Chronic granulomatous disease (CGD) is a rare primary immunodeficiency, but is the most common inherited disorder of the phagocyte functions [1,2]. Phagocyte dysfunctions range from 8 to 18% of all primary immune deficiencies [3,4]. CGD was initially described in the 1950s [5,6], with an incidence ranging from 1/140,000 in Denmark to 1/1,111,000 in Korea, 1/200,000–250,000 in the USA and Europe and 1/190,000 in Israel [7–10]. The National Laboratory for Leukocyte Functions evaluated 1296 patients in Israel over the past 24 years, referred because of recurrent, severe pyogenic infections and CGD was diagnosed in 51 patients (3.9%) (Figure 1) [1]. CGD is caused by defects in the genes encoding the phox protein subunits of the phagocyte NADPH oxidase. The mode of inheritance could be either X-linked or
autosomal recessive (AR) [11,12]. There is a failure to activate the ‘respiratory burst’ that normally accompanies the phagocytic cells: neutrophils, monocytes, eosinophils and macrophages. The catalytic conversion of molecular oxygen into reactive oxygen intermediates (ROIs) is impaired, rendering the patient susceptible to recurrent infections. CGD still causes significant morbidity and mortality. Infections in CGD are caused by a narrow spectrum of catalase-positive microorganisms, Gram-positive and Gram-negative bacteria, opportunistic pathogens and fungi. Occasionally, the infecting etiological agent could be a catalase-negative microorganism, such as certain species of Staphylococcus aureus, Hemophilus influenza and Actinomyces [7–15]. Impaired bactericidal activity due to defective oxidative burst is the
Josef Ben-Ari1, Ofir Wolach2, Ronit Gavrieli3 and Baruch Wolach*3
1Pediatric Intensive Care Unit, Meir Medical Center, Kfar Saba, Israel 2Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel 3The Laboratory for Leukocyte Functions & The Pediatric Immuno-Hematology Clinic, Meir Medical Center, Kfar Saba and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel*Author for correspondence: [email protected]
Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency characterized by the absence or malfunction of the NADPH oxidase in phagocytic cells. As a result, there is an impaired ability to generate superoxide anions and the subsequent reactive oxygen intermediates. Consequently, CGD patients suffer from two clinical manifestations: recurrent, life-threatening bacterial and fungal infections and excessive inflammatory reactions leading to granulomatous lesions. Although the genotype of CGD was linked to the phenotypic expression of the disease, this connection is still controversial and poorly understood. Certain correlations were reported, but the clinical expression of the disease is usually unpredictable, regardless of the pattern of inheritance. CGD mainly affects the lungs, lymph nodes, skin, GI tract and liver. Patients are particularly susceptible to catalase-positive microorganisms, including Staphyloccocus aureus, Nocardia spp. and Gram-negative bacteria, such as Serratia marcescens, Burkholderia cepacea and Salmonella spp. Unusually, catalase-negative microorganisms were reported as well. New antibacterial and antimycotic agents considerably improved the prognosis of CGD. Therapy with IFN-γ is still controversial. Bone marrow stem cell transplantation is currently the only curative treatment and gene therapy needs further development. In this article, the authors discuss the genetic, functional and molecular aspects of CGD and their impact on the clinical expression, infectious complications and the hyperinflammatory state.
Infections associated with chronic granulomatous disease: linking genetics to phenotypic expressionExpert Rev. Anti Infect. Ther. 10(8), 881–894 (2012)
main dysfunction of the phagocytic cells in CGD. Consequently, evaluation of neutrophil functions is the first-line screen required in such patients. The diagnosis requires the demonstration of defective NADPH oxidase by the flow cytometric evaluation with dihydrorhodamine 123 (DHR) fluorescence, which measures the intracellular NADPH oxidase activity, and the dismutase-inhibitable reduction of ferricytochrome c which measures extracellular NADPH oxidase activity. The nitroblue tetrazolium (NBT) assay using the subjective NBT slide test or the ‘modified semiquantitative’ approach could be helpful but is sometimes confusing. Rather than detecting the ‘respiratory burst’ per se the assay relies on the accumulation of formazan precipitate over time. Although it is often easy to discern slight blue or purple from normally stained cells, in some cases it is difficult to diagnose CGD even for skilled laboratory assistants. Thus, in some cases of ‘variants’ with low levels of oxidants, the NBT may give false-positive staining. Missing these CGD variants may have potentially hazardous consequences to the patient. Methods enabling objective quantification of the production of ROIs are cytochrome c reduction and DHR flow cytometry. They are precise and reliable, with high sensitivity, being able to detect the ‘classical’ and the ‘variant’ CGD. In patients with
complete myeloperoxidase def iciency, the cytochrome c reduction is normal but the DHR flow cytometry is abnormal. The molecular and genetic studies will confirm the diagnosis of CGD.
Routine diagnostics show great vari-ability, so it would be advisable to have all CGD patients analyzed at specialized laboratories, in major experience centers [1,16,17]. Furthermore, two independent blood samples and at least two different methods should always be used to estab-lish a definite diagnosis of CGD. A large spectrum of CGD subtypes is determined by the various genetic mutations and the residual ROI production [18–20].
In CGD, hyperinflammatory responses to various stimuli lead to granuloma forma-tion, hence its name CGD. The improved management of patients with CGD resulted in more prominent manifestations of the autoinflammatory expression in adulthood. Studies on the underlying mechanisms of the excessive inflammatory reactions are ongoing [21–23]. CGD patients are at risk of developing autoimmune diseases, as a number of autoimmune disorders have been reported to be associated with CGD, such as juvenile rheumatoid arthri-tis, idio pathic thrombocytopenic purpura, antiphospholipid syndrome, systemic lupus erythematosus and IgA nephropathy [9,10,24]. Hemophagocytic lymphohistiocy-
tosis (HPLH), characterized by hyperinflammation and excessive cytokine release, was also reported in CGD [25].
