Search

Chronic granulomatous disease (CGD) is a rare immunodeficiency disorder characterized by a defective NADPH oxidase complex leading to an impaired respiratory burst and defective killing of pathogens by phagocytes. The most common type of CGD is caused by hemizygous mutations of the CYBB gene on the X chromosome encoding the gp91phox subunit. It usually affects males, yet heterozygous females may rarely manifest clinical signs of the disease due to skewed X chromosome inactivation in leukocytes . Despite advances in gene therapy, hematopoietic stem cell transplantation (HSCT) remains the main definitive treatment. Older patients, however, are at greater risk of HSCT-related complications and mortality and may require a specific approach.

Purpose Chronic granulomatous disease (CGD) is an uncommon, inborn error of immunity. We updated our large, single-center US experience with CGD and describe some newly recognized features. Methods We retrospectively reviewed 26 patients seen from November 2013 to December 2019. Serious infections required intravenous antibiotics or hospitalization. Results There were 21 males and 5 females. The most frequent infectious agents at presentation were aspergillus (4), serratia (4), burkholderia (2), Staphylococcus aureus (2), and klebsiella (2). The most common serious infections at presentation were pneumonia (6), lymphadenitis (6), and skin abscess (3). Our serious infection rate was 0.2 per patient-year from December 2013 through November 2019, down from 0.62 per patient-year from the previous study period (March 1985–November 2013). In the last 6 years, four patients were evaluated for human stem cell transplantation, two were successfully transplanted, and we had no deaths. Several patients had unusual infections or autoimmune manifestations of disease, such as pneumocystis pneumonia, basidiomycete/phellinus fungal pneumonia, and retinitis pigmentosa. We included one carrier female with unfavorable Lyonization in our cohort. Conclusion We update of a large US single-center experience with CGD and describe some recently identified features of the illness.

Background Autosomal recessive (AR) PKCδ deficiency is a rare inborn error of immunity (IEI) characterized by autoimmunity and susceptibility to bacterial, fungal, and viral infections. PKCδ is involved in the intracellular production of reactive oxidative species (ROS). Material and Methods We studied a 5-year old girl presenting with a history of Burkholderia cepacia infection. She had no history of autoimmunity, lymphocyte counts were normal, and no auto-antibodies were detected in her plasma. We performed a targeted panel analysis of 407 immunity-related genes and immunological investigations of the underlying genetic condition in this patient. Results Consistent with a history suggestive of chronic granulomatous disease (CGD), oxidative burst impairment was observed in the patient’s circulating phagocytes in a dihydrorhodamine 123 (DHR) assay. However, targeted genetic panel analysis identified no candidate variants of known CGD-causing genes. Two heterozygous candidate variants were detected in PRKCD: c.285C > A (p.C95*) and c.376G > T (p.D126Y). The missense variant was also predicted to cause abnormal splicing, as it is located at the splice donor site of exon 5. TOPO-TA cloning confirmed that exon 5 was completely skipped, resulting in a truncated protein. No PKCδ protein was detected in the patient’s neutrophils and monocyte-derived macrophages. The monocyte-derived macrophages of the patient produced abnormally low levels of ROS, as shown in an Amplex Red assay. Conclusion PKCδ deficiency should be considered in young patients with CGD-like clinical manifestations and abnormal DHR assay results, even in the absence of clinical and biological manifestations of autoimmunity.

Background: Chronic granulomatous disease (CGD), one of the phagocytic system defects, is the primary immunodeficiency caused by dysfunction of the NADPH oxidase complex which generates reactive oxygen species (ROS), which are essential for killing pathogenic microorganisms, especially catalase-positive bacteria and fungi. Objective: The objective of our study was to assess the clinical and laboratory characteristics, treatment modalities, and prognosis of patients with CGD. Methods: We retrospectively reviewed 63 patients with CGD who have been diagnosed, treated, and/or followed-up between 1984 and 2018 in Hacettepe University, Ankara, in Turkey, as a developing country. Results: The number of female and male patients was 26/37. The median age at diagnosis was 3.8 (IQR: 1.0–9.6) years. The rate of consanguinity was 63.5%. The most common physical examination finding was lymphadenopathy (44/63), growth retardation (33/63), and hepatomegaly (27/63). One adult patient had squamous cell carcinoma of the lung. The most common infections were lung infection (53/63), skin abscess (43/63), and lymphadenitis (19/63). Of the 63 patients with CGD, 6 patients had inflammatory bowel disease (IBD). Twelve of the 63 patients died during follow-up. CYBA, NCF1, CYBB, and NCF2 mutations were detected in 35%, 27.5%, 25%, and 12.5% of the patients, respectively. Conclusion: We identified 63 patients with CGD from a single center in Turkey. Unlike other cohort studies in Turkey, due to the high consanguineous marriage rate in our study group, AR form of CGD was more frequent, and gastrointestinal involvement were found at relatively lower rates. The rate of patients who treated with HSCT was lower in our research than in the literature. A majority of the patients in this study received conventional prophylactic therapies, which highlight on the outcome of individuals who have not undergone HSCT.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by defects in the NADPH oxidase complex. Mutations in NCF2 encoding the cytosolic factor p67phox result in autosomal recessive CGD. We describe three patients with a novel c.855G>C NCF2 mutation presenting with diverse clinical phenotype. Two siblings were heterozygous for the novel mutation and for a previously described exon 8-9 duplication, while a third unrelated patient was homozygous for the novel mutation. Mutation pathogenicity was confirmed by abnormal DHR123 assay and absent p67phox production and by sequencing of cDNA which showed abnormal RNA splicing. Clinically, the homozygous patient presented with suspected early onset interstitial lung disease and NCF2 mutation was found on genetic testing performed in search for surfactant-related defects. The two siblings also had variable presentation with one having history of severe pneumonia, lymphadenitis, and recurrent skin abscesses and the other presenting in his 30s with discoid lupus erythematosus and without significant infectious history. We therefore identified a novel pathogenic NCF2 mutation causing diverse and unusual clinical phenotype.

X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype. We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types. The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well. This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.

