The long road to optimal management for chronic granulomatous disease.

for the p22 phox , p47 phox , p67 phox , and p40 phox subunits. The disease is characterized by increased susceptibility to recurrent and severe infections of bacterial and fungal origin and a high rate of inflammatory complications, including inflammatory bowel disease; granuloma formation in the liver, lungs, and skin; and inflammation leading to strictures that affect the gastrointestinal and urinary tracts. In the absence of treatment, the disease has a high mortality rate early in life. 2,3 There is substantial evidence that the severity of clinical manifestations of the disease reflects the degree of residual (if any) NADPH oxidase activity, 4 which can be readily measured by using the dihydrorhodamine test. The relative distribution of XL-CGD versus AR-CGD varies depending on the geographic context. In the United States approximately 65% of the patients have XL-CGD. Deficiency of p47 phox accounts for 20% of all cases, and p67 phox and p22 phox defects have been identified in 5% of patients each. 3 By contrast, AR-CGD has a higher prevalence in areas with a high consanguinity rate. 5 Previous studies had shown that AR-CGD is often characterized by delayed clinical onset and a higher survival rate than XL-CGD. 6 Thebestlineoftreatment forpatientswithCGDisstillamatter of contention. Medical management based on prompt and aggressive diagnostic work-up and treatment of active infections, rigorous use of antibacterial and antifungal prophylaxis (and possibly of IFN-g), and judicious use of steroids in patients with granuloma and other autoimmune manifestations is effective in reducing the risk and rate of severe complications 1,2 but does not provide a definitive cure, which can be provided by allogeneic hematopoietic cell transplantation (HCT). Initial results of HCT in patients with CGD were often controversial, but improved outcome with robust and stable myeloid chimerism has been reported more recently. 7 Moreover, use of reduced-intensity conditioning regimens has decreased the risk of transplantationrelated complications. However, limited information is available when comparing the long-term outcome of patients treated by medical management versus HCT. Consequently, which patients (and when in the course of disease) would benefitmost from HCT isstillamatterofdebate.Finally,genetherapywouldhaveseveral theoretic advantages over HCT, including prompt availability of the patient’s own hematopoietic stem cells, with no risk of graft-versus-host disease. However, lack of sustained gene marking in the myeloid compartment in early trials resulting in negligiblefunctionalcorrectionofthediseaseandseriousadverse events (myelodysplasia and acute myeloid leukemia) caused by insertional mutagenesis have been reported. 8 Two recent articles published in the Journal offer important contributions on controversial aspects of the disease. Koker et al 5 have reported on the clinical, genetic, and functional characterization of 89 Turkish patients with CGD. In this series XL-CGD accounted for a minority (38.2%) of the patients. Careful genetic and functional characterization of the defect allowed the authors to attempt correlation between the severity of the clinical phenotype on the one hand and the nature of the genetic defect or residual functional activity on the other. All 17 patients with p47 phox deficiency included in this study showed residualNADPHoxidaseactivity;bycontrast,all31patientswith XL-CGD and the vast majority of patients with AR forms other than p47 phox deficiency belonged to the oxidase-null group. This difference in residual functional activity had important consequences on the natural history of the disease. In particular, 82.4% of patients with XL-CGD presented with clinical symptoms at less than 1 year, whereas only 50% of the patients with AR-CGD had such an early onset. Mean age at the time of laboratory diagnosis was significantly higher in patients with the p47 phox defect (7.32 years) than in patients affected with XL-CGD (2.72 years) or the oxidase-null p22 phox (3.8 years) or p67 phox (3.3 years) defects. Moreover, severe infections (Aspergillus species‐induced pneumonia, suppurative lymphadenitis, and deep-seated abscesses), chronic lung disease, and failure to thrive were significantly more common in patients with oxidase-null than in those with oxidase-residual activity. By contrast, no differences were observed in the frequencies of autoimmune/inflammatory complications, anemia, and occurrence of BCG-itis. Severe infections (especially of fungal origin) were the leading cause of death. Eight of the 9 deceased patients From a theDivisionof Immunologyandthe Manton Centerfor Orphan Disease Research,