The diagnosis and management of CGD require a careful clinical approach and a meticulous evaluation of the patient. Early diagnosis is important for better care and for prolonging CGD patient survival. Clues for considering the diagnosis are a suggestive family history, the type of infecting isolate, the severity and recurrence of infections, tissue abscesses and granulomas, and the patients’ response to antibiotic–antifungal therapy. The family history of severe or unusual infections in males (for the X-linked form of CGD) and consanguineous parents (for the AR form of the disease) provide important clues for the clinician’s diagnosis. Furthermore, a past history of opportunistic infections typical for this disease, such as pneumonia caused by Aspergillus spp., Nocardia spp., Actinomyces spp. and Burkholderia cepacia, lymphadenitis or skin/subcutaneous abscesses caused by Serratia marcescens or Granulibacter bethedensis, or osteomyelitis caused by S. marcescens or Aspergillus spp., should prompt an evaluation of the patient for CGD. Failure to thrive is a typical feature of children with CGD and is a result of repeated and/or prolonged hospitalizations that are associated with the chronic nature of this disease and its complications. Thus, failure to thrive in
66.4%
0.9%7.2%
26.4%
Normalevaluation
Idiopathicphagocyticdysfunction
Primary phagocyticdisorder
(8.1%)
Figure 1. Incidence of the phagocytic dysfunction in 1000 patients with recurrent severe infections. Overall, 67.3% (66.4%+0.9%) had a normal evaluation and 33.7% (26.4%+7.2%) had impairment of one or more steps of phagocytic activity: impaired chemotaxis was shown in 16.6%, impaired superoxide production in 6% and impaired bactericidal activity in 24.5%. Diagnosis of a primary phagocytic disorder was established in 81 patients: chronic granulomatous disease (n = 48), neutrophil G6PD deficiency (n = 3), leukocyte adhesion deficiency 1 (n = 4), Myeloperoxidase deficiency (n = 2), hyper-IgE syndrome (n = 21), Chediak–Higashi syndrome (n = 3). Neutrophil function impairment was found in 7.2 % of these patients, yet nine patients (0.9%) had a normal phagocytic evaluation (two of three patients with neutrophil G6PD deficiency and seven out of 21 with hyper-IgE syndrome).
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the appropriate clinical context is an negative sign and should prompt the clinician to evaluate the immune system, including the possibility of CGD.
Although for many years, CGD was believed to occur in early infancy with a fatal outcome, later reports indicate that the disor-der may present in adulthood, with a variable clinical course [26,27]. Both prenatal and preimplantation diagnosis are now feasible.
As in other immune deficiencies, malignancies may develop in CGD patients [28]. Leukemia and solid tumors were reported in patients with CGD, but whether malignancies occur at higher rates among these patients awaits further observations [9,29,30].
The advent of new antimicrobial and antifungal therapy, the use of prophylactic antibacterial along with antimycotic agents and the aggressive therapy of acute infections have markedly improved the clinical course of patients with CGD [31]. The use of prophylaxis with recombinant IFN-γ still remains controver-sial in most European countries. The International CGD Group showed efficacy of IFN-γ with a reduction of severe infections and hospitalizations, regardless of the pattern of inheritance, while others did not demonstrate such an efficacy [31–34]. Treatment of patients with allogeneic bone marrow transplantation (BMT) is currently the only established curative treatment for CGD and is increasingly used with encouraging results [35–38]. Gene therapy is promising, although needs further development [39,40].
The authors aim to review and discuss the genetic variability of CGD with its unpredictable clinical expression, the scope of infections reported in association with the disease and the specific management as reported at different medical centers in the USA, Europe and the Eastern world.
The genetic variability of CGD & its clinical expressionCGD may be X-linked recessive (XLR) or an AR disorder [11,17–19,41]. Nonsense mutation, missense mutations, frameshift, deletions or insertions and splice site mutations were reported in CGD. The mutated CYBB gene, encoding the enzymatic center of the NADPH oxidase gp91phox is on the X chromosome. It accounts for approximately two-thirds of the CGD patients in the Western world, determining a significant male predominance (Table 1). The AR expressions occur from mutations in CYBA, NCF1 and NCF2 genes, encoding the p22phox (<5%), p47phox (about 25–30%) and p67phox (<5%) subunits, respectively. Recently, a mutation in the NCF4 gene, encoding the p40phox subunit, was reported in one patient [42]. Nonetheless, in Israel and Iran, the AR forms are predominant. Table 1 shows comparative demographic data of North America, Europe, Iran and Israel, representing diverse and ethnically pluralistic populations. The disease has no predilection for selective populations. The XLR pattern of inheritance comprised 65–82% of CGD patients in North America and Europe [9–15], while in Israel and Iran, the AR pattern was predominant (63 and 87%, respectively), because of the high rate of consanguinity in these communities [8,43]. The diagnosis in these series was delayed in most patients with CGD, particularly in the AR form of inheritance, mainly in the NCF1-p47phox pattern [8], which has the milder clinical expression of CGD. Accordingly, Figure 2 displays the age at diagnosis in 51 Israeli CGD patients:
a third were diagnosed during the first year of life, another third below 6 years of age and 88% below 10 years of age. In 12% of the patients, the diagnosis was established in adulthood, over 18 years of age.
Although the genotype of the disease was linked to the pheno-typic expression of CGD, this connection is still controversial and poorly understood. Based on different clinical parameters, patients with the XLR form of the disease appeared to have a more severe clinical phenotype than those with the AR forms [8–10]. Consequently, patients with X-linked inheritance were diagnosed significantly earlier, with poorer survival than those with AR forms. Furthermore, the XLR form is the most common type associated with gastrointestinal manifestations and also has a higher prevalence of chronic inflammatory manifestations, such as gastrointestinal (GI) and genitourinary obstructions [10,44]. Nevertheless, the diagnosis of X-linked variants, in which a non-functional protein is present, usually manifests as a pheno typically milder disease [45,46]. Interestingly, while most patients with the p47phox deficiency were reported to have a milder phenotypic expression of CGD, other patients with AR-inheritance forms, including some with the deficient p47phox, have been reported as suffering from recurrent, life-threatening infections, like those with the classical X-linked form.
