6.1. Haematopoietic stem cell transplantation (HSCT/HCT)
HCT is the principal treatment available for managing CGD with favourable results regardless of symptoms, age, sex, or mutations [
73,
74,
75]. Transplantation therapy has an overall survival rate of more than 90 % in children less than 14 years and has improved in the last decade, particularly with early diagnosis [
74]. Additionally, HCT is associated with event-free survival rates of more than 80 % in patients with CGD and improves the quality of life [
76].
There are debates about designing optimal conditioning protocols using myeloablative or reduced-intensity regimens [
77].
However, the group of HCT-treated patients demonstrated excellent survival rates, although the risks and benefits still need to be assessed in individual patients. Based on the significant progress of patients with CGD treated with HCT, it is regarded as the only known curative treatment with an improved life expectancy owing to its improved implementation over time [
78,
79,
80,
81].
When Human Leucocyte Antigen (HLA)-matched donor is identified, the source of HCT could be cord blood, bone marrow, or peripheral blood [
75]. Hematopoietic stem cells are drawn and infused into the patient. These are immature cells, and after they develop into platelets, red- and white blood cells. A range from 70-95% is proven as survival rate for this type of immunotherapy. There are several factors that affect the outcome of HCT including the age and clinical status of the child, as earlier HCT is performed would improve its clinical outcome. The patient must be subjected to various chemotherapy treatments. It is done to equip the patient’s immune system to receive new stem cells. In addition, locating HLA-compatible donors is time consuming and the child with CGD must be adequately treated to prevent worsening infections [
82,
83].
6.2. Drug-based treatment
Antimicrobial and antifungal prophylaxis are the most common management routes used to minimise the incidence of infections. However, treating with antibiotics is contraindicated in healthy patients because of antibiotic resistance. Most studies suggest a link between aggressive antibiotic use and preventing the spread of infection in patients with CGD [
23,
24].
Drugs such as trimethoprim-sulfamethoxazole reduce the occurrence of bacterial infections in patients with CGD but do not interfere considerably with the gut microbiome [
28]. Patients with sulfamethoxazole allergy have other options, such as cloxacillin and ciprofloxacin [
74]. A concern arises in pregnancy since trimethoprim is a folic acid antagonist, which increases the high risk for congenital disabilities and is discontinued during pregnancy [
73]. Itraconazole considerably reduces invasive fungal infections, and newer azole drugs, such as voriconazole, posaconazole, and isavuconazole, are available, providing more options for treating these fungal infections [
73].
Itraconazole should be provided as a long-term and possible lifelong treatment option to prevent fungal infections in children with CGD. However, regular monitoring of liver function is required during itraconazole therapy [
28]. In cases where patients are intolerant to itraconazole, posaconazole is a safer and more effective option [
74].
In patients with CGD, bacterial infections are commonly caused by
Staphylococcus aureus,
Aspergillus spp.,
Nocardia spp.,
Burkholderia spp., and
Serratia spp. [
84] and several antimicrobials have been therapeutically used [
13,
85,
86].
CGD treatment should start at the earliest occasion, and before the microbiological cultures are available. Antimicrobials should be given parenterally. Bacterial infections such as
S. aureus and gram-negative bacteria, including
B. cepacia complex, can be treated with a combination of ceftazidime and nafcillin and or a carbapenem. However,
Burkholderia is typically resistant to most aminoglycosides. If the infection persists for 24–48 h, then more diagnostic test should be done to identify the responsible microorganism. Additional antibiotic coverage such as adding high-dose intravenous trimethoprim-sulfamethoxazole to cover ceftazidime-resistant
B. cepacia and
Nocardia should be made available [
86,
87].
If fungus is identified, antifungal treatment should be institutionalised even before the diagnosis is confirmed. Lung and bone aspergillosis are very prevalent and require prolonged therapy. The echinocandin antifungals including micafungin, caspofungin, and anidulafungin can effectively treat refractory
Aspergillosis in patients unresponsive to lipid-formulated amphotericin B and azoles. Intravenous antifungals must be early considered in CGD patients [
87].
Treatment using TNF-alpha inhibitors in patients with CGD could help improve the outcome of severe inflammatory complications despite the associated risk factors. This treatment could provide short-term benefits in selected patients with CGD with severe inflammatory complications awaiting HCT [
88]. There is conflicting evidence regarding infliximab, a TNF-alpha inhibitor, causing rapid improvement; however, it is associated with an increased risk of severe infections and death in patients with CGD and should be strictly avoided. It is owing to a study involving five patients [
23,
74]. In addition, corticosteroid use has proven beneficial for CGD colitis; however, their use has traditionally been contraindicated in patients with CGD and active infection. In conjunction with appropriate antimicrobials, steroids help treat hyperactive inflammatory responses [
73,
74]. Corticosteroids, despite their effectiveness, are associated with long-term complications such as growth retardation, osteoporosis, and an increased risk of infection [
40,
89,
90,
91,
92].
To determine the optimal treatment for patients with CGD, a European study compared conventional treatments with HCT. Some patients under conventional treatment did not improve. Seventy-six per cent (76 %) of these patients were affected by inflammatory complications, whereas 85 % developed at least one infection even with conventional treatments, the most common being skin infection and pneumonia [
93].