PURPOSE: Haploidentical related donor (HRD) transplantation was performed in 7 recipients with chronic granulomatous disease (CGD) who had no matched-related or unrelated donor. METHODS: Peripheral blood cell (PBC) products were used with a conditioning regimen consisting of low-dose cyclophosphamide, fludarabine, total body irradiation, and busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of high-dose post-transplant cyclophosphamide and sirolimus. Recipients were ages 14–26 years, and 3 had severe infections active at transplant. RESULTS: All 7 recipients achieved full engraftment with complete donor chimerism early in the post-transplant period. Acute GVHD occurred in all cases and was grade 3 or steroid refractory in 3. Two patients with steroid-refractory GVHD died. Three patients with severe infectious complications active at transplant, 1 Nocardia pneumonia and 2 extensive invasive fungal infections), survived and were cured of their infection at last follow-up. Bacterial disease occurred post-transplant in all recipients, and viral infections/reactivation were common, including 4 cases of BK virus–associated hemorrhagic cystitis. CONCLUSIONS: Seven patients with CGD achieved rapid and full-donor engraftment from HRDs utilizing PBCs and a conditioning regimen with PTCy and sirolimus GVHD prophylaxis. However, the incidence of grade 3 and steroid-refractory GVHD was high and led to 2 deaths. Patients with active infections at transplant had successful transplant courses and were cured of their disease. Although there was an initial success with this regimen, the cumulative experience does not support its use in CGD due to an unacceptable rate of severe GVHD.

Granulocyte transfusions are sometimes used as adjunctive therapy for the treatment of infection in patients with chronic granulomatous disease (CGD). However, granulocyte transfusions can be associated with a high rate of alloimmunization, and their role in CGD patients undergoing hematopoietic cell transplantation (HCT) or gene therapy (GT) is unknown. We identified 27 patients with CGD who received granulocyte transfusions pre- (within 6months) and/or post-HCT or GT in a retrospective survey. Twelve patients received granulocyte transfusions as a bridge to cellular therapy. Six (50%) of these patients had a complete or partial response. However, six of 10 (60%) patients for whom testing was performed developed anti-HLA antibodies, and three of the patients also had severe immune-mediated cytopenia within the first 100days post-HCT or GT. Fifteen patients received granulocyte transfusions post-HCT only. HLA antibodies were not checked for any of these 15 patients, but there were no cases of early immune-mediated cytopenia. Out of 25 patients who underwent HCT, there were 5 (20%) cases of primary graft failure. Three of the patients with primary graft failure had received granulocyte transfusions pre-HCT and were subsequently found to have anti-HLA antibodies. In this small cohort of patients with CGD, granulocyte transfusions pre-HCT or GT were associated with high rates of alloimmunization, primary graft failure, and early severe immune-mediated cytopenia post-HCT or GT. Granulocyte transfusions post-HCT do not appear to confer an increased risk of graft failure.

This is a functional characterization of a novel CYBA variant associated with normal DHR flow cytometry. Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by recurrent bacterial and fungal infections and dysregulated inflammatory responses due to defective phagocytic cell function leading to the formation of granulomas. CGD patients have pathogenic variants in any of the five components of the phagocytic NADPH oxidase, which transfers electrons through the phagosomal membrane and produces superoxide upon bacterial uptake. Here, we report a pediatric female patient with a novel homozygous missense variant (c.293C T, p.(Ser98Leu)) in CYBA, encoding the p22The patient presented with severe recurrent pneumonia. Specific pathogens identified included Burkholderia and Serratia species suggesting neutrophil functional abnormalities; however, the dihydrorhodamine-1,2,3 (DHR) flow cytometric and cytochrome c reduction assays for neutrophil respiratory burst fell within the low side of the normal range. Western blot and flow cytometric analysis of individual NADPH oxidase components revealed reduced levels of p22Although this patient did not exhibit all the classic features of CGD, such as granulomas and skin infections, she had recurrent pneumonias with oxidant-sensitive pathognomonic organisms, resulting in appropriate targeted CGD testing. This case emphasizes the need to contextually interpret laboratory data, especially using clinical findings to direct additional assessments including genetic analysis.

Chronic granulomatous disorder (CGD) is a primary immunodeficiency which is frequently complicated by inflammatory colitis and is associated with systemic inflammation. Herein, we aimed to investigate the role of the microbiome in the pathogenesis of colitis and systemic inflammation.We performed 16S rDNA sequencing on mucosal biopsy samples from each segment of 10 CGD patients' colons and conducted compositional and functional pathway prediction analyses.The microbiota in samples from colitis patients demonstrated reduced taxonomic alpha-diversity compared to unaffected patients, even in apparently normal bowel segments. Functional pathway richness was similar between the colitic and non-colitic mucosa, although metabolic pathways involved in butyrate biosynthesis or utilization were enriched in patients with colitis and correlated positively with fecal calprotectin levels. One patient with very severe colitis was dominated by Enterococcus spp., while among other patients Bacteroides spp. abundance correlated with colitis severity measured by fecal calprotectin and an endoscopic severity score. In contrast, Blautia abundance is associated with low severity scores and mucosal health. Several taxa and functional pathways correlated with concentrations of inflammatory cytokines in blood but not with colitis severity. Notably, dividing patients into "high" and "low" systemic inflammation groups demonstrated clearer separation than on the basis of colitis status in beta-diversity analyses.The microbiome is abnormal in CGD-associated colitis and altered functional characteristics probably contribute to pathogenesis. Furthermore, the relationship between the mucosal microbiome and systemic inflammation, independent of colitis status, implies that the microbiome in CGD can influence the inflammatory phenotype of the condition.

We sought to further investigate the efficacy and safety of pioglitazone for chronic granulomatous disease (CGD) patients with severe infection. CGD patients with severe infection were enrolled and treated with pioglitazone for 90 days. The degree of improvement in infection and the changes of dihydrorhodamine-123 (DHR) were used to evaluate the efficacy of pioglitazone. The adverse reaction of pioglitazone was also investigated. We planned to enroll 30 patients at first in the study. However, the study was terminated due to negative results from all 3 enrolled patients. The 3 patients were diagnosed with CGD by clinical characteristics, DHR analysis, and genetics analysis. Mutations were CYBB (c.177C>A; p.C59X) in P1, CYBB (c.1498G>T; p.D500Y) in P2, and NCF2 (c.137T>G; p.M46R) in P3, respectively. The age of onset of the 3 patients was within 2 years after birth. The most common sites of infection were lung, lymph node, skin, and soft tissue, which were experienced in all 3 patients. The age of administration with pioglitazone was 5.2 years, 16 years and 11.1 years, respectively. The 3 patients experienced no improvement in severity of infection and stimulation index of the DHR did not also improve after receiving pioglitazone 10, 45 and 90 days, respectively. No drug-related adverse reaction was found during the period of pioglitazone. Low dose of pioglitazone did not improve the severity of infection and production of ROS in CGD patients with severe infection.

