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Background. Although prognosis of Chronic Granulomatous Disease (CGD) has greatly improved, few studies have focused on its long-term outcome. We studied the clinical course and sequelae of CGD patients diagnosed before age 16, at various adult time points. Method. Cross-sectional French nationwide retrospective study of patients screened through the National Reference Center for Primary Immunodeficiencies (CEREDIH) registry. Results. Eighty CGD patients (71 males [88.7%], 59 X-linked [73.7%], median age 23.9 years [minimum, 16.6; maximum, 59.9]) were included, Median ages at diagnosis and last follow-up were 2.52 and 23.9 years, respectively. Seven patients underwent hematopoietic stem cell transplantation. A total of 553 infections requiring hospitalization occurred in 2017 patient-years. The most common site of infection was pulmonary (31%). Aspergillus spp. (17%) and Staphylococcus aureus (10.7%) were the commonest pathogens. A total of 224 inflammatory episodes occurred in 71 patients, mainly digestive (50%). Their characteristics as well as their annual frequency did not vary before and after age 16. Main sequelae were a small adult height and weight and mild chronic restrictive respiratory failure. At age 16, only 53% of patients were in high school. After age 30 years, 9/13 patients were working. Ten patients died during adulthood. Conclusions. Adult CGD patients displayed similar characteristics and rates of severe infections and inflammatory episodes that those of childhood. The high rate of handicap has become a matter of medical and social consideration. Careful follow-up in centers of expertise is strongly recommended and an extended indication of curative treatment by HSCT should be considered.

In chronic granulomatous disease of childhood, killing of microorganisms is impaired because of defects in the production of hydrogen peroxide. In this controlled study, 39 patients were treated in alternate years with either itraconazole or placebo, once per day. There were seven serious infections during treatment with placebo, and only one during treatment with itraconazole. Chronic granulomatous disease of childhood is a rare group of inherited disorders of phagocytic cells characterized clinically by recurrent life-threatening infections and excessive granuloma formation. 1 Phagocyte migration and phagocytosis are normal, but killing of microorganisms is impaired because of defective production of hydrogen peroxide and related products of oxygen metabolism. A variety of biochemical defects lead to the disorder. The current mortality rate is 2 to 5 percent per year. 2 In the absence of prophylaxis with antibiotics or interferon gamma, patients with chronic granulomatous disease have severe infections due to catalase-positive bacteria and fungi about once a year. Prophylaxis with . . .

Chronic granulomatous disease (CGD) is characterized by life-threatening bacterial and fungal infections. Treatment with posaconazole led to a complete response in 7 of 8 patients with CGD with invasive mold infections (7 proven cases and 1 possible case) after failure or intolerance of treatment with standard antifungal agents. In this preliminary study, salvage treatment with posaconazole was safe and effective.

Patients with chronic granulomatous disease (CGD) have a mutated NADPH complex resulting in defective production of reactive oxygen species; these patients can develop severe colitis and are highly susceptible to invasive fungal infection. In NADPH oxidasedeficient mice, autophagy is defective but inflammasome activation is present despite lack of reactive oxygen species production. However, whether these processes are mutually regulated in CGD and whether defective autophagy is clinically relevant in patients with CGD is unknown. Here, we demonstrate that macrophages from CGD mice and blood monocytes from CGD patients display minimal recruitment of microtubule-associated protein 1 light chain 3 (LC3) to phagosomes. This defect in autophagy results in increased IL-1β release. Blocking IL-1 with the receptor antagonist (anakinra) decreases neutrophil recruitment and T helper 17 responses and protects CGD mice from colitis and also from invasive aspergillosis. In addition to decreased inflammasome activation, anakinra restored autophagy in CGD mice in vivo, with increased Aspergillus-induced LC3 recruitment and increased expression of autophagy genes. Anakinra also increased Aspergillus-induced LC3 recruitment from 23% to 51% (P < 0.01) in vitro in monocytes from CGD patients. The clinical relevance of these findings was assessed by treating CGD patients who had severe colitis with IL-1 receptor blockade using anakinra. Anakinra treatment resulted in a rapid and sustained improvement in colitis. Thus, inflammation in CGD is due to IL-1–dependent mechanisms, such as decreased autophagy and increased inflammasome activation, which are linked pathological conditions in CGD that can be restored by IL-1 receptor blockade.

