Chronic Granulomatous Disease: a Comprehensive Review

Abstract

Chronic granulomatous disease (CGD) is a primary immunodeficiency of phagocyte function due to defective NADPH oxidase (phox). Compared with the common types of CYBB/gp91^phox, NCF1/p47^phox, and CYBA/p22^phox deficiency, NCF4/p40^phox deficiency is a mild and atypical form of CGD without invasive bacterial or fungal infections. It can be diagnosed using serum-opsonized E.coli as a stimulus in dihydrorhodamine (DHR) assay. Patients with CYBC1/Eros deficiency, a new and rare form of CGD, present as loss of respiratory burst and gp91^phox expression in phagocytes. Neutrophils from patients with CGD are deficient in neutrophil extracellular traps (NETosis), autophagy, and apoptosis. The hyper-activation of NF-ĸB and inflammasome in CGD phagocytes also lead to long-lasting production of pro-inflammatory cytokines and inflammatory manifestations, such as granuloma formation and inflammatory bowel disease-like colitis. Patients with CGD and X-linked female carriers also have a higher incidence of autoimmune diseases. The implementation of antimicrobial, anti-fungal, and interferon-γ prophylaxis has greatly improved overall survival. Residual NADPH oxidase activity is significantly associated with disease severity and the chance of survival of the patient. New therapeutic approaches using immunomodulators for CGD-related inflammatory manifestations are under investigation, including pioglitazone, tamoxifen, and rapamycin. Hematopoietic stem cell transplantation (HSCT) is the curative treatment. Outcomes of HSCT have improved substantially over the last decade with overall survival more than 84-90%, but there are debates about designing optimal conditioning protocols using myeloablative or reduced-intensity regimens. The gene therapy for X-linked CGD using hematopoietic stem and progenitor cells transduced ex vivo by lentiviral vector encoding the human gp91phox gene demonstrated persistence of adequate oxidase-positive neutrophils in a small number of patients. Gene therapy using genome-editing technology such as CRISPR/Cas9 nucleases is a promising approach for patients with CGD in the future.

Keywords: Chronic granulomatous disease; Gene therapy; Interferon-γ; Prophylaxis; Transplantation.