Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft-versus-host disease. Graft failure or receipt of a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.

Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium.

Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Pyroptosis was the primary bacterial clearance mechanism in the spleen, but both pyroptosis and interleukin-18 (IL-18)-driven natural killer (NK) cell responses were required for liver defense. NK cells cleared hepatocyte replication niches via perforin-dependent cytotoxicity, whereas interferon-γ was not required. These insights suggested a therapeutic approach: exogenous IL-18 restored perforin-dependent cytotoxicity during infection by the inflammasome-evasive bacterium Listeria monocytogenes. Therefore, inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens.

Correction: Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

The original version of this article unfortunately contained the missing author, Caridad Martinez. The authors would like to correct the list. We apologize for any inconvenience that this may have caused. The correct author list is shown above.

Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking. METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016. RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT. CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability.

BACKGROUND: Chronic granulomatous disease (CGD) is characterized by recurrent life-threatening bacterial and fungal infections and aberrant inflammation. Mutations in CYBB cause X-linked CGD and account for 65% to 70% of cases in Western countries. OBJECTIVE: We sought to understand the clinical manifestations associated with the X-linked CGD carrier state. METHODS: We undertook a comprehensive retrospective study of 162 affected female subjects. We examined dihydrorhodamine 123 (DHR) oxidation data for percentage of X-chromosome inactivation. We correlated lyonization (%DHR+) with clinical features. Where possible, we followed %DHR+ values over time. RESULTS: Clinical data were available for 93 female subjects: %DHR+ values were 46% (mean) and 47% (median; SD, 24). Using the %DHR+ value as the criterion for X inactivation, 78% of patients had levels of inactivation of 20% to 80%, suggesting random inactivation that was independent of age. In contrast, carriers with CGD-type infections had median %DHR+ values of 8% (n = 14; range, 0.06% to 48%), and those with only autoimmune or inflammatory manifestations had median %DHR+ values of 39% (n = 31; range, 7.4% to 74%). Those with both infections and autoimmunity had low %DHR+ values (n = 6; range, 3% to 14%). A %DHR+ value of less than 10% was strongly associated with infections (odds ratio, 99). Strong association persisted when %DHR+ values were less than 20% (odds ratio, 12). Autoimmunity was not associated with %DHR+ values. In 2 sets of identical twins, the %DHR+ populations tracked closely over time. Although the %DHR+ populations were very similar between sisters, those between mothers and daughters were unrelated. CONCLUSIONS: A low %DHR+ value strongly predicts infection risk in X-linked CGD carriers, and the carrier state itself is associated with autoimmunity.

Methylotroph Infections and Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by a defect in production of phagocyte-derived reactive oxygen species, which leads to recurrent infections with a characteristic group of pathogens not previously known to include methylotrophs. Methylotrophs are versatile environmental bacteria that can use single-carbon organic compounds as their sole source of energy; they rarely cause disease in immunocompetent persons. We have identified 12 infections with methylotrophs (5 reported here, 7 previously reported) in patients with CGD. Methylotrophs identified were Granulibacter bethesdensis (9 cases), Acidomonas methanolica (2 cases), and Methylobacterium lusitanum (1 case). Two patients in Europe died; the other 10, from North and Central America, recovered after prolonged courses of antimicrobial drug therapy and, for some, surgery. Methylotrophs are emerging as disease-causing organisms in patients with CGD. For all patients, sequencing of the 16S rRNA gene was required for correct diagnosis. Geographic origin of the methylotroph strain may affect clinical management and prognosis.

GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome.

Previous reports of GATA2 mutations have focused on the coding region of the gene or full gene deletions. We recently identified 2 patients with novel insertion/deletion mutations predicted to result in mRNA nonsense-mediated decay, suggesting haploinsufficiency as the mechanism of GATA2 deficient disease. We therefore screened patients without identified exonic lesions for mutations within conserved noncoding and intronic regions. We discovered 1 patient with an intronic deletion mutation, 4 patients with point mutations within a conserved intronic element, and 3 patients with reduced or absent transcription from 1 allele. All mutations affected GATA2 transcription. Full-length cDNA analysis provided evidence for decreased expression of the mutant alleles. The intronic deletion and point mutations considerably reduced the enhancer activity of the intron 5 enhancer. Analysis of 512 immune system genes revealed similar expression profiles in all clinically affected patients and reduced GATA2 transcript levels. These mutations strongly support the haploinsufficient nature of GATA2 deficiency and identify transcriptional mechanisms and targets that lead to MonoMAC syndrome.

