Patients with CGD are disposed to frequent infections because the immune system is unable to kill invading bacteria and fungi. For this reason, everyone diagnosed with CGD is recommended to take daily antibiotics (Song et al. 2011). The CGD Society calls “daily antibacterial and antifungal prophylaxis…the single most important factor in keeping CGD patients well” (www.cgdsociety.org). Prophylactic antibacterial co-trimoxazole is generally well-tolerated in CGD patients and has been shown in cohort studies to significantly improve quality of life and long-term survival (Martire et al. 2008). Co-trimoxazole is a combination of two antibiotics, sulfamethoxazole and trimethoprim, which inhibit bacterial folate synthesis. It is preferable for use in CGD patients because of the drugs’ lipophilicity, which causes the drug to concentrate inside cells (Margolis et al. 1990). This property of co-trimoxazole also protects the gut microbiome against its broad-spectrum antibiotic activity. Prophylactic antifungal medications are also indicated for daily use in CGD patients. The most popular of these is itraconazole, which has minimal side effects and is effective in reducing fungal infections and improving long-term survival (Falcone and Holland 2012). Itraconazole inhibits synthesis of ergosterol, a component of fungal cell membranes. It is preferable to other antifungal medications because of its broad spectrum of action and its effectiveness against Aspergillus species, which are the leading cause of fungal infection and death in CGD patients (Falcone and Holland 2012).
Small Molecule Therapy
Because of the complexity of CGD and the heterogeneity of its molecular causes, there is no drug that can currently restore NADPH oxidase function. However, pioglitazone has been shown to confer the ability to generate reactive oxygen species back to phagocytes by agonizing the peroxisome proliferator-activated receptor γ (PPARγ) (R. F. Fernandez-Boyanapalli et al. 2015). By increasing the intracellular generation of reactive oxygen species, pioglitazone can help bridge the gap between normal and CGD-impaired superoxide generation and antimicrobial ability. Pioglitazone also reduced symptoms of acute inflammation in mouse models of CGD by acting at PPARγ, forming a ligand-receptor complex that regulates the innate immune response by inhibiting the transcription factor NF-κB (R. Fernandez-Boyanapalli et al. 2010). Recall that NADPH oxidase also regulates NF-κB by inhibiting it, and that loss of function of NADPH oxidase is believed to give rise to uncontrolled inflammation. Pioglitazone is a promising future drug to reducing CGD-associated inflammation.
CGD can be cured by hematopoietic stem cell transplant (HSCT) (Chiriaco et al. 2015). In this procedure, haploidentical multipotent hematopoietic stem cells are derived from bone marrow or umbilical cord blood of a donor. The patient’s bone marrow must be killed off by radiation or chemotherapy, before the donor stem cells are surgically implanted. In the context of CGD, HSCT allows for the introduction of new stem cells into the bone marrow, with intact genomes encoding functional NADPH oxidase. These give rise to phagocytes with restored antimicrobial ability and superoxide generativity. HSCT has now effectively been completed even in patients with active and life-threatening infection, and remains the only long-term cure for CGD (Parta et al. 2015). However, the application of this treatment is complicated as the donor and patient must be HLA-compatible to minimize the risk of rejection. Although immunosuppressant drugs are used in other diseases to alleviate this risk, they are especially risky in patients with CGD whose immune systems are already impaired (Parta et al. 2015). Inflammation associated with NADPH oxidase deficiency can affect the longevity of HSC treatments, and so they are not a cure-all for CGD (Weisser et al. 2016). Despite these issues, HSCT stands out as a uniquely curative treatment option for CGD.