Chronic granulomatous disease (CGD) is the most common phagocyte defect disease. Here, we describe 114 CGD patients in our center and report a rare female infant with XL-CGD to provide a better understanding of diagnosis, treatment, and prenatal diagnosis of CGD. Patients were diagnosed by DHR-1,2,3 flow cytometry assays and gene analysis. X chromosome inactivation analysis and gp91phox protein test were used for a female infant with XL-CGD. XL-CGD accounts for the majority of cases in China and results in higher susceptibility to some infections than AR-CGD. The DHR assay can help diagnose CGD quickly, and atypical results should be combined with clinical manifestations, genetic analysis, and regular follow-up. For prenatal diagnosis, both gDNA and cDNA genotypes of amniotic fluid cells should be identified, and cord blood DHR assays should be performed to identify female XL-CGD patients.

Purpose Colitis is a common and serious complication of chronic granulomatous disorder (CGD) and requires assessment. Colonoscopy is invasive and carries risks of serious complication. We therefore assessed non-invasive monitoring via magnetic resonance imaging (MRI). We also evaluated fecal calprotectin (FCP), the Harvey-Bradshaw index (HBI) clinical score, and serum cytokines. Methods We recruited 10 patients with CGD (8 males, mean age 29.6 years), scored a modified HBI, and obtained stool for FCP. The following day we took blood for cytokine measurement via Luminex, performed MR enterography (scored by two independent radiologists using three systems: London score, CDMI, and MaRIA) followed by colonoscopy with disease activity measurement via ulcerative colitis endoscopic index of severity (UCEIS). We assessed patient experience after each investigation and overall preference with follow-up questionnaires. Results MRI scores correlated well with colonoscopic gold standard (for London score R2 0.91, p

Chronic granulomatous disease (CGD) is a primary immunodeficiency for which allogeneic hematopoietic stem cell transplant (HSCT) offers potential cure. Direct comparison of HSCT to non-HSCT management in the North American population was performed to identify clinical factors associated with overall survival (OS) and transplant-related survival (TRS). Retrospective review of CGD subjects enrolled in the United States Immunodeficiency Network. Survival was estimated by the Kaplan-Meier method and modeled by proportional hazards regression. We identified 507 patients (66% CYBB mutants) diagnosed in 1953–2016. Fifty underwent allogeneic HSCT. Median follow-up was 9.1 years after diagnosis (0–45.8 years). OS was negatively associated with CYBB mutation (HR = 6.25; p = 0.034) and not associated with HSCT (88% v. 85% ± HCT) (HR = 1.26; p = 0.65). Transplant at ≤ 14 years old was associated with improved TRS (93% v. 82% at T + 60 months) (HR = − 4.51; p = 0.035). Patients transplanted before 15 years old had fewer severe infections pre-HSCT (mean 0.95 v. 2.13; p = 0.047). No mortality was reported in patients receiving stem cells from matched siblings. Infection incidence declined post-HSCT in subjects with greater than or equal to four infections pre-HSCT (p = 0.0010). Compared to non-HSCT patients ≥ 15 years old, post-transplant survivors had higher mean performance score (93.2 v. 85.9; p = 0.0039) and lower frequency of disability (11% v. 52%; p = 0.014). Allogeneic HSCT was associated with reduced infection incidence and improved functional performance, but not with a change in overall survival. Transplant-related survival was elevated in patients undergoing HSCT before 15 years old. Consider HSCT prior to late adolescence in patients with severely diminished reactive oxygen intermediate synthesis, particularly if a matched sibling is available.

X-linked chronic granulomatous disease (XL-CGD), a rare primary immunodeficiency due to a defect in the gp91phox NADPH oxidase subunit, results in recurrent, severe infection, inflammation, and autoimmunity. Patients have an absent, or significantly reduced, neutrophil oxidative burst. Due to lyonization, XL-CGD carriers have a dual population of functional and non-functional phagocytes and experience a range of symptoms including increased risk of autoimmunity, fatigue, and infection. Patients with CGD have poorer quality of life (QoL) than normal controls. We evaluated QoL and psychological health in UK XL-CGD carriers. Recruited participants completed the Medical Outcomes Study Short Form 36 version 2 (SF-36 V2), providing an overall score for mental and physical health. Psychological health was assessed using the Hospital Anxiety and Depression Scale (HADS) questionnaire. Seventy-five XL-CGD carriers were recruited from 62 families, median age 43 years (range 3–77). Fifty-six were mothers, 6 grandmothers, and 13 siblings. Sixty-two completed the SF36v2 and had reduced QoL scores compared with adult CGD patients and a UK age-matched female control cohort, indicating a reduced QoL. Sixty-one completed a HADS questionnaire. Over 40% experienced moderate or greater levels of anxiety with only one third being classified as normal. Higher anxiety scores significantly correlated with higher depression scores, lower self-esteem, presence of joint or bowel symptoms, and higher levels of fatigue (p

Most of the literature on liver abscess in chronic granulomatous disease (CGD) emanates from developed countries. Data from developing countries are scarce. In this study, we report clinical features, microbiological profile, and treatment difficulties encountered while managing liver abscesses in patients with CGD at a tertiary care centre in North-West India. Case records of children with CGD and liver abscesses at Pediatric Immunodeficiency Clinic, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India were analyzed. Seven of 68 patients (10.29%) with CGD presented with hepatic abscess. One patient had 2 recurrences. All were males and age-range at presentation was 7 months–22 years. Mutation analysis was carried out in all patients—3 had defects in CYBB gene; 2 in NCF1; 2 in NCF2 gene. Staphylococcus aureus was isolated from 5 patients. Duration of antimicrobial treatment ranged from 3 weeks to 7 months. Open drainage was required in 1 patient, and 1 patient was treated with a prolonged course of prednisolone. Two children succumbed to the illness. This is the largest reported experience of liver abscesses in patients with CGD from the developing world. Staphylococcus aureus was the commonest pathogen isolated. In our experience, prolonged courses of antimicrobials are usually necessary in these patients. Glucocorticoids can reduce inflammatory response and facilitate early resolution of abscesses in CGD.

