Because severe G6PD deficiency can be a phenocopy of chronic granulomatous disease with regard to the cellular and clinical phenotype, careful evaluation of neutrophil function seems mandatory in these patients to decide on appropriate anti-infective preventive measures. Determining the level of G6PD enzyme activity should be followed by analysis of reactive oxygen species production and NET formation to decide on required antibiotic and antimycotic prophylaxis.

Background: Chronic granulomatous disease (CGD) is caused by a malfunctioning nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytes, leading to impaired bacterial and fungal killing and hyperinflammation.Objective: To characterize macrophage subsets and cytokine/chemokine signaling loops involved in CGD tissue hyperinflammation.Methods: Cytokine/chemokine production and surface marker expression were analyzed in inflamed tissue of four CGD patients and compared to cytokine/chemokine released by CGD macrophages upon priming to different macrophage subpopulations. Furthermore, the re-priming capacity of CGD pro-inflammatory M1 to M2a anti-inflammatory macrophages was evaluated.Results: In human CGD inflammatory tissue, IL-18 and IFN-γ were detected in significant quantity. Immunofluorescence analysis identified macrophages as one source of IL-18 in inflamed tissue. In vitro, CGD macrophages could be primed and re-primed into all inflammatory/anti-inflammatory macrophage subpopulations. IL-18 was also released by M1 CGD and control macrophages.Conclusion: CGD pro-inflammatory M1 macrophages remain M1 primed in vivo. As CGD M1 macrophages can be re-primed to anti-inflammatory M2a phenotype in vitro, macrophages are kept in M1 state in vivo by a persistent pro-inflammatory environment. Our results suggest a paracrine signaling loop between M1 macrophage derived IL-18 and non-macrophage derived IFN-γ maintaining macrophage pro-inflammatory activity in CGD tissue.