Treatments and Disease Management

Preventing Infection

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

Structure of pioglitazone. Obtained from Google images.
Structure of pioglitazone. Obtained from Google images.

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.

A flowchart summarizing the pathways of PPARy activation. Note the ligand-PPARy complex acts to inhibit the same transcription factor as does NADPH oxidase. (Fernandez-Boyanapalli et al. 2015)
A flowchart summarizing the pathways of PPARy activation. Note the ligand-PPARy complex acts to inhibit the same transcription factor as does NADPH oxidase. (Fernandez-Boyanapalli et al. 2015)

Curing CGD

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.

8 Replies to “Treatments and Disease Management”

  1. Nice job on this project. Two questions – Could you expand on the process of agonizing the phagocytes with pioglitazone, and is the HSCT treatment a permanent solution or are recurring rounds of cell transplants required?

    1. Sure Brian, thanks for your questions! First, pioglitazone agonizes the PPARγ receptor, nuclear membrane receptors which when activated can function as transcription factors. By activating PPARγ, pioglitazone effectively inhibited the transcriptional activity of NF-κB and prevented the synthesis of pro-inflammatory peptides. During phagocyte activation, PPARγ also acts as a signalling intermediate between NADPH oxidase activation and mitochondria during phagocyte activation, and enhances ROS production by the mitochondria. In this case, agonizing PPARγ with pioglitazone increased generation of ROS in mitochondria. I believe there is just one lab exploring the use of pioglitazone, and these authors commented in 2015 that the exact molecular events that occur between pioglitazone binding and increased mtROS generation are the subject of future investigation. See doi: 10.1016/j.jaci.2014.10.034 for this research if you have time!

      With regard to your second question, HSCT is theoretically a permanent treatment but depends on the degree of donor chimerism. Essentially this “chimerism” is the extent to which donor and patient bone marrow tissue have mixed, which indicates the success of the transplant. Recurring rounds of transplant may be necessary in patients with CGD due to the deteriorative impact of chronic inflammation on the transplanted marrow. However, HSCT is often met with a high long-term degree of donor chimerism and is often curative after one myeloablative transplantation. See doi: 10.1016/j.bbmt.2012.02.002 for a number of CGD cases successfully treated with HSCT.

  2. Hi Elliott, really great job explaining the intricacies of this disease. I personally have a really tough time with immunity so I commend you for being able to pick this disease apart and explain it so well. My question is regarding the treatment of CGD by preventing infection. Specifically, when you talk about co-trimoxazole, you mention that it functions by inhibiting bacterial folate synthesis. Based on the research of your project and our discussions of folate in class, can you explain how this is effective in combatting CGD?

    1. Thanks Stephanie! Co-trimoxazole is actually a pair of antibiotics administered together, which inhibit bacterial folate synthesis to kill the bacteria. This treatment is not effective against CGD itself but does protect the patient from recurring bacterial infections, which in CGD can be extremely life threatening. One clarification I could offer you is that CGD is not an inherently fatal condition. Rather its weakening effects on the immune system allow for recurrent and deadly bacterial and fungal infections, which can be fatal, and so preventative antibiotic medications are a treatment option.

  3. Hi Elliott, Good job with a cool disease! I found it really interesting that antibiotic prophylaxis is the recommended treatment for the disease, especially since the medical field is generally trying to minimize the use of antibiotics whenever possible to stop drug resistant bacterial strains. Do patients need to take antibiotics for their entire life? Generally the likelihood of developing a drug resistance infection increases with increased duration of antibiotics, so have there been any reports of drug-resistant infections in patients with GCD? If there aren’t any currently reported problems, do you think that could pose a problem for patients in the future, especially with the increasing ubiquity of Multi-Drug Resistant organisms in hospitals and doctor’s offices? It seems like that might be a problem after HSCT as well, so perhaps that is just a risk patients will have to be aware of?

    1. Hi Michael, thanks for your perspective on antibiotic resistance. Patients with CGD are recommended to constantly take antibiotics and antifungals to prevent a potentially life-threatening infection. I have come across cases of Co-trimoxazole resistant infections in CGD and they are especially severe, such as this case of co-trimoxazole resistant osteomyelitis: https://www.ncbi.nlm.nih.gov/pubmed/21246245. Fungi may also develop antifungal resistance, such as this case of multiple-azole-resistant Aspergillus osteomyelitis, which was successfully treated following surgical intervention https://www.ncbi.nlm.nih.gov/pubmed/21246245. Drug resistance is a real risk patients must be aware of, because it is increasingly prevalent today, whereas in the past it has been quite uncommon. It’s important that we continue to explore new prevention strategies and therapeutic interventions to combat the evolution of these pathogens.

  4. Great project Elliott, very interesting and detailed. Under the symptoms of the disease, you mention that the body has no way of getting rid of granulomata and so they build up in hollow organs. Did you come across any research that stated whether these treatment options effectively halt or slow granulomata formation. I would assume that using antibiotics and antifungals, or using pioglitazone, would decrease the body’s need to form granulomata in response to pathogens and microbes. Are the symptoms associated with granulomata build up permanent, even with these treatments; until a drug option to break down ganulomata is viable, as suggested in conclusions and future works?

    1. Hi Zach, thanks for your question. To my knowledge the granulomata may resolve themselves once the infection is cured and the pathogens have been killed off. However, depending on the type and severity of infection, granuloma formation may cause scar or necrotic tissue to accumulate, which can be relatively permanent. By killing the pathogens, granulomatous lesions typically do resolve. In patients receiving HSCT, the successful transplant allowed for a subsequent reduction in granulomatous lesions that had formed before the treatment. I used this resource to answer your question: https://www.ncbi.nlm.nih.gov/pubmed/11259721.

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