In the US series, it was reported that specific pathogens were significantly associated with the XLR form rather than the AR inheritance; for example, Aspergillus spp. in pneumonia and in lung abscesses; Staphylococcus spp. and Serratia spp. in subcu-taneous tissues and in suppurative adenitis; Staphyloccocus spp. in liver abscesses; Salmonella spp. and Burkholderia cepacea in septicemia/fungemia; and Serratia spp. and Aspergillus spp. in osteomyelitis [10].
A possible explanation for the discrepancy between the geno-type and phenotype expression in CGD could be the variability in the residual ROI production. In a recent study on 287 patients with CGD from 244 families, having a history of liver abscesses, rise in alkaline phosphatase and decreased platelet counts, were reported [20]. The authors claim that the patients that have residual ROI suffer from less severe illness and have improved long-term survival, independent of the specific NADPH oxi-dase mutation. Patients with the NCF1 mutations and most of those with CYBB missense mutations had more residual ROI production than those with the nonsense mutations [20]. The authors can differentiate between two groups associated with the X-linked inheritance based on their genetic mutations and ROI production: those with missense mutations and those with all other mutations. Patients with missense mutations and significant residual ROI production have later onset and improved life expectancy (Table 1 & 4). Of note, there are patients without such residual activity who are doing remarkably well, whereas some patients with residual activity suffer from recur-rent severe infections. Recently, the authors reported a defective pathway of NADPH activation in two XLR-CGD patients with residual ROI production. In both, missense mutations affected the membrane-bound NADPH oxidase component involved in docking of the cytosolic p47phox subunit [45]. These patients
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had H2O
2 generation of 17 and 33% of normal controls and
consequently presented with a milder clinical expression of the disease. Stasia et al. also reported two XLR-CGD patients with missense mutations and classified them as X91+, according to the normal expression of flavocytochrome b559 and the lack of superoxide production [46]. The interaction between gp91phox and p47phox is disturbed; electrons accumulate in FAD and may be passed on inefficiently directly to oxygen, thus producing H
2O
2 without the intermediate superoxide [47].
The authors can summarize that although certain correla-tions were reported between the genotypic/phenotypic expres-sion of CGD, the clinical expression of the disease is unpre-dictable, regardless of the pattern of inheritance. At one end of the spectrum, patients suffer from severe life-threatening infections with prominent manifestations of autoinflammatory responses, while at the other end, there are patients exhibiting
mild infections. ROI production could assist the physician to predict the prognosis to some extent.
Infectious & noninfectious manifestations of CGDToday, the authors can discriminate between two clinically differ-ent manifestations in CGD patients, infections and inflammatory reactions, both closely interrelated and well defined as two sides of a coin [21].
Infections associated with CGD: pathogens, location & managementIn infected CGD patients, as in the context of other immunode-ficiencies, an active approach for isolating the pathogen should be undertaken. This includes early culturing of body secretions and obtaining fresh tissue by the use of needle biopsies for cul-ture, histopathology and molecular studies. This will allow the
Table 1. Characteristics of patients with chronic granulomatous disease in major studies.
Wolach [8]†,‡ Martire et al. [13]
van den Berg et al. [9]
Winkelstein et al. [10]
Liese et al. [14]
Jones et al. [15]
Fattahi et al. [43]
Publication year 2008 2008 2009 2000 2000 2008 2011
Country of study Israel Italy Europe USA Germany UK & Ireland Iran
XLR a. 0.2§ (0–1) 1.2 (0–5) NR NR X910 0.3¶ (0.1–10.4) NR 0.4 (0–0.7)¶
b. 11.5 (1.5–32) X91- 3.6¶ (0.1–22.5)
AR 2.9 (0–22) 2.5 (0–9) NR NR 1.1 (0.2–12)¶ NR 1.7 (0–17)¶
†Updated in 2012 by addition of 13 patients to the previous study.‡Pattern of mutations: for gp91phox, six nonsense mutations, six missense mutations, one deletion, three insertions; for p22phox, three missense mutations, five insertions; for p47phox, 11 nonsense mutations and three deletions; for p67phox, five nonsense mutations, two deletions and six insertions.§We can differentiate between two groups in the X-linked inheritance patients, based on their genetic mutations: those with all mutations except missense mutations (a) and those with missense mutations (b). Patients with missense mutations have later onset and improved life expectancy. A unique heterozygous XLR-chronic granulomatous disease female, with very late onset (age 66 years) due to skewed lionization was excluded from the statistical evaluation.¶Median (range).AR: Autosomal recessive; NR: Not reported; XLR: X-linked recessive.
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tailoring of an appropriate and specific therapy against the pathogen prior to ini-tiation of the treatment.
The physician’s awareness and experi-ence, the comprehensive anamnesis and management leads to the appropriate evalu-ation, prompt diagnosis and suitable ther-apy. Periodic clinical evaluation of CGD patient condition is mandatory.
Recurrent infections in patients with CGD, even when caused by the same micro-organism, are usually the result of reinfec-tion rather than relapse [48]. Determining the pathogen and its location is crucial for successful management. Several molds and bacteria are hard to identify and the development of molecular diagnostic tools of infected tissues should be improved. Following hematogenous and contiguous spread, superficial and/or systemic infections of each and every one of the internal organs could develop. These infections could undergo abscess formation, mainly located in the skin and subcutaneous soft tissues, lungs, lymph nodes and liver. Unusually, the bones, kidneys, synovial membranes and CNS are involved [8–15].
