contraindicated in CGD as it may lead to severe local and regional BCG disease [25]. Live bacterial vaccines are probably best avoided (eg, Salmonella). Live viral vaccines are recommended since viral infections are handled normally in CGD. All inactivated or subunit vaccines are recommended, following the same schedule in normal children. (See «Immunizations in patients with primary immunodeficiency».)

Acute infections — Life-threatening infections may occur at any time in patients with CGD, even in those who have been free of infections for months or years. Early diagnosis and treatment are critical.

Monitoring and diagnosis — Serious infections, particularly those caused by fungi, may be asymptomatic or minimally symptomatic at presentation. Several interventions are suggested to monitor for and diagnose infection:

●The frequency with which patients with CGD should be monitored varies with age, severity, family support, and proximity to care. We suggest patients be seen yearly or more often depending upon their frequency of infections and clinical status. Fungal infections are more often clinically silent than bacterial ones. Significant increases in erythrocyte sedimentation rate or C-reactive protein should prompt a search for hidden infections, even when the white blood cell count is normal. We suggest checking both of these nonspecific markers of inflammation at every encounter to aid in early detection of occult infection. Elevation is usually obvious and occurs in response to both bacterial and fungal infections, although bacterial infections tend to elicit higher levels than fungal ones.

●An elevated inflammatory marker should prompt imaging with plain radiographs, ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI), depending upon the suspected organ involved. The authors obtain chest CT scans when there are concerns about occult infection. The chest physical examination is extremely unreliable for pneumonia in patients with CGD because of the abnormal inflammatory response in the lung. The evolution of infections should be followed closely with CT (chest) or MRI or ultrasound (soft tissue) until resolution and/or stabilization of the lesions since these infections may not fully respond to conventional durations of therapy.

●A definitive microbiologic diagnosis is essential for directing therapy because the differential diagnosis for infection includes bacteria, Nocardia, mycobacteria, and fungi. Empiric antimicrobial treatment prior to obtaining specimens for the identification of the specific pathogen is discouraged in the absence of life-threatening infection. Biopsies to identify the pathogen should be insisted upon before the initiation of therapy and not after empirical therapy has failed.

Treatment — Treatment of acute infections must be aggressive. Cultures are obtained first, if possible (see ‘Monitoring and diagnosis’ above). Patients are then treated empirically for gram-negative, gram-positive, and fungal infections until the pathogen is identified. Several weeks of parenteral therapy are usually required, often followed by a few months of oral therapy. Ultimately, management of infections depends on the microbiology, but some general approaches can be outlined. The organ and species distribution of severe infections in CGD lends some guidance to empiric coverage [26].

●Empiric initiation of trimethoprim-sulfamethoxazole (TMP-SMX; 15 mg/kg/day based upon the trimethoprim component, maximum dose 640 mg), a fluoroquinolone or carbapenem at high dose (to cover gram-negative infection), and voriconazole (6 mg/kg every 12 hours for two doses followed by 4 mg/kg every 12 hours; refer to the Lexicomp drug information monograph included within UpToDate for maximum doses based upon age and weight) is appropriate for pneumonias, pending microbiology and after diagnostic specimens have been obtained. Carbapenems cover the majority of gram-negative pathogens and Nocardia. Patients rarely develop staphylococcal pneumonias after the initiation of prophylaxis. Most Burkholderia, Serratia, and Nocardia infections are sensitive to TMP-SMX. The use of TMP-SMX as therapy for infections that have occurred despite TMP-SMX prophylaxis is highly effective and may reflect either dose response or a failure of patients to actually take their prophylaxis [27].

●Liver abscesses in immunocompetent patients typically are caused by enteric organisms and are liquid and easily drainable. In contrast, liver abscesses encountered in CGD are usually staphylococcal, consist of a dense and caseous material, and have often required excisional surgery [28]. Glucocorticoids along with antibiotics have proved to be successful in the management of staphylococcal liver abscesses in CGD in several case series [29-31], with an associated reduction in the need for percutaneous or open liver drainage of abscesses, and are the preferred therapy for liver abscess in CGD and appear to lead to better outcomes with less recurrence and lower mortality [31]. (See «Pyogenic liver abscess».)