Management of inflammatory complications of chronic granulomatous disease (CGD) is challenging. The aim of this study was to assess safety, with a focus on infections, and effectiveness of tumor necrosis factor alpha (TNF-α) blockers in CGD patients.A retrospective, single-center cohort study of CGD patients treated by anti-TNF-α agents at Necker-Enfants Malades University Hospital (Paris, France) and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH).Between 2006 and 2019, 14 (X-linked: n = 10, 71.4%; autosomal-recessive: n = 4, 28.6%) CGD patients with gastrointestinal (n = 12, 85.7%), pulmonary (n = 10, 71.4%), cutaneous (n = 3, 21.4%), and/or genitourinary (n = 2, 14.3%) inflammatory manifestations received one or more doses of infliximab because of steroid-dependent (n = 7, 50%), refractory (n = 4, 28.6%) inflammatory disease or as first-line drug (n = 2, 14.3%; missing data, n = 1). All patients received adequate antimicrobial prophylaxis. Infliximab achieved complete (n = 2, 14.3%) or partial (n = 9, 64.3%) response in 11 (78.6%) patients. Seven (50%) patients were switched to adalimumab. During anti-TNF-α treatment, 11 infections (pneumonia, adenitis, invasive candidiasis, each n = 2; intra-abdominal abscess, bacteremic salmonellosis, Pseudomonas aeruginosa-related folliculitis, cat-scratch disease, proven pulmonary mucormycosis, each n = 1) occurred in 7 (50%) patients. All infectious complications had a favorable outcome. Anti-TNF-α treatment was definitively stopped because of infection in two patients. Nine (64.3%) patients finally underwent hematopoietic stem cell transplantation. No death occurred during follow-up.Anti-TNF-α treatment could improve the outcome of severe inflammatory complications in CGD patients, but increases their risk of infections. We suggest that anti-TNF-α treatment might be of short-term benefit in selected CGD patients with severe inflammatory complications awaiting hematopoietic stem cell transplantation.

Nocardiosis is a life-threatening infectious disease. We aimed at describing nocardiosis in patients with primary immunodeficiency diseases (PID). This international retrospective cohort included patients with PID and nocardiosis diagnosed and/or published from Jan 1, 2000, to Dec 31, 2016. To identify nocardiosis cases, we analyzed PID databases from the French National Reference Center for PID (Paris, France) and the National Institute of Health (NIH, United States of America) and we performed a literature review on PubMed. Forty-nine cases of nocardiosis associated with PID were included: median age at diagnosis of nocardiosis was 19 (0–56) years and most cases were observed among chronic granulomatous disease (CGD) patients (87.8%). Median time from symptoms to diagnosis of Nocardia infection was 20 (2–257) days. Most frequent clinical nocardiosis presentation was pneumonia (86.7%). Twelve-month mortality rate was 4.2%, and 11.9% of patients experienced a possible recurrence of infection. Nocardiosis more frequently led to the diagnosis of PID among non-CGD patients than in CGD patients. Non-CGD patients experienced more cerebral nocardiosis and more disseminated infections, but mortality and recurrence rates were similar. Highest incidences of nocardiosis among PID cohorts were observed among CGD patients (0.0057 and 0.0044 cases/patient-year in the USA and in France, respectively), followed by IL-12p40 deficiency. Among 49 cases of nocardiosis associated with PID, most patients had CGD and lung involvement. Both mortality and recurrence rates were low.

Clinical diagnosis and treatment for chronic granulomatous disease (CGD) have advanced greatly in recent years. However, CGD patients in China have unique clinical features and infection spectrums, which are challenging to their caretakers. Here, we summarized the clinical characteristics, genetic features, treatment, and prognosis of CGD in a single center in Shanghai. One hundred sixty-nine CGD patients were recruited between January 2004 and May 2017 based on clinical diagnosis. Electronic medical charts were reviewed to collect clinical data. Among the 169 patients recruited, CYBB mutations were identified in 150 cases, whereas CYBA mutations were identified in 7 cases, NCF1 in 5, and NCF2 in 7. The medium age at onset was 1 month (interquartile range 1–3). The medium age at diagnosis was 8 months (interquartile range 3–19). The most common infection sites were the lung (95.9%), lymph node (58.5%), skin (45.4%), intestinal (43.1%), and perianal (38.5%). Bacillus Calmette-Guerin (BCG) infections were common (59.2%). In addition, other non-infectious complications were also common, including anemia (55.4%) and impaired liver functions (34.6%). Thirty-one patients received stem cell transplantation. By the end of this study, 83/131 patients survived. Similar to other non-consanguineous populations, X-linked CGD accounted for the majority of the cases in China. However, BCG infections were a clinical challenge unique to China. In addition, severe infections were the major cause of death and the overall mortality was still high in China.

The purpose of this study was to evaluate engraftment and adverse events with a conditioning and prophylactic regimen intended to achieve high rates of engraftment with minimal graft-versus-host disease (GVHD) in allogeneic transplantation for chronic granulomatous disease in a single center. Forty patients, 37 male, with chronic granulomatous disease were transplanted. Transplant products were matched sibling peripheral blood stem cells (PBSCs) in four and matched unrelated donor (MUD) bone marrow in three, and one patient received mismatched unrelated PBSCs. Thirty-two patients received MUD PBSCs. All patients received a conditioning regimen of busulfan/alemtuzumab (with low-dose total body irradiation for MUD recipients) with sirolimus graft-versus-host disease prophylaxis. Engraftment occured in 38/40 recipients (95%). Acute or chronic GVHD occurred in 18 (45%) and 5 (12.5%), respectively, with 6 episodes of grades III–IV and/or steroid refractory GVHD. Overall survival was 33/40 (82.5%) and event-free survival was 30/40 (80%). Successful engraftment was associated with myeloid and NK cell, but not CD3+ chimerism. Myeloid engraftment was greater than 70% in 30/32 recipients at mean follow-up of 3.4 years. Evidence of persistent immunodeficiency was not seen in successful transplants. Attempts to rescue failed or poorly functioning grafts were associated with unacceptable morbidity and mortality. A reduced-intensity allogeneic transplant protocol based on alemtuzumab and busulfan with sirolimus GVHD prophylaxis produced high rates of successful engraftment and minimal regimen-related toxicity. Prolonged clinical follow-up has confirmed its efficacy in ameliorating CGD-related disease. Outcomes were not acceptable with donor cell infusion rescue of cause with poor graft function.