Infecting pathogens in CGDTable 2 shows the type of infection and the infecting pathogens in major series of CGD. There is a clear impact of the epidemiol-ogy on the pathogen isolated. In North America, the majority of the infections in CGD are caused by S. aureus, S. marcescens, the B. cepacea complex, Nocardia and Aspergillus species [10–12]. Gram-negative bacteria, such as Escherichia. coli, Klebsiella, Proteus, Salmonella spp. and S. marcescens are more common in Europe and the eastern Mediterranean area than in North America. Similarly, Candida spp. follow the same pattern of dis-tribution. By contrast, the prevalence of the Nocardia spp. (cat-alase-positive, Gram-positive rod bacteria) is higher in North America, most probably reflecting the different epidemiological environment. Additionally, in other parts of the world, such as China, Hong Kong, Iran and Latin America, other microbial agents predominate in CGD, such as Mycobacterium tuberculosis, including BCG-itis following BCG vaccination [49]. However, localized, nondisseminated BCG infection and non-miliary pul-monary tuberculosis are the types usually encountered in these CGD patients. Recently, the intracellular protozoa Leishmania infantum, endemic in the Mediteranian coast, was described in three out of 20 patients with CGD [50].
The Penicillium spp., seldom reported as human pathogens, were found in CGD patients in southeast Asia [51]. Bacterial infections and their clinical expression in CGD patients were extensively reported in various large series [8–15]. In the present study, the authors will focus on recent studies dealing with inva-sive fungal diseases as well as new pathogens associated with CGD. Invasive fungal disease (IFD) could be life-threatening and represent a third of deaths in CGD patients [52,53]. The most
common genus of fungus was Aspergillus, spp. accounting for 18–40% of all IFDs. Aspergillus fumigatus is the main pathogen isolated from tissues of infected CGD patients, causing a high rate of morbidity and mortality [54,55]. The advent of the newer azole antifungal therapy (voriconazole and posaconazole) has dramatically changed the outcome of these infections [56–58]. Aspergillus spp. infections can often be indolent and afebrile, with few if any symptoms. Isolation of the microorganism is very important to institute appropriate and successful ther-apy. A computed tomo graphy-guided needle biopsy, if pos-sible, is very helpful, whereby the needle must have a sufficient diameter. Aspergillus viridinutans has emerged over time and has been shown to be very virulent, causing a distinct form of aspergillosis similar to Aspergilus nidulans [55]. It is char-acterized by chronicity, propensity to spread in a contiguous manner across anatomical planes, causing bone and chest wall lesions and sometimes extrathoracic dissemination as vertebrae, brain, spine, diaphragm and liver (Table 3). The emergence of increasing resistance to the azoles resulted in the successful use of intravenous caspofungin in combination with extensive surgical intervention (abscess drainage, multiple debridement, lobectomy and thoracic mass excision) [57,58]. In most studies, clinicians do not use corticosteroids in the treatment of IFD. Nonetheless, in refractory fulminant mulch pneumonitis and in overtly exuberant inflammatory response, corticosteroids could be considered [59].
Recently, actinomycosis was reported as a new pathogen in ten CGD patients, from immunodeficiency centers in the USA and Europe [60]. Actinomycosis diagnosis could be delayed because of nonspecific and prolonged symptoms. In CGD, this infection could be an invasive, debilitating condition. It is a slowly progressive chronic infection that commonly manifests as pneumonia, cervicofacial or abdominal infections (Table 3). Long-term treatment with high-dose intravenous penicillin is required.
Nocardia asteroides is the most common strain, caus-ing pleuropulmonary nocardiosis. The infection can spread
20
5
0
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D p
ati
en
ts (
n)
0<1 1<5 5<10 10<20
Age at diagnosis (years)
20<30 30<40 40<50 50<60 60<
15
10
Total XLR AR
Figure 2. Age distribution of the study participants according to the mode of inheritance. Eighty-eight percent of the patients were diagnosed before 10 years of age and 12% after 18 years of age. In total, 51 patients; XLR, 16 patients; AR, 35 patients. AR: Autosomal recessive; XLR: X-linked recessive.
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hematogenously from the lungs to the central nervous system, joints, soft tissue and viscera. Nocardia brasiliensis mainly causes skin, soft tissue abscesses and cellulitis, sometimes turning into
mycetoma, a chronic skin indurated granulomatous tumor-like mass (Table 3) [61,62]. High-dose trimethoprim– sulfamethoxazole (TMP/SMX; co-trimoxazole) is the treatment of choice for
Table 2. Overview of the location of infections and infecting pathogens in major studies of chronic granulomatous disease.
Wolach [8]† Martire et al. [13]‡
van den Berg et al. [9]§
Winkelstein et al. [10]¶
Liese et al. [14] #
Jones et al. [15]††
Fattahi et al. [43]
Publication year 2008 2008 2009 2000 2000 2008 2011
Country of study Israel Italy Europe USA Germany UK & Ireland
Iran
Patients (n) 51 60 429 368 39 94 93
Location of infectious episodes (%)
Pneumonia/lung abscess 71 80 66 95¶ 67 62 57
Supp. lymphadenitis 55 35 50 53 72 40 65.6
Liver abscess 49 20 32 27 41 29 29
Cutaneous/subcutaneous infections
43 80 53 54¶ 72 – 53.8
Osteomyelitis 22 9 13 25 15 12 30.1
Sepsis 27 22 20 18¶ 23 23 NR
Supp. otitis media 16 13 14 3.5 33 (ENT) – 7.5
Gastroenterocolitis 22 25 48 2.4¶ 44 37 33.3
Gingivo-stomatitis 22 35 18 2.4 26 24 NR
Perianal/perirectal abscess 14 15 21 15 21 28 10
Genitourinary infections 16 15 22 3.3¶ 10 11 15.1
CNS infections 8 6 7 3¶ <1 2 10.8
Infecting organism (%)
Staphaphyloccocus spp. 49 20 30 28 30 26 11
Escherichia coli 22 2 – – 5 – 2
Salmonella spp. 18 2 16 <1 6 7 6.5
Serratia marcescens 16 10 4 5 <1 – 1
Pseudomonas spp. 10 2 2 3 9 <1 1
Burkholderia cepacea 12 2 <1 8 – 5 –
Mycobacterium spp. 4 2 2 – – – 16
Nocardia spp. 2 – <1 7 – <1 1
Other Gram-negative organisms
18 6 2 3 9 – 6.5
Aspergillus spp. 31 32 26 41 8 13 18
Candida spp. 16 14 6 2 10 – 2†Updated in 2012 by addition of 13 patients to the original study.‡Martire et al. Location of infections found in 47 chronic granulomatous disease-patients and pathogen isolations from 50 infectious episodes.§Van den Berg et al. reported the total number of isolations from infectious episodes.¶Winkelstein et al. reported pneumonia (79%) and lung abscesses (16%), separately in 60 patients; cutaneous/subcutaneous infections included subcutaneous abscesses (42%), cellulitis (5%), impetigo (5%) and paronychia (1.35%); bacteremia and fungemia were reported as sepsis; gastrointestinal infections included gastroenteritis (1.6%) and abdominal abscesses (0.8%); genitourinary infections included six patients with urinary tract infection and two with kidney abscesses; CNS infections include brain abscess and meningitis was reported among 15 patients (4%).#Liese et al. reported location of infections based on 478 infectious episodes. Lung infections include pneumonias, of them 8% of patients suffered from lung abscess; liver abscesses include all intra-abdominal abscesses; otitis media include all ENT infections. Infecting pathogens were isolated in 151 (31%) of 478 infectious episodes that occurred in 77% of patients.††Jones et al. reported on numbers of isolates of 127 infectious episodes. ENT: Ear, nose and throat; NR: Not reported; Supp.: Suppurative.