●Lymphadenitis is usually staphylococcal and often necrotic. These infections may respond faster to surgical excision along with antimicrobials. In view of the frequency of methicillin-resistant Staphylococcus aureus (MRSA) in the community, the authors start therapy with vancomycin or an oxazolidinone and then adjust antibiotics when culture results are available. (See «Cervical lymphadenitis in children: Diagnostic approach and initial management», section on ‘Initial laboratory evaluation and management’.)

●Granulibacter bethesdensis is a gram-negative rod that causes necrotizing lymphadenitis in CGD. It grows slowly on Legionella or tuberculosis media and appears to respond to ceftriaxone [32,33].

●Chromobacterium violaceum can cause bacteremia and sepsis in CGD and typically responds to TMP-SMX, quinolones, or carbapenems [34].

●Nocardia species cause severe infection, typically of the lung, in patients with CGD. Nocardia are the only pathogens that routinely cause pulmonary cavitation in patients with CGD, which is distinct from the causes of cavitary lung disease in other patient populations. We suggest initiating therapy with TMP-SMX (15 mg/kg/day) and meropenem (1 gram every eight hours) when Nocardia infection is suspected. Refractory cases may respond to linezolid at doses that are reduced to one-half of the dose used to treat rapidly growing bacteria, such as staphylococci. Nocardia live in decaying matter and therefore are often inhaled along with fungi. This is manifest by coinfection with fungi in one-third of Nocardia cases [35]. Glucocorticoids along with antibiotics may also help in the management of Nocardia pneumonias, which can be necrotic and inflammatory [36].

●In general, fungal infections are more indolent, and bacterial infections are more acute. However, acute fulminant pneumonitis with hypoxia can occur after inhalation exposure to mulch, compost, hay, or dirt, which typically contain high levels of fungi [37]. This presentation of «mulch pneumonitis» is virtually pathognomonic of CGD and requires urgent institution of antifungals and glucocorticoids to control severe pulmonary inflammation and hypoxia. This condition represents the simultaneous evolution of infection and inflammatory response to the fungal cell wall.

●The primary site of Aspergillus infection is generally the lung, but the non-fumigatus aspergilli, such as Aspergillus nidulans, have a high propensity to spread to adjacent bone and to disseminate [38]. Surgical debridement is indicated for non-fumigatus Aspergillus infections that are refractory to medical therapy. (See «Treatment and prevention of invasive aspergillosis».)

●Granulocyte transfusions have been used in some patients with CGD [39-43]. However, such transfusions often lead to alloimmunization, which may significantly impair the likelihood of successful hematopoietic cell transplantation (HCT) later on. Thus, in view of the increasing desirability of HCT in CGD, we reserve granulocyte transfusions for severe disease only. Methods to prevent alloimmunization during granulocyte transfusions have included use of sirolimus or rituximab, but none have been studied prospectively.

●CGD patients with severe infections have been successfully treated with systemic glucocorticoids in addition to antimicrobial agents [29,30,36]. However, it is critical that appropriate antimicrobial therapy is in place before glucocorticoid therapy is initiated since treatment with glucocorticoids can mask symptoms and increase the risk of local spread of infection. Important examples of this are in CGD liver abscess, Nocardia pneumonia, and mulch pneumonitis. This is distinct from the use of glucocorticoids for granulomatous complications in CGD, such as gastric outlet obstruction or colitis. (See ‘Therapy for inflammatory manifestations’ below.)

●HCT has been used successfully to clear refractory infections [44,45]. These infections tend to be fungal and persistent, often with extensive bone or visceral involvement. (See ‘Hematopoietic cell transplantation’ below.)