Cerebrospinal fluid HIV-1 compartmentalization in a patient with AIDS and acute varicella-zoster virus meningomyeloradiculitis.

We report a case of AIDS presenting as varicella-zoster virus (VZV) meningomyeloradiculitis associated with human immunodeficiency virus (HIV) quasispecies compartmentalization within the cerebrospinal fluid (CSF), and a CSF viral load that was 1 log higher than in peripheral blood. Prolonged antiviral therapy for both VZV and HIV type 1 was associated with partial resolution.

Rothia aeria neck abscess in a patient with chronic granulomatous disease: case report and brief review of the literature.

Rothia aeria caused a necrotic lymphadenitis and neck abscess in a patient with CGD. This infection was aggressive, crossed tissue planes, required two surgeries, as well as prolonged antibiotics for complete resolution. Rothia aeria is a rare pathogen that can be added to the spectrum of agents causing disease in CGD, a finding that further reinforces the importance of microbiologic identification of infections in this patient population.

Streptococcal infections in patients with chronic granulomatous disease: case report and review of the literature.

Streptococcus intermedius caused a liver abscess in a patient with chronic granulomatous disease (CGD). In contrast to typical staphylococcal abscesses in CGD, this abscess was liquid, easily drained, and resolved without surgery or steroids. This case and literature review provide insight into this organism's pathogenesis, including in CGD.

Invasive fungal infection in chronic granulomatous disease: insights into pathogenesis and management.

PURPOSE OF REVIEW: Invasive fungal infections (IFIs) remain a major cause of death in patients with chronic granulomatous disease (CGD). We discuss the new insights into the pathogenesis, diagnosis, prevention, and management of invasive fungal infections in patients with CGD. RECENT FINDINGS: CGD has the highest prevalence of IFIs among the immunodeficiencies. Infections typically involve the lung, and the most commonly isolated pathogen is Aspergillus spp. However, IFIs due to rare opportunistic filamentous fungi are increasingly reported. Most IFIs are diagnosed on routine chest imaging, and serum markers such as galactomannan and 1,3-ß-D-glucan are of limited value in CGD. Routine use of itraconazole for prophylaxis continues to be recommended, although posaconazole may be an alternative. Management of IFIs is typically centered on prolonged courses of antifungal therapy. Surgery may be required for complete resolution, especially in the setting of osteomyelitis or infections due to Aspergillus nidulans or other poorly responsive molds. Hematopoietic stem cell transplantation (HSCT) cures CGD and may be appropriate in select patients with refractory IFIs. SUMMARY: Management of IFIs in CGD has significantly improved over the last decade. Earlier diagnosis of IFIs, accurate identification of pathogens, and development of reliable susceptibility testing are areas for future emphasis. HSCT is a promising therapy, even during refractory infections in CGD.

Gastrointestinal Complications in Chronic Granulomatous Disease.

Almost half of patients with chronic granulomatous disease (CGD) suffer from gastrointestinal (GI) inflammation, the pathogenesis of which is complex and multifactorial. As a result, the management of CGD-associated GI inflammation remains challenging due to its chronicity and difficulty in managing the simultaneous need for immunomodulation with increased susceptibility to infection. In order to contextualize prospective treatment interventions for CGD-associated GI inflammation, we have reviewed the clinical presentation, pathogenesis and current management of this disease. Increased understanding of the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex 2 (NOX2)-derived reactive oxygen species (ROS) in inflammatory bowel disease (IBD) will likely reveal novel targets for therapeutic intervention.

Colitis susceptibility in p47(phox-/-) mice is mediated by the microbiome.