Chronic granulomatous disease (CGD) is an inherited phagocytic disorder characterized by recurrent infections with usually catalase-positive organisms. Infections in CGD from developing countries are expected to be different from those in the Western countries. We report the profile of infections in children diagnosed with CGD from a tertiary care center in North India. Case records of children diagnosed with CGD at Pediatric Immunodeficiency Clinic, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India, from August 1993 to April 2016 (23 years) were analyzed. Thirty-eight children were diagnosed to have CGD. Median follow-up of patients was 2 years (interquartile range 0.75, 6.0). Staphylococcus aureus and Pseudomonas spp. were the two most common causative bacteria isolated. Aspergillus was the most common fungus isolated. The most common organ involved was the lung (94.7%). Liver abscesses were identified in 5 patients (13.2%), and 20 (52.6%) patients had lymphadenitis. Infections with Pseudomonas spp. were high in our cohort (15.7%) compared to the other studies. Infections with some unusual organisms (e.g., Fusarium dimerium and Chryseobacterium gleum) were also seen in our cohort. Children with X-linked CGD presented earlier and also had a greater number of infections as compared to autosomal recessive CGD. Various socioeconomic factors coupled with the lack of awareness and paucity of readily available diagnostic facilities for primary immunodeficiencies accounted for a late clinical presentation with severe infections and increased mortality (28.9%) in our cohort. However, mortality was similar in X-linked and autosomal recessive CGD as was the number of fungal infections. The incidence of infections and mortality was significantly lower after initiation of antibacterial and antifungal prophylaxis.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0–186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.

The ubiquitous calcium-independent phospholipase A2 enzyme (iPLA2) is inhibited by calmodulin binding and known to be responsible for phospholipid remodeling housekeeping functions including granule exocytosis-associated membrane fusion in normal human neutrophils. We evaluate in human neutrophils the iPLA2 secretagogue effects using normal neutrophils, where reactive oxygen species (ROS) generation has been blocked by diphenyleneiodonium, as well as in neutrophils from chronic granulomatous disease (CGD) patients.Neutrophils were pretreated with W7, a calmodulin inhibitor known to activate iPLA2 and exocytosis of granules, and vesicles as well as intra- and extra-microbicidal activity against Staphylococcus aureus and Aspergillus fumigatus were evaluated.W7 increases exocytosis of primary, secondary, and tertiary granules and vesicles and improves neutrophil microbicidal activity against S. aureus and A. fumigatus.In neutrophils, calmodulin-mediated iPLA2 inhibition controls granule and vesicle exocytosis in the phagosome and in the extracellular microenvironment. Relieving iPLA2 inhibition results in increased exocytosis of primary, secondary, and tertiary granules and secretory vesicles with correction of defective intracellular and extracellular microbicidal activity. In CGD patients presenting ROS defective production, this increase in the non-oxidative killing pathway partially corrects their microbicidal defects.

An abnormal regulation of immune responses leads to autoimmune and inflammatory manifestations in patients with primary immunodeficiencies (PIDs). The objective of our study was to evaluate the frequency of non-infectious and non-malignant manifestations in a large cohort of patients included in the Slovenian national PID registry and to assess the time of manifestation onset with respect to the time of PID diagnosis. Medical records of registered patients were reviewed. Data on autoimmunity, lymphoproliferation, autoinflammation, allergies, PID diagnosis, and underlying genetic defects were collected and analyzed. The time of each manifestation onset was determined and compared with the time of PID diagnosis. As of May 2015, 247 patients with 50 different PIDs were registered in the Slovenian national PID registry (147 males, 100 females; mean age 20 years). Mean disease duration was 14 years; 78 % of patients were younger than 18 years; and 22 % of patients were adults. Diagnosis of PID was genetically confirmed in 51 % of patients. Non-infectious and non-malignant manifestations were present in 69/235 (29 %) patients, including autoimmune manifestations in 52/235 (22 %), lymphoproliferative/granulomatous in 28/235 (12 %), autoinflammatory in 12/247 (5 %), and allergic manifestations in 10/235 (4 %) of all registered patients. Autoimmune manifestations were present in all patients whose PIDs were classified as diseases of immune dysregulation, 47 % of patients with chronic granulomatous disease, and 38 % of patients with predominantly antibody immune deficiencies. A high prevalence of non-infectious and non-malignant manifestations among patients in the Slovenian national PID registry suggests common genetic factors of autoimmunity, inflammation, and immunodeficiency. Patients with PID should be routinely screened for autoimmune and inflammatory manifestations at the time of PID diagnosis and during the long-term follow up.

The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75% for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations. A myeloablative reduced toxicity HSCT was completed using an unrelated bone marrow donor. With the increasing cases of immune dysregulation being discovered with hypomorphic RAG variants, the use of HSCT may advance to the forefront of treatment. This case serves to discuss indications of HSCT, approaches to preparative therapy, and the potential complications in this growing cohort of patients with immune dysregulation and RAG deficiency.

International audience; Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients' clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families.

Chronic granulomatous disease (CGD) is an inherited mutational defect in any of the NADPH oxidase complex, CYBB (gp91-phox), NCF1 (p47-phox), CYBA (p22-phox), NCF2 (p67-phox), or NCF4 (p40-phox) leading to inability of phagocytes to perform effective respiratory burst and thus diminished killing of bacteria and fungi. The identification of defective proteins aids in establishing a diagnosis prior to genetic analysis, which is rather labor-intensive, expensive, and time-consuming. The present study aims at assessing the NADPH proteins by performing the intracellular staining with specific monoclonal antibodies and their assessment on flow cytometry. The use of flow cytometry is less laborious and faster to perform than western blot. It also confirms the diagnosis of CGD and detects the affected components allowing proper management of patients. Twenty-eight patients from 25 different kindred, clinically suspected as CGD were recruited in Egypt. Dihydrorhodamine test was performed to confirm the diagnosis of the patients. Intracellular staining of NADPH components using specific monoclonal antibodies was performed followed by flow cytometric analysis. The present study revealed that the most common defective protein in our cohort is p22-phox, found in 13 patients (46.4 % of cases) followed by p47-phox in 8 patients (28.6 %), gp91-phox in 5 patients (17.9 %), and finally p67-phox in 2 patients (7.1 %). In countries with limited resources and yet large number of CGD patients, the analysis of the defective proteins by flow cytometry is an optimum solution for confirming the diagnosis and is a step for targeted sequencing in families seeking prenatal diagnosis.