Key role for superoxides In chronic granulomatous disease (CGD), phagocytes lack NADPH oxidase activity and are unable to generate superoxide, making sufferers susceptible to recurrent microbial infections. The precise mechanism involved — and the reasons for exaggerated inflammation in CGD — are unclear. Experiments in genetically engineered CGD mice infected with Aspergillus fumigatus , a frequent infection in CGD patients, supports the theory that superoxide-dependent conversion of tryptophan to kynurenine is defective in CGD, compromising antimicrobial resistance, inflammation, and T-cell homeostasis through a single, as yet unknown mechanism. The finding raises the possibility that replacement therapy with natural kynurenines might help control pathologic inflammation and susceptibility to infection in CGD patients. Chronic granulomatous disease is associated with lack of NADPH activity in phagocytes and characterized by recurrent bacterial and fungal infections as well as exagerated inflammation. This paper shows that the excessive inflammation can be attributed to the lack of NAPPH-derived reactive oxygen which is required for the conversion of tryptophan to kynurenine. Half a century ago, chronic granulomatous disease (CGD) was first described as a disease fatally affecting the ability of children to survive infections. Various milestone discoveries have since been made, from an insufficient ability of patients’ leucocytes to kill microbes to the underlying genetic abnormalities 1 . In this inherited disorder, phagocytes lack NADPH oxidase activity and do not generate reactive oxygen species, most notably superoxide anion, causing recurrent bacterial and fungal infections. Patients with CGD also suffer from chronic inflammatory conditions, most prominently granuloma formation in hollow viscera. The precise mechanisms of the increased microbial pathogenicity have been unclear 2 , and more so the reasons for the exaggerated inflammatory response 3 , 4 , 5 , 6 . Here we show that a superoxide-dependent step in tryptophan metabolism along the kynurenine pathway is blocked in CGD mice with lethal pulmonary aspergillosis, leading to unrestrained Vγ1 + γδ T-cell reactivity, dominant production of interleukin (IL)-17, defective regulatory T-cell activity and acute inflammatory lung injury. Although beneficial effects are induced by IL-17 neutralization or γδ T-cell contraction, complete cure and reversal of the hyperinflammatory phenotype are achieved by replacement therapy with a natural kynurenine distal to the blockade in the pathway. Effective therapy, which includes co-administration of recombinant interferon-γ (IFN-γ), restores production of downstream immunoactive metabolites and enables the emergence of regulatory Vγ4 + γδ and Foxp3 + αβ T cells. Therefore, paradoxically, the lack of reactive oxygen species contributes to the hyperinflammatory phenotype associated with NADPH oxidase deficiencies, through a dysfunctional kynurenine pathway of tryptophan catabolism. Yet, this condition can be reverted by reactivating the pathway downstream of the superoxide-dependent step.

Background. Chronic granulomatous disease (CGD) is due to defective nicotinamide adenine dinucleotide phosphate oxidase activity and characterized by recurrent infections with a limited spectrum of bacteria and fungi as well as inflammatory complications. To understand the impact of common severe infections in CGD, we examined the records of 268 patients followed at a single center over 4 decades. Methods. All patients had confirmed diagnoses of CGD, and genotype was determined where possible. Medical records were excerpted into a standard format. Microbiologic analyses were restricted to Staphylococcus, Burkholderia, Serratia, Nocardia, and Aspergillus. Results. Aspergillus incidence was estimated at 2.6 cases per 100 patient-years; Burkholderia, 1.06 per 100 patient-years; Nocardia, 0.81 per 100 patient-years; Serratia, 0.98 per 100 patient-years, and severe Staphylococcus infection, 1.44 per 100 patient-years. Lung infection occurred in 87% of patients, whereas liver abscess occurred in 32%. Aspergillus incidence was 55% in the lower superoxide-producing quartiles (quartiles 1 and 2) but only 41% in the higher quartiles (rate ratio, <0.0001). Aspergillus and Serratia were somewhat more common in lower superoxide producing gp91phox deficiency. The median age at death has increased from 15.53 years before 1990 to 28.12 years in the last decade. Fungal infection carried a higher risk of mortality than bacterial infection and was the most common cause of death (55%).Gastrointestinal complications were not associated with either infection or mortality. Conclusions. Fungal infections remain a major determinant of survival in CGD. X-linked patients generally had more severe disease, and this was generally in those with lower residual superoxide production. Survival in CGD has increased over the years, but infections are still major causes of morbidity and mortality.