BACKGROUND: Chronic granulomatous disease (CGD) is caused by defects in nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) complex subunits (gp91(phox) (a.k.a. Nox2), p47(phox), p67(phox), p22(phox), p40(phox)) leading to reduced phagocyte-derived reactive oxygen species production. Almost half of patients with CGD develop inflammatory bowel disease, and the involvement of the intestinal microbiome in relation to this predisposing immunodeficiency has not been explored. RESULTS: Although CGD mice do not spontaneously develop colitis, we demonstrate that p47(phox-/-) mice have increased susceptibility to dextran sodium sulfate colitis in association with a distinct colonic transcript and microbiome signature. Neither restoring NOX2 reactive oxygen species production nor normalizing the microbiome using cohoused adult p47(phox-/-) with B6Tac (wild type) mice reversed this phenotype. However, breeding p47(phox+/-) mice and standardizing the microflora between littermate p47(phox-/-) and B6Tac mice from birth significantly reduced dextran sodium sulfate colitis susceptibility in p47(phox-/-) mice. We found similarly decreased colitis susceptibility in littermate p47(phox-/-) and B6Tac mice treated with Citrobacter rodentium. CONCLUSIONS: Our findings suggest that the microbiome signature established at birth may play a bigger role than phagocyte-derived reactive oxygen species in mediating colitis susceptibility in CGD mice. These data further support bacteria-related disease in CGD colitis.

Framingham risk score and early markers of atherosclerosis in a cohort of adults infected with HIV.

BACKGROUND: The utility of the Framingham risk score among individuals infected with HIV is poorly understood. We examined the association of Framingham risk scores with surrogate markers of atherosclerosis in a carefully characterized cohort of adults infected with HIV. METHODS: We calculated Framingham risk scores and measured carotid intima-media thickness (c-IMT) and coronary artery calcium (CAC) scores in 334 participants from the Nutrition for Healthy Living study. Cardiovascular risk factors, c-IMT and CAC scores were assessed for each Framingham risk subgroup (low versus intermediate/high risk). We used adjusted and unadjusted linear and logistic regression to examine the association between clinical factors and Framingham risk group with c-IMT and CAC scores. RESULTS: Patients with intermediate/high Framingham risk scores were more likely to have internal c-IMT ≥ 1.0 mm (26% versus 12%; P=0.003) and common c-IMT ≥ 0.8 mm (22% versus 5%; P < 0.001). These patients were also more likely to have detectable CAC (78% versus 48%; P < 0.001). Intermediate/high Framingham risk scores were significantly associated with internal c-IMT ≥ 1.0 mm (odds ratio 2.65 [95% confidence interval 1.37-5.13]) and common c-IMT ≥ 0.8 mm (odds ratio 5.24 [95% confidence interval 2.39-11.50]). Intermediate/high Framingham risk scores were also significantly associated with detectable CAC (odds ratio 3.84 [95% confidence interval 2.05-7.16]). The addition of HIV-related variables did not improve the accuracy of the Framingham risk score. CONCLUSIONS: Our study shows that increased Framingham risk scores are associated with abnormal early and late surrogate markers of atherosclerosis in adults infected with HIV, and might predict the risk of cardiovascular complications in this population.

Micronutrient concentrations and subclinical atherosclerosis in adults with HIV.

BACKGROUND: Extremes in micronutrient intakes are common in HIV-infected patients in developed countries and may affect the progression of atherosclerosis in this population. OBJECTIVE: We completed a cross-sectional study examining the association between serum micronutrient concentrations and surrogate markers of atherosclerosis in a cohort of HIV-infected adults. DESIGN: We measured serum selenium, zinc, vitamin A, and vitamin E concentrations as well as carotid intima-media thickness (c-IMT) and coronary artery calcium (CAC) in 298 Nutrition for Healthy Living participants. We assessed cardiovascular disease risk factors, c-IMT, and CAC for each micronutrient tertile by using a chi-square test for binary variables and analysis of variance for continuous variables. We performed multivariate regression of c-IMT and CAC with each micronutrient with adjustment for HIV-related and cardiovascular disease risk factors. RESULTS: In the multivariate analysis, the highest tertile of serum vitamin E concentration was associated with higher common and internal c-IMT and CAC scores (P < 0.05 for c-IMT and CAC). Participants with higher vitamin E concentrations were more likely to have detectable CAC (50% compared with 44% compared with 67% for tertiles 1, 2, and 3, respectively; P = 0.004) and common c-IMT >0.8 mm (5% compared with 4% compared with 17% for tertiles 1, 2, and 3, respectively; P = 0.002). Other than vitamin E, micronutrients had no association with markers of atherosclerosis. CONCLUSIONS: Our study showed that elevated serum vitamin E concentrations are associated with abnormal markers of atherosclerosis and may increase the risk of cardiovascular complications in HIV-infected adults.