Common severe infections in chronic granulomatous disease

Abstract

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.

Keywords: CGD; bacterial infection; fungal infection; superoxide production; survival.

Figure 1.

Overall proportion of severe infections. The percentage of patients is shown for each genotype.

Figure 2.

Frequency (%) of organisms isolated according to site of infection.

Figure 3.

CGD Deaths over the period 1970–2012. A, Ages at death for the entire cohort over time. B, Ages at death separated by p47^phox (open squares) and gp91^phox (closed circles). C, Ages at death separated by higher (open squares) and lower (closed circles) superoxide production. The Y axis is age at death, the X axis is years. The dotted line in figures B and C is average age at death (23 years) over the entire cohort over the entire period. The solid lines represent the fitted correlations. Abbreviations: CGD, chronic granulomatous disease; SO, superoxide.