Therapy for inflammatory manifestations — Gastrointestinal manifestations associated with CGD include esophageal stricture, gastric outlet obstruction, and colitis (including inflammatory bowel disease) [46]. Urologic findings include ureteral and urethral strictures, bladder granulomata, and cystitis. Other inflammatory manifestations include interstitial pneumonitis and neutrophilic dermatosis. Oral glucocorticoids are the most common therapy used for inflammatory manifestations of CGD. Glucocorticoid-sparing therapies include long-term treatment with anti-inflammatory drugs such as azathioprine. Sulfasalazine derivatives are effective for bowel disease. Other agents have been used less frequently, including granulocyte colony-stimulating factor (G-CSF), cyclosporine, and thalidomide. HCT is also effective in resolving inflammatory complications such as colitis in both X-linked and autosomal-recessive CGD [44,47]. (See «Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis», section on ‘Inflammatory and other manifestations’ and ‘Hematopoietic cell transplantation’ below.)

Obstructive lesions of the gastrointestinal and genitourinary tracts and CGD-associated colitis typically respond to glucocorticoids [46,48-50]. Oral prednisone (1 mg/kg/day) is usually initiated after biopsy confirmation of the granulomata and exclusion of active infection. This dose can be tapered gradually over a period of three to six months. However, relapses following discontinuation are common. Over 40 percent of patients may require long-term, low-dose prednisone therapy. Low-dose prednisone (5 to 10 mg daily) is not typically associated with significant adverse effects, such as increased risk of infection, but it may have effects on growth velocity and bone density. (See «Major side effects of systemic glucocorticoids».)

Glucocorticoid-sparing therapies include long-term treatment with aspirin (eg, sulfasalazine [46] or mesalamine [51]) or mercaptopurine (eg, azathioprine [52]) derivatives. Antimicrobials, such as ciprofloxacin (500 mg twice daily) and metronidazole (500 mg twice daily), are also used but have not been studied. Infliximab and other inhibitors of tumor necrosis factor (TNF) alpha function are effective in inducing remission in glucocorticoid-dependent patients, but they profoundly increase the risk of severe infections in CGD to a much greater extent than that seen in other conditions [46,53]. In addition, closure of enteroenteric fistulae on infliximab therapy can lead to the development or worsening of abscesses due to the occlusion of drainage tracts [53]. We avoid TNF-alpha blockade in patients with CGD because of the substantial risks of severe and fatal infection [53]. If TNF-alpha blockade is deemed necessary, we recommend intensified antifungal and antibacterial prophylaxis coupled with aggressive and frequent vigilance for infection.

Case reports suggest that CGD-associated colitis may respond to granulocyte or granulocyte macrophage colony-stimulating factors (G-CSF and GM-CSF, respectively) [54,55]. Results from a case series suggest that inflammatory manifestations may respond to thalidomide, an immunomodulatory agent with TNF-alpha antagonist properties [56]. In this series, eight patients with refractory inflammatory conditions were treated with thalidomide (50 to 100 mg/day orally at bedtime) and followed for a median of 30 months. Disease remission at six months was seen in four of six patients with colitis, three of four patients with lung manifestations, one patient with neutrophilic dermatosis, and one patient with granulomatous hepatitis. A partial response was seen in the other two patients with colitis. Thalidomide was discontinued in two patients due to axonal neuropathy in one patient and venous thrombosis related to a central venous line in another.

Autophagy may be abnormal in CGD due to reduced reactive oxygen species production with increased release of interleukin (IL) 1-beta. Blocking IL-1 may decrease IL-1-beta exposure and restore normal autophagy. Two patients with CGD colitis treated with the IL-1 receptor antagonist anakinra for three months were reported to have had immediate and persistent symptomatic improvement [57]. In contrast, anakinra was ineffective in five patients with CGD colitis [58].

A single case of fistulizing CGD colitis that had partially responded to thalidomide was successfully treated with vedolizumab, an anti-integrin molecule used in Crohn disease [59]. Subsequent cases with moderate response have been reported in abstract form.

Curative therapies — HCT is the only established curative therapy for CGD. However, trials for CGD gene therapy are underway and are also likely to prove curative.

Hematopoietic cell transplantation — Successful HCT is a definitive cure for CGD [44,45,60,61]. As success increases and morbidity and mortality are reduced, early HCT becomes a desirable and appropriate choice for patients with CGD. The estimated HCT event-free survival rate for patients with CGD is >80 percent; overall survival is approximately 90 percent, with improved quality of life as well; and transplant outcomes continue to improve [62].