Chronic granulomatous disease (CGD) is characterized by mutation in any one of the five genes coding NADPH oxidase components that leads to functional abnormality preventing the killing of phagocytosed microbes by affecting the progression of a respiratory burst. CGD patients have an increased susceptibility to infections by opportunistic and pathogenic organisms. Though initial diagnosis of CGD using a nitroblue tetrazolium (NBT) test or dihydrorhodamine (DHR) test is relatively easy, molecular diagnosis is challenging due to involvement of multiple genes, presence of pseudogenes, large deletions, and GC-rich regions, among other factors. The strategies for molecular diagnosis vary depending on the affected gene and the mutation pattern prevalent in the target population. There is a paucity of molecular data related to CGD for Indian population. This report includes data for a large cohort of CGD patients (n = 90) from India, describing the diagnostic approach, mutation spectrum, and novel mutations identified. We have used mosaicism in mothers and the expression pattern of different NADPH components by flow cytometry as a screening tool to identify the underlying affected gene. The techniques like Sanger sequencing, next-generation sequencing (NGS), and Genescan analysis were used for further molecular analysis. Of the total molecularly characterized patients (n = 90), 56% of the patients had a mutation in the NCF1 gene, 30% had mutation in the CYBB gene, and 7% each had mutation in the CYBA and NCF2 genes. Among the patients with NCF1 gene mutation, 82% of the patients had 2-bp deletion (DelGT) mutations in the NCF1 gene. In our cohort, 41 different mutations including 9 novel mutations in the CYBB gene and 2 novel mutations each in the NCF2, CYBA, and NCF1 genes were identified. Substantial number of the patients lack NCF1 gene on both the alleles. This is often missed by advanced molecular techniques like Sanger sequencing and NGS due to the presence of pseudogenes and requires a simple Genescan method for confirmation. Thus, the diagnostic approach may depend on the prevalence of affected genes in respective population. This study identifies potential gene targets with the help of flow cytometric analysis of NADPH oxidase components to design an algorithm for diagnosis of CGD in India. In Indian population, the Genescan method should be preferred as the primary molecular test to rule out NCF1 gene mutations prior to Sanger sequencing and NGS.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that is characterized by susceptibility to bacterial and fungal infections. Various mutations in CYBB encoding the gp91(phox) subunit of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase impair the respiratory burst of all types of phagocytic cells and result in X-linked CGD (X-CGD). We here sought to evaluate the underlying cause in an attenuated phenotype in an X-CGD patient. The patient is a 31-year-old male who had been diagnosed as having X-CGD based on the absence of nitroblue tetrazolium reduction and the presence of a CYBB mutation at the age of 1 year. He has been in good health after overcoming recurrent bacterial infections in infancy. We investigated genomic DNA analysis of CYBB gene, residual activity of NADPH oxidase, and expression of gp91(phox) in both polymorphonuclear leukocytes (PMNs) and monocytes/macrophages in the present patient. Although his underlying germline mutation, c.1016C > A (p.P339H) in the CYBB gene, was identified in both PMNs and monocytes, the expression and functional activity of gp91(phox) retained in monocytes/macrophages, in stark contrast to markedly reduced PMNs. Our results indicate that residual reactive oxygen intermediates (ROI) production in PMNs plays an important role in infantile stage in X-CGD, but thereafter retained function of monocytes/macrophages might compensate for the function of NADPH oxidase deficient PMNs and might be an important parameter for predicting the prognosis of X-CGD patients.

The original version of the article, “Raised Serum IL-8 Levels Are Associated with Excessive Fatigue in Female Carriers of X-Linked Chronic Granulomatous Disease in the UK” incorrectly listed the name of the fourth author as Fai W. Ng. The correct spelling of the author’s name is WF Ng.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that is characterized by susceptibility to bacterial and fungal infections. CGD patients also suffer from immune regulatory disorders, such as CGD-associated bowel inflammation with granuloma, which could be caused by excessive inflammation without demonstrable infection. We investigated the clinical manifestation of interstitial lung disease (ILD) resulting from excessive inflammation in X-linked CGD patients. Pulmonary CT images and testing of serum KL-6 levels were performed to assess ILD in the patients. For this study, patients with pulmonary lesions due to demonstrable infections were excluded from among ILD patients. Among 33 CGD patients, four developed ILD; they had increased reticulo-nodular opacities on CT images and elevated serum KL-6 levels. Histopathological examinations revealed multiple homogeneous microgranulomas in the lesions of inflammatory cell infiltration. Mononuclear cells obtained from their pulmonary lesions produced higher amounts of inflammatory cytokines than the peripheral blood mononuclear cells of CGD patients, suggesting that the only infiltrating cells in the pulmonary lesions were activated and produced large amounts of inflammatory cytokines in ILD patients. Interestingly, an anti-inflammatory drug, such as a corticosteroid or thalidomide, but not anti-bacterial or anti-fungal drugs, improved CT image findings and reduced their KL-6 levels. CGD patients’ daily exposures to inhaled antigens may induce excessive reactions with the production of inflammatory cytokines leading to the development of ILD with multiple microgranulomas, which could be due to an inadequate production of reactive oxygen species in CGD.

Chronic granulomatous disease (CGD) is an inherited disorder, with phagocytes failing to produce antimicrobial superoxide due to deficient NADPH oxidase activity. Mutations in the gene encoding CYBB are responsible for the majority of the CGD cases. To date, there have been no reports on large samples of children with CGD in China. Therefore, in this study, we described the clinical and molecular features of 38 suspected CGD patients from 36 unrelated Chinese families. Clinical diagnosis was performed using dihydrorhodamine assays detected by flow cytometry. Molecular analysis was used to identify underlying CGD-causative genes. The mean age of onset in our 38 patients was 3.4 months, while the mean age at diagnosis was 31.7 months. Apart from recurrent pneumonia and abscesses, tuberculosis (TB) and Bacille Calmette-Guerin (BCG) infections were notable features in our cohort. Overall, 17 cases died and patient 1 did not participate in the follow-up period . In total, we identified 29 different CYBB gene mutations in 31 patients. We found NCF1 and CYBA mutations in 3 and 2 patients, respectively. In addition, we identified 31 carriers and prenatally diagnosed 4 CGD and 4 healthy fetuses. The results of our study demonstrate that children with BCG infections or recurrent TB infections should have immune function screening tests performed. Moreover, newborns with family histories of primary immunodeficiency diseases should avoid of BCG vaccination. Molecular analysis is an important tool for identifying patients, carriers, and high-risk CGD fetuses.

