title: Residual NADPH oxidase and survival in chronic granulomatous disease.
abstract: BACKGROUND
  Failure to generate phagocyte-derived superoxide and related reactive oxygen intermediates (ROIs) is the major defect in chronic granulomatous disease, causing recurrent infections and granulomatous complications. Chronic granulomatous disease is caused by missense, nonsense, frameshift, splice, or deletion mutations in the genes for p22(phox), p40(phox), p47(phox), p67(phox) (autosomal chronic granulomatous disease), or gp91(phox) (X-linked chronic granulomatous disease), which result in variable production of neutrophil-derived ROIs. We hypothesized that residual ROI production might be linked to survival in patients with chronic granulomatous disease.
  
  
  METHODS
  We assessed the risks of illness and death among 287 patients with chronic granulomatous disease from 244 kindreds. Residual ROI production was measured with the use of superoxide-dependent ferricytochrome c reduction and flow cytometry with dihydrorhodamine oxidation assays. Expression of NADPH oxidase component protein was detected by means of immunoblotting, and the affected genes were sequenced to identify causal mutations.
  
  
  RESULTS
  Survival of patients with chronic granulomatous disease was strongly associated with residual ROI production as a continuous variable, independently of the specific gene affected. Patients with mutations in p47(phox) and most missense mutations in gp91(phox) (with the exception of missense mutations in the nucleotide-binding and heme-binding domains) had more residual ROI production than patients with nonsense, frameshift, splice, or deletion mutations in gp91(phox). After adolescence, mortality curves diverged according to the extent of residual ROI production.
  
  
  CONCLUSIONS
  Patients with chronic granulomatous disease and modest residual production of ROI have significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. The production of residual ROI is predicted by the specific NADPH oxidase mutation, regardless of the specific gene affected, and it is a predictor of survival in patients with chronic granulomatous disease. (Funded by the National Institutes of Health.).
authors.affiliation: Clinical Services Program, SAIC-Frederick, Frederick, Maryland, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Feld
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Pike
authors.forename: Beatriz E
authors.initials: BE
authors.lastname: Marciano
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.forename: Suk See
authors.initials: SS
authors.lastname: DeRavin
authors.forename: Debra A Long
authors.initials: DA
authors.lastname: Priel
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Soule
authors.forename: Kol A
authors.initials: KA
authors.lastname: Zarember
authors.forename: Harry L
authors.initials: HL
authors.lastname: Malech
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: John I
authors.initials: JI
authors.lastname: Gallin
mesh_terms: D000704:Analysis of Variance; D005260:Female; D005838:Genotype; D006105:Granulomatous Disease, Chronic / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D009154:Mutation; D019255:NADPH Oxidases / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D010641:Phenotype; D016016:Proportional Hazards Models; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D016019:Survival Analysis
chemical_list: D017382:Reactive Oxygen Species; D019255:NADPH Oxidases