The cornerstones of therapy in CGD are currently (1) prevention and early treatment of infections, (2) aggressive use of parenteral antibiotics for most infections, (3) use of prophylactic TMP-SMX (5 mg/kg/ day of trimethoprim) or dicloxacillin (25 to 50 mg/kg/day) for sulfa allergic patients, (4) prophylactic itraconazole (200 mg/day if 13 years of age or older or if weighing at least 50 kg, or 100 mg daily if younger than 13 years of age or weighing less than 50 kg), and (5) use of pro phylactic recombinant human interferon-γ (rIFN-γ; 0.05 mg/m2 or 0.0015 mg/kg if less than 0.5 m2 three times per week). Using these guidelines, the prognosis for patients with CGD has improved dramatically since the disorder was first described in the 1950s, when almost all patients died in childhood. In a large study based on data collected by a CGD registry in the United States in the 1990s, the overall mortality rate was estimated to be 5% per year for X-CGD and 2% per year for AR CGD, and a more recent single-institutional study of 76 patients reported an overall mortality rate of 1.5% per year.
There is a general consensus that a large majority of newly diagnosed children should survive well into their adult years with aggressive and careful management. While survival is improved, many of these adults continue to have significant complications due to chronic inflammation. The quality of their survival is further affected by the paucity of providers with sufficient experience in the management of this very rare disorder. As already noted, patients with deficiency of p47phox have a tendency for milder disease compared with those with flavocytochrome-negative CGD. On the other hand, some patients (usually X-linked) prove to have more frequent serious infections or inflammatory complications (or both), likely because of the effects of modifier genes; these patients may warrant more aggressive treatment such as bone marrow transplantation (BMT).
Several approaches can be used to prevent infections. Patients with CGD should receive all their routine immunizations on sched ule (including live virus vaccines), with influenza vaccine administered each year as well. Cuts and skin abrasions should be cleansed promptly with soap and water and a topical antiseptic applied (2% hydrogen peroxide, Betadine ointment, or both). Frequent brushing, flossing, use of antibacterial mouthwash, and professional cleaning of teeth can help prevent gingivitis. Constipation should be avoided because it can lead to rectal or anal fissures and abscesses. Early anal infections can be treated with soaking in soapy water (with or without betadine). The frequency of pulmonary infections can be reduced by not using commercially available bedside humidifiers; avoiding smoking (cigarettes and marijuana); and refraining from handling decaying plant materials (e.g., hay, mulch, rotting sawdust), which often contain numerous Aspergillus spp. Avoidance of construction sites, especially demolition of old buildings that may harbor fungi, is recommended. There have been clear outbreaks of Aspergillus pneumonias in immunosuppressed children visiting hospitals undergoing renovation.
There is clear evidence that chronic prophylactic TMP-SMX can decrease the number of bacterial infections in CGD patients by more than half without a concomitant increased risk of fungal infection. In addition, itraconazole is an effective agent for prophylaxis for fun gal infections in CGD. Liver function tests should be monitored in patients receiving itraconazole.
Prophylactic rIFN-γ has been another mainstay of current management of CGD. The clinical benefit of rIFN-γ is probably related to generally enhanced phagocyte function and killing by nonoxidative mechanisms because its use is not accompanied by any measurable improvement in NADPH oxidase activity in the vast majority of CGD patients. In the original multicenter trial, patients were randomized in a double-blind fashion to receive either placebo or rIFN-γ (0.05 mg/m2 three times per week). As summarized in Table 1, there was a substantial decrease in the number of serious infections in the rIFN-γ arm. Side effects were observed in some of the patients but typically were restricted to mild fever and flu-like symptoms. Additional adverse reactions, including any increased incidence of chronic inflammatory complications, have not been noted with more prolonged courses of prophylactic rIFN-γ (more than 10 years), and the patients continued to have a substantial benefit, with fivefold fewer serious infections compared with the placebo group in the phase III study in Table 1. This group of patients averaged one serious infection per patient every 4 to 5 years. However, rIFN-γ is used less frequently in Europe because nonrandomized trial data did not suggest much benefit. The use in a cohort followed at the National Institutes of Health was recently reported to be only 36% of patients because of either lack of access or because of side effects (fever, myalgia); the availability of more potent antifungals and oral antibiotics may be a mitigating factor for reducing serious infectious complications in the absence of prophylactic rIFN-γ.
Table1. Efficacy of Interferon-γ in Preventing Serious Infections in Chronic Granulomatous Disease
One of the most frequent errors in the management of CGD patients is the failure to treat potentially serious infections promptly and aggressively with appropriate parenteral antibiotics. Even the best antibiotics can be rendered ineffective if given too late in the course of an infection in CGD. Therefore early intervention is advisable. Although many of the minor infections and low-grade fevers in CGD patients can be managed on an outpatient basis, episodes of consistently high fever over a 24-hour period or clearly established infections (e.g., pneumonia or lymphadenitis) should be treated with parenteral antibiotics that cover, at least initially, S. aureus and enteric gram-negative organisms. Reasonable attempts to define the source of the infection and the responsible microbe should also begin promptly. The use of PCR to supplement culture-based methods to detect microbial pathogens may be very helpful. A few organisms can cause a large inflammatory response, so often an organism cannot be found and empiric treatment must be administered without specific identification of an organism. Monitoring markers of inflammation such as the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) can be very useful, both as a clue to the presence of a significant infection as well as following the patient’s response to therapy. If the patient fails to respond, then more aggressive diagnostic procedures should be instituted (CT, bone, and gallium scans; open biopsies if indicated) and empirical changes in the antibiotics used to broaden coverage to Pseudomonas cepacia. If fungus is identified or strongly suspected, amphotericin B has been the drug of choice in the past, but newer azole antifungal agents such as voriconazole are supplanting its use.