However, CGD may be diagnosed in toddlers or children later than the other primary immunodeficiencies that are often diagnosed in infancy. In addition, patients with CGD can be successfully managed overall without transplantation, and untransplanted survival is better for CGD than for many other primary immunodeficiencies. Thus, the decision to undergo HCT depends upon prognosis, donor availability, access to transplantation, and patient/family preference.

While outcomes may be better in younger patients with less CGD sequelae, HCT is also useful and successful in adult patients and those with recurrent, serious infections despite prophylaxis and/or severe, difficult-to-treat inflammatory disease [41,44,63]. HCT for active infections should only be performed at centers with experience in this procedure and in the treatment of CGD infections as the risk of death is high. The general approach to HCT in patients with a primary immunodeficiency and to conditioning regimens for HCT are discussed in greater detail separately. (See «Hematopoietic cell transplantation for non-SCID primary immunodeficiencies» and «Preparative regimens for hematopoietic cell transplantation».)

Encouraging results were reported in one series of 27 mostly pediatric, European patients with CGD transplanted with unmodified marrow grafts from human leukocyte antigen (HLA)-identical siblings (25 out of 27) or unrelated (2 out of 27) donors [64]. Absence of pre-existing overt infection appeared as the single best prognostic factor. All patients free of infections at the time of the transplantation (18 out of 18) were alive and well at the time of publication. The four deaths in the study occurred among the nine patients suffering from uncontrolled infections at the time of the procedure. In addition, the four cases of severe graft-versus-host disease (GVHD) occurred in those with overt infections or acute inflammatory disease at the time of the transplant.

Similar findings were reported in another series of 20 mostly pediatric patients in the United Kingdom, in which HCT-associated complications were restricted to those with pre-existing infection or inflammation [47]. One-half of the donors were matched siblings, and the other one-half were unrelated donors. Patients with an unrelated donor received myeloablative conditioning with serotherapy. One patient died from multiorgan failure secondary to disseminated fungal infection after conditioning but prior to HCT. A second patient died after discharge from the hospital from iatrogenic causes related to a previous disseminated fungal infection. Two patients had significant chronic GVHD. Engraftment of neutrophils and adequate chimerism were observed in all transplanted patients. However, two patients required unconditioned bone marrow infusions from the original donors after neutrophil chimerism fell to insufficient levels after the initial engraftment. Colitis resolved, and catch-up growth was seen in the patients with colitis (n = 10) and with growth failure (n = 7) prior to HCT.

Several other studies have examined the use of myeloablative conditioning with serotherapy for patients with unrelated donors. One center performed HCT from matched, unrelated donors in nine patients with CGD [65]. Seven patients were alive and well 20 to 79 months after transplantation. Two patients with restrictive lung disease regained normal lung function. A second center reported on HCT from matched, unrelated donors in seven patients with CGD, all of whom had serious infections prior to transplantation [66]. All seven had full donor neutrophil engraftment, sustained normal levels of oxidative burst, and were alive and well at least one year posttransplant at the time of the report. Three patients developed grade-I acute GVHD of the skin that responded to topical corticosteroids.

Reduced-intensity conditioning regimens have been designed to enhance engraftment and decrease organ toxicity. One such shortened and less toxic conditioning protocol using bone marrow-derived stem cells was tested in three high-risk adult patients with CGD [67]. Patients were pretreated for three weeks with intravenous antibiotics and antifungals prior to transplant. These patients survived the transplant with full donor engraftment and normal neutrophil function at 12 to 27 months.

Important to successful reduced-intensity conditioning with busulfan is targeted drug monitoring and dose adaptation. This requires laboratory measurement of busulfan serum levels and determination of the area under the concentration curve. This individualized approach optimizes both safety and efficacy of busulfan use since metabolism varies with age and genetic factors [68].