Abstract Dysfunction of phagocytes is a relevant risk factor for staphylococcal infection. The most common hereditary phagocyte dysfunction is chronic granulomatous disease (CGD), characterized by impaired generation of reactive oxygen species (ROS) due to loss of function mutations within the phagocyte NADPH oxidase NOX2. Phagocytes ROS generation is fundamental to eliminate pathogens and to regulate the inflammatory response to infection. CGD is characterized by recurrent and severe bacterial and fungal infections, with Staphylococcus aureus as the most frequent pathogen, and skin and lung abscesses as the most common clinical entities. Staphylococcus aureus infection may occur in virtually any human host, presumably because of the many virulence factors of the bacterium. However, in the presence of functional NOX2, staphylococcal infections remain rare and are mainly linked to breaches of the skin barrier. In contrast, in patients with CGD, S. aureus readily survives and frequently causes clinically apparent disease. Astonishingly, little is known why S. aureus, which possesses a wide range of antioxidant enzymes (e.g. catalase, SOD), is particularly sensitive to control through NOX2. In this review, we will evaluate the discovery of CGD and our present knowledge of the role of NOX2 in S. aureus infection. This review discusses the role of generation of reactive oxygen species by the phagocyte NADPH oxidase NOX2 in host–pathogen interaction with a specific focus on S. aureus infections.

Background Non- Aspergillus invasive fungal infections (NAFI) are increasingly reported in patients with Chronic Granulomatous Disease (CGD), but precise clinical descriptions remain scarce. Objective and Methods We conducted a retrospective analysis of NAFI cases among CGD patients in the French National Registry of Primary Immunodeficiencies (CEREDIH) and in a comprehensive literature review. Results We identified 16 proven NAFI (9 molds, 6 yeasts and 1 Pneumocystis ) among 263 CGD patients from CEREDIH and included an additional 106 probable/proven NAFI from a literature review (75 molds, 29 yeasts, 1 Pneumocystis, 1 dimorphic ). Mold NAFI occurred at a median age of 17 years [IQR 9–23], and were mostly located to the lungs (79%, 65/82). Mold NAFI were breakthrough in 59% of patients (35/59), and 24% were receiving immunosuppressive treatments (13/54, mostly high-dose corticosteroids, n = 11). Lung surgical biopsies yielded the highest diagnostic rate (39/39) compared to less invasive methods (BAL 8/18 and transthoracic punctures 8/12). Nine patients with mold NAFI, including 3 refractory cases, were cured after Hematopoietic Stem Cell Transplantation (HSCT). Overall mortality for mold NAFI was 25% (20/81). Yeast infections occurred at a median age of 5 years [IQR 0–13], and 36% were receiving immunosuppressive treatments (5/14, mostly anti-TNF agents, n = 4). Infections were frequently located to lymph nodes or lungs, and 64% (21/33) were disseminated. Two yeast NAFI were cured after HSCT. Mortality was 26% (7/27). Conclusion NAFI in CGD patients are frequently severe, often occur despite prophylaxis and under additional immunosuppression, commonly require invasive procedures for diagnosis, and may be effectively managed with HSCT.

Background. Chronic granulomatous disease (CGD) is a genetic disorder of the phagocyte NADPH oxidase, which predisposes patients to infections and inflammatory complications, including severe colitis. Management of CGD colitis is a challenge because standard immunosuppressive therapy increases the risk of infection in already immunocompromised hosts. Methods. We report the use of infliximab in 5 patients with CGD. Results. Infliximab administration predisposed patients to severe infections with typical CGD pathogens but not mycobacteria, as reported with infliximab in other conditions. In addition to infections, infliximab administration led to successful closure of fistulae, sometimes with other untoward consequences. Infliximab-associated complications were associated with 2 deaths. Conclusions. Infliximab use in the treatment of CGD inflammatory bowel disease requires aggressive antimicrobial prophylaxis, assiduous surveillance for infection, and vigilance for untoward gastrointestinal complications. This experience suggests that infliximab therapy is effective but has untoward consequences in patients with CGD.

Invasive pulmonary aspergillosis (IPA) is a life-threatening complication of chronic granulomatous disease (CGD), a rare inherited disorder of phagocytes that is characterized by a defect in the production of reactive oxygen species (ROS) caused by mutations in NADPH oxidase 2. Here, we report a case of successful treatment of IPA complicated with CGD by the administration of interferon-γ (IFN-γ) in combination with voriconazole. The patient carried a splice site mutation in the CYBB gene, and the neutrophils could produce a certain amount of ROS. In this case, augmentation of ROS generation in the patient’s neutrophils was observed after in vivo IFN-γ treatment, which may be attributable to the induction of a normal CYBB gene in the myeloid progenitor cells. This treatment, in combination with voriconazole, may have contributed to the reversal of IPA in this patient. These results suggest that the in vivo use of IFN-γ may augment ROS generation in CGD neutrophils, thus leading to the successful treatment of severe IPA.