Chronic granulomatous disease: Clinical, molecular, and therapeutic aspects

Abstract

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defects in the genes encoding any of the NADPH oxidase components responsible for the respiratory burst of phagocytic leukocytes. CGD is a genetically heterogeneous disease with an X-linked recessive (XR-CGD) form caused by mutations in the CYBB gene encoding the gp91(phox) protein, and an autosomal recessive (AR-CGD) form caused by mutations in the CYBA, NCF1, NCF2, or NCF4 genes encoding p22(phox) , p47(phox) , p67(phox) , and p40(phox) , respectively. Patients suffering from this disease are susceptible to severe life-threatening bacterial and fungal infections and excessive inflammation characterized by granuloma formation in any organ, for instance, the gastrointestinal and genitourinary tract. An early diagnosis of and the prompt treatment for these conditions are crucial for an optimal outcome of affected patients. To prevent infections, CGD patients should receive lifelong antibiotics and antifungal prophylaxis. These two measures, as well as newer more effective antimicrobials, have significantly modified the natural history of CGD, resulting in a remarkable change in overall survival, which is now around 90%, reaching well into adulthood. At present, hematopoietic stem cell transplantation (HSCT) is the only definitive treatment that can cure CGD and reverse organ dysfunction. Timing, donor selection, and conditioning regimens remain the key points of this therapy. In recent years, gene therapy (GT) for XR-CGD has been proposed as an alternative to HSCT for CGD patients without a matched donor. After the failure of the first trials performed with retroviral vectors, some groups have proposed the use of regulated SIN-lentiviral vectors targeting gp91(phox) expression in myeloid cells to increase the safety and efficacy of the GT protocols.

A Comparison of Human Neutrophils Acquired from Four Experimental Models of Inflammation

“…Defects in neutrophil function have been implicated in a wide range of diseases, from congenital syndromes such as Chronic Granulomatous Disease [1] through to acquired defects in an array of conditions including Chronic Obstructive Pulmonary Disease [2], Crohn’s disease [3], Sepsis [4], Acute Alcoholic Hepatitis [5], and Cirrhotic Liver Disease [6]. …”

An Uncommon Feature of Chronic Granulomatous Disease in a Neonate

“…Staphylococcus aureus , gram negative Enterobacteriaceae , and Aspergillus species are the most common pathogens [5, 6]. In our patient, Gram positive cocci were seen in direct smear, and culture was positive for Staphylococcus aureus .…”

“…Chronic Granulomatous Disease (CGD) is an inherited rare disorder of the immune system and represents with recurrent infections and granuloma formation at different sites [5, 6]. Pneumonia, liver abscess, lymphadenitis, osteomyelitis, and skin (cellulitis or abscesses) are the most important clinical manifestations [4–7].…”

Current status of ex vivo gene therapy for hematological disorders: a review of clinical trials in Japan around the world

“…A total of 10 patients were involved. In both trials, only transient production of ROS-producing neutrophils was detected, and no remarkable long-term clinical benefits accrued [34,[39][40][41].…”