Chronic granulomatous disease (CGD) results from an inherited defect in the phagocytic cells of the immune system. It is a genetically heterogenous disease caused by defects in one of the five major subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. There is a paucity of data from India on CGD. We herein describe the clinical features in 17 children with CGD from a single tertiary referral center in India. A detailed analysis of the clinical features, laboratory investigations and outcome of 17 children 7 with X-linked (XL) and 10 with autosomal recessive (AR) form was performed. Diagnosis of CGD was based on an abnormal granulocyte oxidative burst evaluated by either Nitroblue Tetrazolium (NBT) test or flow cytometry based Dihyrorhodamine 123 assay or both. The molecular diagnosis was confirmed by genetic mutation analysis in 13 cases. The mean age at diagnosis and the age at onset of symptoms was significantly lower in children diagnosed with XL- CGD compared those with AR disease. Mutations were detected in CYBB gene in 6 patients with XL-CGD and NCF-1 gene mutations were observed in 7 cases of AR- CGD. The course and outcome of the disease was much worse in children diagnosed with X-linked form of disease compared to AR forms of the disease; 4/7 (57%) children with X-CGD were dead at the time of data analysis. This is one of the largest series on chronic granulomatous disease from any developing country.

Chronic granulomatous disease is a rare immunodeficiency due to defects in the phagocyte NADPH oxidase. The X-linked form (gp91 (phox) deficiency) accounts for about 70 % of cases; autosomal recessive p47 (phox) deficiency accounts for about 25 % of cases. We identified a 10 % incidence of diabetes in p47 (phox) deficient CGD, but none in X-linked CGD. Renal and cardiovascular diseases were also higher in p47 (phox) deficiency. p47 (phox) deficient CGD has non-infectious morbidities distinct from those in X-linked CGD.

Chronic Granulomatous Disease (CGD) is an uncommon primary immunodeficiency caused by the absence or dysfunction of one of NADPH oxidase subunits, with heterogeneous genetic aetiologies. The aim of this study was the CGD patient registry in Greece, the identification of the responsible genotype and the potential correlation with the patient's clinical phenotype. Medical charts of 24 CGD patients, investigated by NBT test or DHR for NADPH oxidase activity, Western blot analysis for NADPH oxidase component expression and DNA sequencing (pyro- and cycle sequencing) for mutation analysis, were reviewed. All patients, but one, were classified into the different types of CGD. Sixteen patients from 14 unrelated families had X-linked CGD (66.7 %), four had mutations in the NCF1 gene (19 %), and three, from two unrelated families, had mutations in NCF2 (9.5 %) [Corrected]. Fifteen mutations were detected in the CYBB gene, including nonsense (53.8 %), splice site (30.8 %) and missense mutations (7.7 %), and deletions (7.7 %). Two novel mutations were identified; one in CYBB and one in NCF1. Carrier detection for X-CGD revealed that the de novo mutation rate was about 7 %. Prenatal diagnosis identified one affected male in three male fetuses tested. In both the X-linked and the autosomal recessive (AR-CGD) group, the gastrointestinal and respiratory manifestations were more common, followed by lympadenopathy in X-CGD and skin infections in the AR-CGD group. The patients with a mutation in CYBB had a wider variability of clinical manifestations and earlier diagnosis (4.6 years) compared to the AR-CGD group (12.9 years). The incidence of CGD in Greece is estimated at 0.90 (95 % CI 0.89-0.91) per 100,000 live births for the last decade.

Chronic granulomatous disease (CGD) is a genetic disorder in which phagocyte dysfunction leads to recurrent infection. Persistent pulmonary infections sometimes require thoracic surgical intervention. We reviewed our 25-year experience to identify outcomes and prognostic factors associated with thoracic surgery in these patients.A retrospective single-institution review of all patients with CGD from 1990 through 2015 was performed. Univariate analysis identified prognostic variables to include in a Cox model. Overall survival was estimated by the Kaplan-Meier method.We identified 258 patients who had 2221 admissions (both scheduled and emergent). During the period examined, 51 thoracic operations were performed in 13.6 % (35/258) of patients and 2.3 % (35/2221) of overall admissions. Patients undergoing surgery did not have statistically significant differences in disease genotype compared to those that did not require surgery. Pathogens were identified from 67 % (34/51) of specimens. Complications occurred in 27 % (14/51), including 10 % (5/51) with wound and 12 % (6/51) with pulmonary infections. Mortality at 30 and 90 days was 0 and 6 % (3/51), respectively. Overall survival probabilities were 75 and 62 % at 5- and 10-year follow-up (median potential follow-up: 16.5 years), respectively. Undergoing thoracic surgery was associated with an increased hazard ratio for death of 3.71 (p 0.0001). Both chest wall resection and EBL 500 mL were negative prognostic factors (p 0.05).A minority of CGD patients required thoracic surgery for infections refractory to antibiotic or antifungal therapy. Patients who had these operations had significant morbidity and relatively poor long-term survival, particularly in the cases of chest wall resection or significant blood loss.

Chronic granulomatous disease (CGD) is a group of inherited disorder of phagocytes, resulting from mutations in the components of the NADPH oxidase complex. Reduced or absent oxygen radical synthesis seen in these patients leads to impaired killing of intracellular bacteria and fungi. CGD clinically presents with recurrent and life-threatening infections as well as granulomatous inflammatory responses. p47

Objectives Chronic granulomatous disease is a rare phagocyte disorder characterized by an increased susceptibility to infections and inflammatory complications. We describe two patients with chronic granulomatous disease (CGD) complicated by macrophage activation syndrome (MAS) (secondary hemophagocytic lymphohistiocytosis) treated with intravenous immunoglobulin (IVIG). Methods A report of two cases of CGD complicated by MAS who were successfully treated with IVIG was made, and a comparison was made with ten other cases reported in the literature. Results MAS is a severe potentially fatal complication of CGD. Most cases are associated with Burkholderia cepacia and leishmaniasis infection. The treatment of these patients varies between centers, and one example is the use of the HLH-2004 protocol. IVIG could be an effective first line option for this complication in CGD patients. Conclusions The exaggerated inflammatory response characteristic of CGD patients could play a role in the development of this complication. IVIG appears to be a safe and effective first line treatment in these patients.