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Nocardia infections. The new antibiotic linezolid proved to be effective as a second-line drug in the treatment of nocardiosis, with good penetration to the cerebrospinal barrier [31,58].
Leishmaniasis was reported in CGD patients receiving prophy-lactic therapy with TMP/SMX and IFN-γ. They presented with persistent fever, cervical lymphadenopathy, massive hepatospleno-megaly, pancytopenia and infection-associated HPLH. Serologic studies, blood and bone marrow cultures confirmed the diagnosis of leishmaniasis. HPLH is characterized by elevated transaminase values, hyperferritinemia, hypertriglyceridemia and hypofibrino-genemia. The treatment of choice is liposomal amphotericin B. It was reported that the patients not responding to this therapy could receive additional high-dose intravenous immunoglobulin and/or oral miltefosine [50].
Penicillium spp. infections were reported in immune-suppressed patients and in nonimmu-nocompromised patients. They could present with pulmonary disease, with an extension to the 5th rib, causing osteomyelitis. Patients were successfully treated either with amphothericin B or with a combination of voriconazole with surgery [51].
Localization of the infecting pathogens in CGDAs shown in Table 2, pneumonia is a major com-plication in most series, followed by lymphadeni-tis or skin/subcutaneous infections and abscesses in various organs. Conversely, in German and Iranian cohorts, suppurative lymphadenitis was the leading infection. Lung abscesses represented approximately 10–16% of all pulmonary infec-tious episodes. Chest CT scans are useful for detecting early pneumonia, when chest radio-graphs are not contributory. If noninvasive stud-ies are nondiagnostic (e.g., blood and sputum cultures), invasive procedures such as CT scan-guided fine needle aspiration should be consid-ered. Bronchoalveolar lavage or biopsy material should be submitted for bacterial and fungal cul-tures, including for Nocardia and the collected tissue samples for histopathology. Pulmonary granulomatous disease, as defined by negative cultures and histopathological studies, is some-times confused with mycobacterial infection or sarcoidosis.
The predominant isolate from lung abscesses was S. aureus (Table 3), although in the majority of the pulmonary episodes no causative pathogen was cultured. In pulmonary infections, it is not unusual to isolate opportunistic pathogens such as B. cepacea and Burkholderia gladioli, Actinomyces, Aspergillus spp. and Mycobcterium species [12,49,58,60,63]. Occasionally, other rare pathogens such as Cephalosporium, Scedosporium apiospermum,
Paecilomyces variotii, Philalophora richardsiai, Rhodoccocus equi and Chromobacterium violaceum were also cultured in lung infections [9,10,12]. The acute lung inflammatory response in CGD patients could follow inhalation of a large burden of spores or hyphae, lead-ing to acute pneumonitis [64,65]. Lung biopsy shows acute inflam-mation with necrotizing granuloma and fungi. Surgical interven-tion, debridement or resection of infected tissue may be required in order to eradicate lesions with invasive pathogens [66]. Although pulmonary infiltrates could exacerbate, progressing to hypoxia and respiratory insufficiency, discrete infiltrates wane spontaneously, without any intervention. Chronic lung disease leads to severe res-piratory insufficiency, which is one of the major causes of mortality in CGD patients.
Table 3. Location of pathogens in chronic granulomatous disease patients.
Organ infected Clinical expression Pathogen
Lungs Pneumonia Lung abscessPleural effusion
Staphylococcus aureus
Aspergillus spp.
Burkholderia cepacia and gladioli
Pseudomonas aeruginosa
Mycobacterium typical and atypical
Nocardia spp.
Actinomyces spp.
Penicillium spp.
Granulibacter bethedensis
Cephalosporium
Scedosporium apiospermum Paecilomyces variotii
Philalophora richardsiai Rhodoccocus equi
Chromobacterium violaceum
Lymph nodes Lymphadenitis Abscesses
S. aureus
Serratia marcescens
Mycobacterium typical and atypical
Actinomyces spp.
G. bethedensis
GI tract Abdominal pain Gastroenteritis Colitis Granuloma:
Pyloric stenosisIntestinal obstruction
Salmonella spp.
Escherichia coli
Klebsiella
Proteus spp.
P. aeruginosa
B. cepacia Actinomyces spp.
Nocardia spp.
