Survival among patients with chronic granulomatous disease has improved since its first description in the 1950s. This change is attributed to better recognition of the disease and an understanding of its pathophysiology, development of more effective antimicrobial agents,24,25
and bone marrow transplantation.27
Survival in our cohort of 287 patients from 244 families studied over the past 20 years at a single center shows that childhood death from chronic granulomatous disease is now uncommon, as previously described.2,22,28
Previously reported differences in morbidity and mortality between X-linked and autosomal chronic granulomatous disease2,22,29
were seen in our cohort but did not account for the substantial variation in survival rates among our patients. Our data indicate that residual ROI production is more predictive of survival than the specific NADPH-oxidase gene mutation. Even modest residual ROI production (1% of normal production) confers a significant survival benefit. This finding has important implications for the treatment of chronic granulomatous disease.
The longer survival of patients with chronic granulomatous disease has revealed the cumulative effects of frequent serious infections and of a spectrum of noninfectious inflammatory and autoimmune disorders.2,30,31
One important consequence of severe infections — of the lungs and liver, in particular — is a predisposition to subsequent infections.32,33
Furthermore, the exaggerated inflammatory responses of chronic granulomatous disease (e.g., dysregulated cytokine production34,35
and decreased apoptosis36
) probably contribute to increased scar formation, wound dehiscence, stricture development, and other problems that complicate recovery.
Our data indicate that neutrophil production of residual ROI predicts the risk of death among patients with chronic granulomatous disease and that genetic analysis can, in many cases, predict ROI production. Missense and frameshift mutations in gp91phox
were randomly distributed throughout the gene and were generally family-specific, whereas nonsense and spontaneous mutations were concentrated at discrete CpG dinucleotide hotspots, confirming similar findings in other diseases. Little residual ROI production was observed in patients with nonsense, frameshift, splice, or deletion mutations in gp91phox
. Patients with p47phox
deficiency had increased production of neutrophil ROI and increased survival, as compared with patients with nonfunctional gp91phox
mutations. Unexpectedly, patients with missense mutations affecting gp91phox
amino acids 1 to 309 (with the exception of heme-binding His222) had even higher residual ROI production than was observed in patients with p47phox
deficiency. ROI production was not correlated with protein expression. Mutations in the FAD-binding and NADPH-binding domains of gp91phox
may allow normal protein expression but little residual ROI production, indicating the critical role of these domains.19-21
Whereas protein detection provides important clues to the diagnosis of chronic granulomatous disease, quantitative ROI measurement, which correlates closely with gene sequence, is more useful in determining a patient's long-term risk. However, occasional variability in ROI production and clinical outcome in patients with the same mutation — as reported here (in Patients gp91-24a, gp91-25a, and gp91-26a or Patients gp91-98a, gp-99a, and gp-99b) and elsewhere37
— cannot be explained solely by the mutation, suggesting that epigenetic factors or other modifying genes may play an important role.38
Neutrophil ROI production is a measure that can be obtained at diagnosis, correlates with genotype, and is a strong predictor of overall survival in patients with chronic granulomatous disease. Early risk assessment based on ROI production provides additional guidance for the triage of patients for more aggressive therapies such as bone marrow transplantation, which has been shown in other hematologic disorders to be more effective when performed early in life.39,40
Our results do not suggest that the use of established standard-of-care prophylaxis and periodic clinical assessment can be ignored in the case of patients in whom neutrophils produce more residual ROI. However, our finding that even small amounts of neutrophil production of ROI confer a significant survival benefit suggests that therapies promoting even small increases in ROI production may improve survival.