Chronic granulomatous disease (CGD) is a rare immunodeficiency due to a genetic defect in one of the NADPH-oxidase components. We studied CGD inheritance forms (autosomal recessive (AR) or X-linked (XL)) and AR-CGD subtypes in Iran.Clinical and functional investigations were conducted in 93 Iranian CGD patients from 75 families.Most of the patients were AR-CGD (87.1%). This was related to consanguineous marriages (p = 0.001). The age of onset of symptoms and diagnosis were lower in XL-CGD compared with AR-CGD (p Although XL-CGD is the most common type of the disease worldwide, only 12 patients (12.9%) were XL-CGD in our study. The relatively high frequency of AR-CGD is probable due to widely common consanguineous marriages in Iran.

Chronic granulomatous disease (CGD) is an immune deficiency syndrome caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the enzyme that generates reactive oxygen species (ROS) in phagocytizing leukocytes. This study evaluates the NADPH oxidase capacity in two X-linked CGD patients with mutations in gp91(phox) that alter the regions in this membrane-bound NADPH oxidase component involved in docking of the cytosolic component p47(phox). Hydrogen peroxide and superoxide generation, bactericidal activity, and NADPH oxidase protein expression by the patients' neutrophils were measured, and genetic analysis was performed. We report two patients, each with a novel missense mutation in CYBB, the gene that encodes gp91(phox). Surprisingly, neutrophils from these patients showed total absence of superoxide production, although they retained 13-30% of the hydrogen peroxide production capability. We speculate that this is due to direct electron transfer from flavin adenine dinucleotide (FAD) in gp91(phox) to oxygen, leading to inefficient hydrogen peroxide formation instead of efficient superoxide production. X-linked CGD patients with mutations that alter the gp91(phox) protein in regions involved in docking of the cytosolic NADPH oxidase component p47(phox) may have higher than expected hydrogen peroxide generation capability

Chronic granulomatous disease (CGD) is phagocytic cell metabolic disorder resulting in recurrent infections and granuloma formation. This paper reports the favourable outcome of allogeneic transplantation in six high-risk CGD patients. The following donors were used: HLA-matched, related (two) and unrelated (three), and HLA-mismatched, unrelated (one). One patient was transplanted twice using the same sibling donor because of graft rejection at 6 months after reduced-intensity conditioning transplant (fludarabine and melphalan). Myeloablative conditioning regimen consisted of busulphan and cyclophosphamide. Stem cell source was unmanipulated bone marrow containing: 5.2 (2.6-6.5) × 10(8) nucleated cells, 3.8 (2.0-8.0) × 10(6) CD34+ cells and 45 (27-64) × 10(6) CD3+ cells per kilogramme. Graft-versus-host disease prophylaxis consisted of cyclosporine A and, for unrelated donors, short course of methotrexate and anti-T-lymphocyte globulin. Mean neutrophile and platelet engraftments were observed at day 22 (20-23) and day 20 (16-29), respectively. Pre-existing infections and inflammatory granulomas resolved. With the follow-up of 4-35 months (mean, 20 months), all patients are alive and well with full donor chimerism and normalized superoxide production.

Chronic granulomatous disease (CGD) is a rare inherited condition resulting from mutations in the genes that encode the proteins of the NADPH oxidase enzyme in phagocytes, rendering these cells incapable of killing invading pathogens. Patients subtypes are determined by neutrophil functional assays and immunoblotting. Although defects in the X-chromosome-linked gp91-phox component account for the majority of CGD patients in the world, in Iran, there are many CGD patients suffering from the autosomal recessive forms of the disease. Most of these patients show impairment in the synthesis of the 47-kDa cytosolic component p47-phox of the oxidase. The second causative factor of autosomal recessive CGD is deficiency of the 22-kDa component (p22-phox) of the oxidase. Another rare form of the disease is due to mutations in the NCF2 gene encoding the 67-kDa component (p67-phox) of the oxidase. Mutation analysis showed a novel homozygous splice site mutation, c.intron4+1G>T, in CYBA. A novel mutation in NCF2: a gross homozygous deletion of exon 1 and 2, causing p.Met1_Lys58 deletion in p67-phox. We also found a previously published homozygous nonsense mutation, c.196C>T, causing p.Arg66X.33 in p67-phox. Our data show that CGD in Iran is predominantly due to mutations in p47-phox, while the number of mutations in p22-phox is roughly equal to that in gp91-phox. These data indicate that the genetics of CGD are ethnically variable, and this should be considered in approaching families with CGD

IL-12/23-interferon-gamma circuit enhances reactive oxygen species (ROS) synthesis in macrophage to attack intracellular pathogens such as mycobacteria and salmonella. Defective ROS in patients with chronic granulomatous disease (CGD) have increased susceptibility to these pathogens. However, patients with defective IL-12/23-interferon-gamma circuit rather than CGD are not recognized in Taiwan, endemic for tuberculosis and salmonella.The purpose of this study was to identify Taiwanese patients with defective IL-12/23-IFN-gamma circuit.In a long-term molecular study of primary immunodeficiency diseases (PIDD), the tentative CGD patients presenting with Bacille Calmette-Guerin (BCG)-induced infection, refractory atypical mycobacterial cutaneous granuloma and osteomyelitis, recurrent salmonella sepsis, and pneumatocele were studied for the IL-12/23-IFN-gamma circuit. ROS was first measured to exclude CGD. Candidate genes of IL12RB1, IFNRG1, IL12p40, IFNRG2, signal transducer and activator of transcription-1, and NF-kappaB essential modulator and their encoding protein expressions were analyzed.Of the 175 Taiwanese PIDD patients during a 28-year period, three patients from two unrelated families were identified with the hotspot INFRG1 deletion mutation (818del4) and had CGD features, presenting as cutaneous granuloma, and multiple osteomyelitis infected by non-tuberculosis mycobacteria, Mycobacteria avium complex and Mycobacterium scrofulaceum. Another with mis-sense IL12RB1 mutation (Arg211Pro) was noted as recurrent Salmonella enteritidis D sepsis and pneumatocele.Patients with defective IL-12/23-IFN-gamma circuit may resemble or overlap CGD manifestations of refractory cutaneous atypical mycobacterial granuloma and salmonella pneumatocele.

Chronic granulomatous disease (CGD) is a genetically heterogeneous disease characterized by recurrent life-threatening infections with bacteria and fungi as well as dysregulated inflammatory mechanisms. CGD is caused by defects in the NADPH oxidase, the enzyme complex responsible for generation of superoxide and other reactive oxygen species (ROS) in phagocytic cells. In this review we will focus our attention on those particular inflammatory manifestations associated with CGD, their frequencies and the underlying immunologic mechanisms favoring it occurrence.