For inflammatory conditions, steroid treatment with immunosuppressants (such as anti-tumour necrosis factor) is adequate as second-line therapy, as they exhibit some efficacy. However, immunosuppressant (
such as anti-tumor necrosis factor agents, thalidomide, and anakinra) use is still debated because of its risks, notwithstanding its benefits [
77,
94,
95,
96].
Lugo-Reyes
et al. (2022) reported the outcomes of a systematic review and meta-analysis on IFN-γ’s efficacy and safety in CGD. They support the use of IFN-γ in managing patients with CGD. However, the authors did not find sufficient clinical evidence and suggested that more clinical trials are needed to assess the efficacy and long-term safety of IFN-γ. As the longevity of patients with CGD improves, a long-term and detailed assessment of the autoimmune and inflammatory complications associated with chronic IFN-γ therapy is required. For the clinicians whose patients continue to die during adolescence owing to invasive pulmonary aspergillosis, especially in Latin America, The Caribbean and other regions where resources are scant, it is imperative to ascertain the patients who are prescribed long-term use of IFN-γ and also identify the significant risks for complications [
97].
6.2.1. CGD-related inflammatory responses
Patients with CGD rarely present cutaneous symptoms, except in patients with autoimmune disorders such as systemic lupus erythematosus [
98]. Furthermore, there is an increased risk of autoimmune disorders such as inflammatory bowel colitis and inflammatory bowel disease among patients owing to increased activation of NF-kB, increasing the production of proinflammatory cytokines. The inflammatory manifestations of CGD are mainly observed in the GI and urogenital tracts, lungs, and eyes. Inflammation can be suppressed by blocking TNF-alpha and oral corticosteroids [
77].
Immunomodulators for CGD-related inflammatory manifestations are under investigation, including pioglitazone, tamoxifen, and rapamycin [
77].
6.2.2. Hemophagocytic lymphohistiocytosis (HLH)
In addition, patients with CGD experience infection-triggered hemophagocytic lymphohistiocytosis (HLH), which presents as pathological hyperactive inflammation [
99]. Possible pathologies, including CGD, should be considered in children with HLH because it can indicate CGD. An optimal management strategy is yet to be developed for children with CGD who manifest with HLH. Early recognition and proper management of infectious triggers and HLH are crucial to reducing mortality [
100].
6.3. Gene therapy
Gene therapy remains in the experimental stage. A recent human trial involved nine patients with X-linked CGD undergoing
ex-vivo autologous CD34+ haematopoietic stem-and progenitor cell-based lentiviral gene therapy following myeloablative conditioning. Two of the nine patients died during the trial; however, prophylactic antibiotic treatment was no longer required in the surviving patients. Moreover, stable vector copy numbers and no clonal dysregulation or transgene silencing were identified in six surviving patients with CGD [
84,
101,
102,
103].
Current gene therapy trials, which remains experimental, have demonstrated that lentiviruses or gene editing can be used as curative therapy where HCT is inappropriate for a patient and removes the risk of graft-versus-host disease. Notably, in the future, gene therapy could be applied when human leukocyte antigen (HLA)-matched donors are difficult to identify, and HCT is not feasible. It is a promising method that involves the insertion of a functional copy of a gene into the correct cells, where success depends on viral vectors. Lentiviral systems are currently the main techniques used to deliver therapeutic genes in experimental gene therapy for treating CGD [
104]. These advances in gene therapy have facilitated more accurate treatment procedures [
105]. Furthermore, gene therapy as a cure for CGD is a crucial area of research, specifically for patients with X-linked and p47 mutations [
106].
There are promising future approaches for treating patients with CGD, including genome-editing technologies, such as CRISPR/Cas9 nuclease gene therapy [
77,
107] and SIN-lentiviral vectors. A multicenter trial is currently being carried out in the United States and Europe to determine the feasibility of gene therapy for patients with CGD [
74]. Other authors have experimentally reported the use of gene therapy in CGD patients. It
could provide life-saving clinical benefit to CGD patients lacking a suitable donor [
108,
109]
.
6.4. Other therapies
In contrast to the methods used to cope with CGD defects, examination revealed that the direct repair of the defect in CGD could be performed using thymosin β4 subverts. It is in experimental stage and is not a type of gene therapy. Hypothetically, thymosin β4 was seen to restore the body’s ability to remove damaged cells and renew healthier cells in patients with CGD by restoring autophagy and upregulating hypoxia-responsive genes in human and murine CGD. Autophagy, which may help in pathogen elimination, could prevent granuloma formation, commonly seen in CGD [
105,
110]. CGD leads to infections of the liver, lungs, and lymph nodes, and treatment of CGD with prophylactic drugs could be prolonged; therefore, optimal therapy must be chosen for these patients [
28,
74].
Results from cases where multiple granulocyte infusion was performed, although not yet evaluated in controlled studies, suggest its usefulness in treating severe bacterial and fungal infections. Adverse effects, although well tolerated, include fever, developing leucoagglutinin, and rarely pulmonary leukocytosis [
73].