Myeloablative HCT, which seeks to eradicate all recipient hematopoiesis, has a higher risk of morbidity than nonmyeloablative conditioning regimen. Since only 20 percent normal cells are sufficient to prevent and control infections, as shown in lyonized females, approaches that yield stable chimerism might be effective. However, an early study in which nonmyeloablative HCT was performed in 10 patients with CGD to achieve mixed hematopoietic chimerism had poor results [69]. Patients were given T cell-depleted hematopoietic stem cell grafts from HLA-identical siblings. Immune reconstitution was successful in eight patients, but three adult patients died 8 to 14 months after the initial procedure. In patients with successful engraftment, only four serious infections occurred during the follow-up period (median 17 months), and all pre-existing granulomatous lesions resolved. (See «Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis», section on ‘X-linked carriers’.)

In a multicenter, prospective series, 56 patients (mean age 12.7 years, range 0 to 40) were given a reduced-intensity conditioning regimen of high-dose fludarabine, low-dose or targeted busulfan, and serotherapy (antithymocyte globulin, Thymoglobulin, or alemtuzumab) prior to HCT with unmanipulated bone marrow or peripheral blood stem cells from HLA-matched, related donors or HLA-9-of-10 or HLA-10-of-10 matched, unrelated donors (n = 21, n = 10, and n = 25, respectively) [44]. Forty-two patients had intractable infections and/or active inflammatory disease, such as colitis. Overall survival was 93 percent at a median follow-up of 21 months, and the two-year probability of survival was 96 percent, including transplants performed in the setting of ongoing infection and/or inflammatory disease. All surviving patients had stable myeloid donor chimerism of at least 90 percent and had resolution of all infectious and inflammatory conditions. All six cases of acute GVHD grade-II and above and all four cases of chronic GVHD occurred in patients with HLA-matched, unrelated donors. Three patients died from GVHD-related complications. One additional patient, who had an HLA-matched, related donor, had secondary graft failure at nine months and died from hemorrhagic shock 10 days after the second HCT. Two of the surviving patients have fathered children.

Transplants from alternative donors (eg, unrelated, mismatched cord blood donors [70] or donors with less than an HLA-9-of-10 match [71] or haploidentical donors) require specialized centers and are the subject of experimental approaches.

Gene therapy/gene repair — CGD is well suited for gene therapy since it results from single gene defects that almost exclusively affect the hematopoietic system. Retroviral and lentiviral vectors that provide normal gp91phox, p47phox, or p67phox genes can reconstitute NADPH oxidase activity in deficient cells, establishing the proof of principle for gene therapy in CGD [72-74]. A limited number of patients with CGD have been treated with gene therapy. The success rates until now have been low, and there have been severe complications including death due to development of abnormal clonal hematopoiesis caused by vector integration events [75-77]. As a result, gene therapy trials have been limited to high-risk patients with severe CGD who lack an HLA-matched donor. Gene repair of CD34+ hematopoietic stem and progenitor cells (HSPCs) using gene-editing technology may help avoid the complications associated with traditional gene therapy. (See «Gene therapy for primary immunodeficiency».)

Peripheral blood stem cells from five adult patients with p47phox-deficient CGD were transduced ex vivo with a recombinant retrovirus containing a normal p47phox gene and then reinfused [72]. These patients did not undergo myeloablative conditioning. Functionally corrected granulocytes were detectable in peripheral blood, but their peak frequency was only 0.004 to 0.05 percent of total peripheral granulocytes, a level well below the minimum number required for protective activity.

Subsequently, two adults with X-linked CGD received retrovirus-based gene therapy with nonmyeloablative bone marrow conditioning to allow corrected cells an opportunity for expansion [78]. Both patients developed monosomy 7 secondary to insertional activation of ecotropic viral integration site 1 (EVI1) [79], and one of the patients died 27 months after the procedure due to infection. In a different study, three adults with X-linked CGD underwent gene therapy [75]. All three patients achieved early gene marking (26, 5, and 4 percent of neutrophils contained the transferred gene, respectively), and two had sustained low-level correction. One patient had resolution of infections, with 1.1 percent marking at 34 months posttreatment, and the other had 0.03 percent marking at 11 months post-gene therapy, with partial control of infections. The third patient died of an invasive fungal infection approximately six months posttreatment after completely losing gene marking.