G. bethedensis
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In suppurative lymphadenitis S. aureus was the prominent isola-tion (Table 3), although in most cases no causative pathogens were isolated. If there is unresponsiveness to first-line antistaphylococcal drugs, adding teicoplanin to the treatment regimen as a single agent or in combination with ciprofloxacin may be a reasonable option. Both of the latter drugs achieve high intracellular concentrations within the neutrophil [31]. As previously noted, vaccination with BCG frequently results in subsequent localized skin infections and suppurative lymphadenitis (BCG-itis). Patients with CGD are sus-ceptible to tuberculosis. M. tuberculosis or atypical Mycobacterium could be isolated from the infected lymph node and pulmonary tissues [49]. A recent emerging pathogen, Granulibacter bethesden-sis, was reported in North America, Central America and Spain, causing relapsing necrotizing lymphadenitis [67,68]. The clinical expression of lymphadenitis caused by this pathogen differs from
the classic staphylococcal one in several aspects. While staphylococcal lymphadenitis is usually an acute disease localized in the cervical region, the G. bethesdensis induces a chronic disease, with pro-longed fever, located in various lymphatic tissues and viscera such as lymph nodes, liver or spleen. Given the difficulty in growing and identifying the Granulibacter spp., it was recommended that the specimens of lymph nodes of CGD patients be handled with centrifugation, culture and incuba-tion for 3 weeks. The microorganism is slow grow-ing growing and molecular diagnosis (PCR) can be made from fresh tissue. This Gram-negative rod is multidrug resistant and frequently requires surgery in combination with antibiotic therapy. Infections with this isolate show good response to ceftriaxone in combination with amino glycosides or meropenem, or alternatively doxycycline or TMP/SMX [67,68].
As in other organs, S. aureus is the predominant pathogen isolated from skin and subcutaneous abscesses (Table 3), although aseptic granulomas are frequently encountered. Isolates of Aspergillus spp., Staphylococcus epidermidis, S. marcescens and Gram-negative bacteria (Klebsiella pneumoniae, Proteus mirabilis and E. coli) are unusually found in skin and subcutaneous tissues [8–13].
GI manifestations of CGD are frequent [44]. Nontyphoid Salmonella spp. gastroenteritis was reported, but in the vast majority of patients with diarrhea, there is no growth in stool cultures or biopsies. Furthermore, an excessive inflammatory response rather than infectious episodes are the leading manifestation of CGD in the GI tract. Granulomas frequently develop and no pathogens are usually isolated from them.
A report of 140 patients with CGD, followed at the NIH, revealed inflammatory involvement of the GI tract in 32.8%, especially in those with X-linked inheritance (89%) [44]. Abdominal pain
was the most prominent manifestation (100%), followed by hypoal-buminemia (70%). Diarrhea (40%), nausea, vomiting (25%) and occasionally constipation were also reported. This study empha-sizes that GI involvement should be evaluated in patients with CGD who suffer from abdominal pain and hypoalbuminemia [44]. Obstruction of esophageal, gastric, duodenal and other bowel areas was also reported (35%). Granulomatous or ulcerative lesions were diagnosed in the colon by GI imaging (65%), which is important for management and follow-up of these patients. The granuloma formation could be an expression of a dysregulated inflammatory response and/or inefficient degradation of inflammatory mediators in the absence of the normal oxidative burst. Additionally, oxidants are required for the apoptosis of neutrophils at inflammation sites and this process is also delayed [21–23]. Prednisone controlled symp-toms and signs in the majority of the patients, but after tapering
Table 3. Location of pathogens in chronic granulomatous disease patients (cont.).
off the drug, recurrence was observed in most patients (71%) [44]. Holland also reports his successful current practice using small doses of prednisone for a few weeks with a very high relapse rate after tapering off the drug [12]. Additional treatment with antimetabolites and aspirin could be helpful.
Liver abscess was reported in approximately 25–50% of CGD patients. S. aureus was isolated in approximately 50% of hepatic abscesses [69]. Abscesses found in CGD have different clinical and imaging characteristics compared with sporadic hepatic abscesses [70]. Most CGD patients tend to develop abscesses with multiple loculations and with a tendency to recur. Surgical intervention is required in many patients. Recent reports have highlighted the beneficial effect of corticosteroids for patients with liver abscesses unresponsive to antibiotic and/or antifungal therapy [71]. This is in line with the therapeutic efficacy of steroids demonstrated in ‘mulch pneumonitis’.
Osteomyelitis in CGD patients was reported in the setting of local extension or as a part of hematogenous invasive dissemina-tion [72]. Common locations for osteomyelitis in CGD include the lower and upper extremities, the skull and the chest wall. Pathogens isolated in CGD-associated-osteomyelitis included S. aureus, S. marcescens and Aspergillus spp. (Table 3). Most Aspergillus spp. infections of bones are a result of contiguous spread of primary pulmonary infection to adjacent ribs or vertebrae, particularly when caused by the invasive A. nidulans and A. viridinutans [54,55].
Management & outcomeIn all reported series, prophylactic antibiotics were used in over 90% of the patients and antifungal prophylaxis in approxiamtely 50–70% of them (Table 4). Combined prophylactic therapy with TMP/SMX and azole agents (itraconazol or voriconazol) proved to be effective and has become a core treatment in CGD, significantly reducing the rate and severity of infections as well as the hospitali-zation rate [31,73,74]. Oral TMP/SMX at 6 mg/kg/day and itracona-zole at 5 mg/kg/day were administered routinely with infrequent side effects. In addition, antistaphyloccocal penicillins or cepha-losporins could be given as prophylaxis. The active prophylactic approach with antimicrobials and antifungals may be associated with some toxicity. Patients allergic to TMP/SMX may alterna-tively be treated with ciprofloxacin. Severe photosensitivity leading to squamous cell carcinoma and melanoma has been reported with long-term administration of voriconazole [75,76]. Patients receiving voriconazole should use aggressive sun protection. Posaconazole causes less photoreactivity [56]. Renal failure was reported to occur as a result of long-term amphotericin B exposure, more frequently used before the advent of the newer agents.
