INTRODUCTION — Chronic granulomatous disease (CGD) is a genetically heterogeneous condition characterized by recurrent, life-threatening bacterial and fungal infections and granuloma formation. CGD is caused by defects in the phagocyte 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".)
MANAGEMENT — The 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 :
●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) . 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 . 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 . 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 . 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) . 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 . 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 . 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 inborn errors of immunity".)
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 .
●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 .
●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 . 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 . (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'.)
●Chromobacterium violaceum can cause bacteremia and sepsis in CGD and typically responds to TMP-SMX, quinolones, or carbapenems .
●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 . Glucocorticoids along with antibiotics may also help in the management of Nocardia pneumonias, which can be necrotic and inflammatory .
●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 . 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 . 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) . 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 adverse effects of systemic glucocorticoids".)
Glucocorticoid-sparing therapies include long-term treatment with aspirin (eg, sulfasalazine  or mesalamine ) or mercaptopurine (eg, azathioprine ) 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 . We avoid TNF-alpha blockade in patients with CGD because of the substantial risks of severe and fatal infection . 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 . 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 . In contrast, anakinra was ineffective in five patients with CGD colitis .
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 . 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 .
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 inborn errors of immunity" 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 . 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 . 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 . 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 . 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 . 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 .
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 . 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) . 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  or donors with less than an HLA-9-of-10 match  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 "Overview of gene therapy for inborn errors of immunity".)
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 . 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 . Both patients developed monosomy 7 secondary to insertional activation of ecotropic viral integration site 1 (EVI1) , 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 . 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 . 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 .
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 . 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 .
PROGNOSIS — When 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 .
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 . 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 . However, despite improved survival, end-organ complications, including chronic lung disease and liver disease, are still significant in adults .
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 . 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 . 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.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
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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
●Overview – 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.)
●Antimicrobial prophylaxis – 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.)
●Pathogen identification – 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.)
●Medical and surgical treatment of acute infections – 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.)
●Treatment of inflammatory manifestations – 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.)
●Hematopoietic cell transplantation – 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.)
●Prognosis – 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.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.
The editorial staff at UpToDate also acknowledge Sergio D Rosenzweig, MD, who contributed as an author to earlier versions of this topic review.
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