Novel retroviral vectors that are less prone to activating oncogenes and inducing leukemias in transduced cells are now in for use in gene therapy. A self-inactivating (SIN) lentiviral vector, lacking the potent retroviral enhancer elements and showing decreased transactivation potential, is under study for the treatment of X-linked CGD [80]. This SIN vector is employed in a protocol that also incorporates myeloablative conditioning.

CD34+ stem cell mobilization for gene therapy is somewhat lower in patients with CGD than in normal donors, leading to fewer targets for gene correction. This deficit in CD34+ recruitment may be overcome by mobilization with G-CSF and the marrow-releasing agent plerixafor [81].

DNA editing with clustered regularly interspaced short palindromic repeat/CRISPR-associated 9 (CRISPR/Cas9) can be used to repair defective genes and is under investigation in X-linked CGD. Using this technology, >20 percent of HSPCs had sequence-confirmed repair of the cytochrome b-245, beta subunit (CYBB) gene, and myeloid cells had functional NAPDH oxidase in vitro [82]. Transplantation of these repaired HSPCs into a mouse model of severe combined immunodeficiency (SCID) resulted in production of functional human myeloid and lymphoid cells. No errors were detected in the DNA sequence surrounding the area of repair. Despite early challenges, advances in gene therapy for patients with CGD will probably expand this option for definitive therapy. Initial trials are focused on X-linked CGD, but progress in gene-editing technologies and vector development will most likely enable future extension of gene therapy to autosomal-recessive forms of CGD [83].

PROGNOSISWhen the first 92 patients with «fatal granulomatous of childhood» were reported, 45 had already died, 34 of them before the age of seven years. Since then, survival has dramatically improved, and CGD is now a disease that is eminently survivable into adulthood [17,20,24,26,84-86]. Survival is better in autosomal-recessive forms of CGD compared with X-linked CGD [14,26,87].

The average patient now survives at least 40 years due in large part to routine lifelong use of prophylactic antimicrobial agents. Prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) became routine in the 1980s and prophylactic itraconazole in the 1990s. Patients treated with highly active antimicrobials since diagnosis who have not yet reached 30 years are expected to have even greater longevity. However, respiratory fungal infections (primarily with Aspergillus species) are still the leading cause of death [26].

In series with fewer than 100 patients, published survival rates at 20 years of age ranged from 73 to 87 percent, with a mean survival of approximately 18 years for patients with X-linked CGD and 36 years for autosomal-recessive CGD [24,85,86]. Higher median survival (38 years for X-linked CGD and 50 years for autosomal-recessive CGD) was seen in a European survey of 429 patients, despite only 71 percent of patients receiving antibacterial prophylaxis and 53 percent receiving antifungal prophylaxis [88]. The median age at death increased from 15.5 years before 1990 to 28.1 years in the decade ending in 2012 in a series of 268 patients from a single center in the United States [26]. However, despite improved survival, end-organ complications, including chronic lung disease and liver disease, are still significant in adults [89].

Residual production of reactive oxygen intermediates (ROIs) was strongly associated with increased survival, independent of the specific gene mutated, in a series of 287 patients [87]. Higher levels of residual ROI production were seen in patients with p47phox mutations and gp91phox missense mutations in the first 309 amino acids of the gp91phox molecule compared with other mutations that cause CGD. This is important because it provides a genetic determinant that is directly linked to a functional test and to survival, obviating the need for functional neutrophil testing that is performed in a specialized laboratory.

Quality of life for CGD patients has also improved dramatically. Better therapies are needed for certain manifestations of CGD, such as inflammatory bowel disease. However, antimicrobial prophylaxis with TMP-SMX (cotrimoxazole), itraconazole, and interferon (IFN) gamma, as well as early diagnosis and aggressive treatment of infections, have dramatically reduced the incidence of life-threatening infections [12]. Protocols for hematopoietic cell transplantation (HCT) are improving, offering promise for definitive correction. Gene therapy approaches are under development and may eventually replace HCT. Until then, HCT is the recommended curative approach for those with available donors. (See ‘Hematopoietic cell transplantation’ above and ‘Gene therapy/gene repair’ above.)