The use of prophylaxis with recombinant IFN-γ remains contro-versial. The International CGD Group showed efficacy of IFN-γ inducing a significant reduction of severe infections and hospitali-zations, regardless of the pattern of inheritance [32]. Furthermore, administration for a long period of time was well tolerated in 62% of the patients, with no severe adverse events [33]. Others reported that the drug had no effect on NADPH oxidase activity [34]. The molecular mechanisms associated with host defense improvement induced by IFN-γ in CGD patients are unknown. The prolonged
use of IFN-γ is well tolerated and appears safe, without serious toxicity. The cost of long-term prophylactic IFN-γ is high and it needs to be injected intramuscularly twice or three-times a week, making compliance rather poor. Consequently, IFN-γ is less administered outside North America (Table 4). There are no controversies between therapists regarding the need for vacci-nations, which should be administered to all CGD patients as routinely recommended, except for BCG.
Infections should be treated aggressively and when feasible with agents directed to the specific isolated microorganism, prior to initiating antimicrobial therapy. Persistent, refractory infec-tions that involve deep soft tissue or bone are most effectively treated with a combination of prolonged antimicrobial therapy and surgery.
In those patients with severe infections, refractory to therapy, adjunctive granulocyte transfusions have been used. Transfused granulocytes retain respiratory burst activity and appear to func-tion normally. Usually transfused leukocytes are well tolerated, although development of leukoagglutinins could lead to their rapid loss and unusual pulmonary leukostasis and alloimmunization [17].
BMT is currently the only curative therapy for CGD. Major improvements include reduced intensity of conditioning regi-mens and transplantation from matched, unrelated donors or cord blood donors. Patient selection and the correct timing for this procedure remains a matter of controversy. Ideally, infections and inflammatory lesions should be well controlled in CGD before BMT. However, patients with recurrent life-threatening infec-tion and those refractory to treatment should undergo BMT as early as possible [35]. In European studies cure rates among BMT survivors approached 85% [36]. In all engrafted survivors, mostly children, previous existing infections and chronic inflammatory lesions cleared, gradually improving the lung oxygen saturation and reversing the clubbing of fingers. Excellent outcomes have been reported using in vivo T-cell depletion in matched unrelated donors [37]. High long- term donor chimerism and excellent sur-vival of CGD patients were reported using cord blood or bone marrow myeloablative transplantation [38].
Gene therapy is a promising approach under development. Gene therapy currently focuses on the use of a lentivector that seems to be safer and more efficient in transducing hematopoi-etic stem cells, with less insertional mutagenesis. However, more clinical experience with self-inactivating lentivirus vectors is needed. These lentivectors require an internal promoter to drive production of the therapeutic transgene. Designing lentivectors for X-linked-CGD is problematic because mammalian inter-nal promoters are not sufficiently active to achieve functional correction of the defected gene. The lentivector development for X-linked-CGD is currently focused on finding the best internal promoter to achieve functional correction of the gene marked [39,40]. Although very promising, this approach remains experimental.
Currently, the predictive mortality rate of patients with CGD (Kaplan–Meier log rank statistics) in different series range from 20 to 40 years for the XLR-CGD form of inheritance and from 38 to 50 years for the AR-CGD mode.
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Noninfectious manifestations associated with CGD: pathogenesis & managementIn vitro studies showed that the phagocytes in CGD display exag-gerated mediator responses to various stimuli [77]. In CGD, there is hyperinflammatory dysregulation, incrementing the proinflamma-tory mediators and blunting the anti-inflammatory cytokines [21–23]. These patients are predisposed to generate noncaseating granulomas in the GI tract, as well as in the genitourinary tract and in the CNS, leading to obstructive complications. Uncommonly, portal hyper-tension may develop in CGD following recurrent infections of the liver with the associated injury to microvasculature, and probably in the context of the hyperinflammatory state [78]. The granuloma involvement of the bowel may mimic that of Crohn’s disease [79]. In CGD, the clinical manifestations lack the classical extraintes-tinal manifestations associated with Crohn’s disease. Most CGD patients with intra-intestinal granulomas demonstrate a rapid and
good response to low doses of steroids [44], supporting the inflam-matory etiology of the granulomata. Other than steroids, treatment of the granuloma with methotrexate has also been successfully used in CGD as in other autoimmune disorders.
Recently, various pathomechanisms for the hyperinflamma-tory reaction in CGD patients were proposed. These included reduced neutrophil apoptosis and efferocytosis, dysbalanced innate immune receptors and induction of the highly proinflam-matory Th17 cells. These cells have been found to be involved in chronic inflammatory processes and in several autoimmune diseases [21–23]. In addition, the expression of the enzyme indola-mine 2,3-dioxygenase at the border of the granulomata at the expense of superoxide is a common feature that has been estab-lished in mice [80]. The absence of ROIs in CGD phagocytes resulted in exaggerated TNF-α production and inflammasome activity [21–23,81].
Table 4. Treatment strategies and outcomes in chronic granulomatous disease studies.