●Basics topic (see «Patient education: Chronic granulomatous disease (The Basics)»)

SUMMARY AND RECOMMENDATIONS

●The cornerstones of chronic granulomatous disease (CGD) management are antimicrobial and immunomodulatory prophylaxis, early diagnosis of infections, and aggressive management of infectious complications. (See ‘Management’ above.)

●We recommend that patients with CGD receive lifelong antifungal plus antibacterial prophylaxis with or without immunomodulatory therapy (Grade 1A).

•We suggest using trimethoprim-sulfamethoxazole (TMP-SMX) for antibacterial prophylaxis (Grade 2C). We typically administer 5 mg/kg/day, based upon the trimethoprim (TMP) component, administered orally in two divided daily doses. Alternative antibacterial options include beta-lactamase resistant penicillins, cephalosporins, trimethoprim alone, and fluoroquinolones. (See ‘Antibacterial prophylaxis’ above and ‘Management’ above.)

•We suggest antifungal prophylaxis with itraconazole (Grade 2B). For children who cannot swallow pills, we administer 5 mg/kg oral solution once daily, maximum dose 200 mg. For patients able to swallow pills, we use the capsule strength closest to 5 mg/kg/day (100 mg or 200 mg capsule). Interactions between azole antifungals and glucocorticoids are possible and can lead to high glucocorticoid exposure. (See ‘Antifungal prophylaxis’ above.)

•We suggest the addition of interferon (IFN) gamma therapy to antimicrobial and antifungal prophylaxis (Grade 2B). Recommended dosing is 50 mcg/m² subcutaneously three times per week; for children less than 0.5 m², 1.5 mcg/kg subcutaneously three times weekly. We would not use IFN-gamma during active infections. (See ‘Immunomodulatory therapy with interferon-gamma’ above.)

●A definitive microbiologic diagnosis is essential for properly directing therapy. Biopsies to identify the exact pathogen should be insisted upon before the initiation of therapy and not after empirical therapy has failed. (See ‘Acute infections’ above.)

●Treatment of acute infections should be aggressive. Once cultures have been obtained, acutely ill patients are treated empirically for gram-negative, gram-positive, Nocardia, and fungal infections until the pathogen is identified. Several weeks of therapy are usually required. Surgical removal of refractory fungal infections is advisable if they are localized. Curettage and drainage of liver abscesses are unnecessary as long as a microbiologic diagnosis is available, appropriate antibiotics are given, and glucocorticoids are administered. Granulocyte transfusions are an option in severe cases but are accompanied by a significant risk of alloimmunization, which may complicate subsequent hematopoietic cell transplantation (HCT). (See ‘Acute infections’ above.)

●Oral glucocorticoids are the most common therapy used for inflammatory manifestations of CGD. Glucocorticoid-sparing therapies include long-term treatment with anti-inflammatory drugs, such as azathioprine. Sulfasalazine derivatives are effective for bowel disease. Other agents have been used less frequently, including granulocyte colony-stimulating factor (G-CSF), cyclosporine, and thalidomide. Use of tumor necrosis factor (TNF) alpha inhibitors in patients with CGD is associated with a high risk of severe infection and death. HCT is effective in resolving inflammatory complications. (See ‘Therapy for inflammatory manifestations’ above.)

●Successful HCT is a definitive cure for CGD. Outcomes are generally better in younger patients with less CGD sequelae, but HCT is also effective in patients with recurrent, serious infections despite prophylaxis and/or severe, difficult-to-treat infections or inflammatory disease. (See ‘Hematopoietic cell transplantation’ above.)

●The morbidity and mortality of CGD have improved significantly since the advent of prophylactic antimicrobial and immunomodulatory therapy. The average age of survival is undefined in the setting of newer antimicrobials, but it is at least 40 years and will continue to increase. (See ‘Prognosis’ above.)

ACKNOWLEDGMENTThe editorial staff at UpToDate would like to acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

The editorial staff at UpToDate would also like to acknowledge Sergio D Rosenzweig, MD, who contributed as an author to earlier versions of this topic review.

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Хроническая гранулематозная болезнь

Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis

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Chronic granulomatous disease: Treatment and prognosis

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