Wolach et al. [8]
Martire et al. [13]
van den Berg et al. [9]
Winkelstein et al. [10]
Liese et al. [14]
Jones et al. [15]
Fattahi et al. [43]
Publication year 2008 2008 2009 2000 2000 2008 2011
Prophylaxis
Antibacterial prophylaxis (%)
92† 92 71¶ 89‡‡ 72§§ 100 94.6
Antifungal prophylaxis (%)
63‡ 83# 53†† NR 21¶¶ 93 48.4
IFN-γ (%) 14 53 33 73 NR 35 54.8
Treatment strategies
Surgical intervention (%)
59 NR NR NR NR NR
Steroids (%) 29 NR NR NR NR 42 NR
Bone marrow transplant (%)
22 10 6 <1% NR 13 2
Granulocyte transfusion
0 NR 7 15 NR 13 NR
Outcome
Mortality (%) 24 13 20 17.6 20 59 10
Remarks Mean survival time§ XLR##a.18 years b.>62 years AR: 38 years
Survival rates at 10, 20 and 25 years were 97, 83 and 46%, respectively
Mean survival time 37.8 years for XLR and 49.6 years for AR
5-year survival 88 and 76% for AR & XLR, respectively
Overall survival at 10, 20 and 30 years was 91, 86 and 54%, respectively
Overall survival at 10, 20, 30, 40 and 50 years 88, 73, 55, 28 and 12%, respectively
†95% of patients received trimethoprim–sulfamethoxazole, 29% received cephalexin and 21% received ciprofloxacin.‡85% of patients received itraconazole and 15% received voriconazole.§Kaplan–Meier logrank test (p < 0.05).¶42% of patients received trimethoprim–sulfamethoxazole, 4% received ciprofloxacin, 3% received clindamycin and 3% received rifampicin.#48% of patients received itraconazole, 3% received fluconazole and 2% received either amphotericin B or voriconazole (data at diagnosis).††47% of patients received itraconazole, 15% received amphotericin B and 7% received ketoconazole.‡‡Trimethoprim–sulfamethoxazole or diclocxacillin.§§All treated patients received trimethoprim–sulfamethoxazole; data at diagnosis.¶¶All treated patients received itraconazole.##We can differentiate between two groups in the X-linked inheritance based on their genetic mutations: (a) those with all mutations except missense mutations and (b) those with missense mutations. Patients with missense mutations have later onset and improved life expectancy [20]. A unique heterozygous XLR chronic granulomatous disease female with very late onset (age 66 years) due to skewed lionization was excluded from the statistical evaluation.AR: Autosomal recessive; NR: Not reported; XLR: X-linked recessive.
Ben-Ari, Wolach, Gavrieli & Wolach
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Continuous efforts should be invested to better understand the pathogenesis of the disease and to further improve the management of CGD and its complications.
Expert commentary & five-year viewCGD is a rare inherited stem cell disease with significant rates of morbidity and mortality. Advances in diagnosis and in the understanding of pathogenic pathways in this disease as well as progress in management strategies have brought about a signifi-cant improvement in the morbidity profile and the mortality rates among patients with CGD.
Assessment of neutrophil functions via functional and bio-chemical assays remains the first step for diagnosing CGD. Current technology allows the determination of the differ-ent genetic subtypes of this disorder. Laboratory assays show great variability; therefore, assessment of neutrophil functions should be performed at specialized and experienced laborato-ries. Correlation between the disease genotype and phenotype was reported, but could not always be predicted. Specific gene mutations were reported to be correlated with the severity of the disease and with the long-term survival. Furthermore, recent findings have correlated biochemical characteristics of CGD to severity of disease and outcome. Patients with residual ROIs have better prognosis. Both prenatal and preimplantation diagnosis are now feasible.
The clinical expression of CGD may be blunted and clinician awareness coupled with a thorough evaluation of the patient is imperative. Appropriate complementary studies are mandatory to evaluate the patient status and the complications that com-monly develop in the course of the disease. Isolating the patho-gen requires early culturing of body secretions and may eventu-ally require fresh tissue biopsies for culture, histopathology and molecular studies. In recent years, rare pathogens were reported
in CGD, and they could be closely related to the epidemiology of endemic areas. Early diagnosis and treatment is important for better care and improved survival of the patient. The advent of new antibiotics and antifungal agents contributed enormously to the management of the patients. The effectiveness of IFN-γ is still controversial.
The only curative treatment modality today is hematopoietic stem cell transplantation (HSCT). Outcome after transplan-tation was shown to be superior among patients transplanted early in the course of their disease, prior to development of significant sequelae following recurrent severe infections and the associated hyperinflammatory state. Nevertheless, as the clinical expression of CGD is variable, the decision to pro-ceed to HSCT should be made on individual clinical grounds. Although optimally HSCT is recommended when acute com-plications are under control, it still remains a viable option for those chronically infected or those unresponsive to standard therapy.
As the genetic lesion in CGD involves metabolic genes not engaged in cell proliferation and since a minimal functional correction of neutrophil activity is sufficient for disease allevia-tion, gene therapy could be an optimal modality for treatment. However, at this time, the functional correction of neutrophils is insufficient and short-lived. Gene therapy remains at this time an experimental approach for treatment of CGD.
Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Chronic granulomatous disease (CGD) is a rare primary immunodeficiency characterized by failure to activate the ‘respiratory burst’ in the phagocytic cells due to defects in the genes encoding the phox protein subunits of the phagocyte NADPH oxidase.
• CGD patients suffer from recurrent, life-threatening bacterial and fungal infections.
• The production of residual reactive oxygen intermediates (ROIs) can predict survival in patients with CGD, independently of the specific gene affected. Most patients having residual ROIs have less severe illness and improved long-term survival. ROI production could assist the physician to predict the prognosis to some extent.
• The authors can differentiate between two groups in the X-linked inheritance, based on their genetic mutations and ROI production: those with missense mutations and those with all other mutations. Patients with missense mutations have later onset and improved life expectancy. The classical X-linked CGD usually presents as a severe disease, diagnosed earlier in life with shorter life expectancy.
• Clinical expression may be blunted and clinician awareness coupled with a thorough evaluation is imperative. Isolating the pathogen requires early culturing of body secretions and may eventually require fresh tissue biopsies for culture, histopathological and molecular studies.
• Significant progress was achieved with the advent of new antibiotics and antifungal agents. The use of trimethoprim–sulfamethoxazole along with the antifungal azoles has become a basic strategy for prophylaxis. Although the use of IFN-γ was shown to be beneficial as prophylaxis, its use still remains controversial.
• In CGD, there is hyperinflammatory reactivity to various stimulants, causing granulomatous lesions that eventually result in organ dysfunction.
• Treatment of CGD patients with allogeneic stem cell transplantation is currently the only established curative treatment with encouraging results.
• Gene therapy, although very promising, remains at this time an experimental approach for the treatment of CGD.
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