Even with appropriate antibiotics, certain types of infections respond slowly and may require many months of therapy. This point about duration of treatment is critical. Especially deep tissue infections such as pneumonia require continued treatment until they are clear radiographically, and the sedimentation rate has normalized. This can take many months of intensive treatment. Otherwise, the infection will recur and long-term complications such as emphysema develop. In this sense, treatment of infection in CGD is very different than the normal population. Surgical drainage or resection can sometimes play a key role in accelerating healing of certain types of infection such as lymphadenitis, osteomyelitis, and abscesses of visceral organs such as the liver or lung. Corticosteroids in combination with high-dose antibiotics can help to avoid surgical intervention for liver abscesses. Finally, granulocyte transfusions may be of benefit in the treatment of stubborn or life-threatening infections.
Recurrent fever in CGD always raises the possibility of infection in these patients; however, the MAS-HLH spectrum of disorders should be considered, especially if the patient has splenomegaly, leukopenia, or thrombocytopenia. If significant MAS/HLH is suspected, IFN-γ should be stopped. As in inflammatory disorders such as rheumatoid arthritis, secondary MAS-HLH has been reported in CGD, often in association with bacterial or fungal infection, and is probably often overlooked. Specific treatment may be indicated, especially if the patient has significant cytopenias or evidence of hepatic dysfunction.
Inflammatory complications of CGD can occur at all ages but can be an increased burden in adults. These can be challenging to treat in CGD because use of agents to suppress the inflammatory response can increase the risk of fungal or bacterial infections. Judicious use of corticosteroids can be indicated, including in cases of severe asthma, esophageal strictures, gastric antral narrowing, granulomatous cystitis, inflammatory bowel disease, or certain cases of pneumonia. Clear evidence shows that corticosteroids are beneficial in these clinical settings because the steroids induce rapid regression of obstructive symptoms at low oral doses (e.g., 1 mg/kg/ day of prednisone). Steroids can be lifesaving in young children with airway obstruction because of inflammation. Because of the exaggerated inflammatory reaction seen in CGD, there can be significant swelling in the airway and compression by pulmonary nodes that can block air movement and impede drainage. In these cases, the physician and patient should be aware of the risks of the additional immunosuppression caused by corticosteroids, particularly for fungal infection. Corticosteroids have also emerged as important component of treating Staphylococcal liver abscesses in combination with antibiotics, with improved outcomes and often avoidance of invasive procedures for abscess drainage. In colitis, steroid-sparing agents such as sulfasalazine and azathioprine for colitis can be helpful. Biologic agents such as TNF-α inhibitors or those blocking IL-1 are also occasionally used in patients with difficult-to-manage inflammatory disease, but with caution due to the increased risk of infection. The chronic lung disease that can develop in older patients with CGD can be difficult to treat and may be an indication for stem cell transplantation.
Rare patients with X91° CGD have genomic deletions that span the gp91phox gene and the Xk gene, which encodes a membrane protein necessary for expression of the Kell genes. Absence of the Xk gene product results in the McLeod syndrome, in which red blood cells have weak Kell antigens and variable acanthocytosis along with nerve and muscle disorders related to its expression in nonerythroid tissues. Transfusion of patients with McLeod syndrome poses a serious problem because they can develop alloantibodies of wide specificity that can preclude any further transfusions except with Kell-negative blood products. McLeod-matched blood is extremely rare, and patients with this syndrome should have their own blood frozen in case it is needed. Note that use of maternal blood does not solve the problem because only 50% of the mother’s blood will match. Because of the difficulty in finding blood, transfusion with non-McLeod blood is likely to occur. Although management is difficult and use of steroids is necessary, the hemolytic anemia can be managed successfully.
Allogeneic hematopoietic stem cell transplant (HSCT) can be used to treat CGD, including using matched unrelated donors.10,16 Because of risks associated with this procedure, HSCT was previously considered only for patients who have a fully human leukocyte antigen (HLA)-matched sibling and frequent and severe infections or refractory gastrointestinal disease despite aggressive medical management. However, reduced-intensity conditioning regimens for allogeneic transplantation with sibling or nonsibling donors have now been successfully used for HSCT in CGD and has a high curative rate with low mortality.10,16 Which patients with CGD should undergo trans plantation is an individualized decision, particularly for those with residual NADPH oxidase activity, for adults, or when well-matched donor marrow is not available. The best results are in young patients without preexisting complications. Because it is currently not possible to predict which patients will develop significant inflammatory com plications such as gastrointestinal or lung disease later in life, trans plantation in the first decade of life should be strongly considered for any patient with a fully HLA-matched healthy sibling or fully matched high-resolution HLA-typed unrelated donor, regardless of infection history. The indications for transplant in adults should be carefully assessed in consultation with an experienced HSCT center, although results in recent years have been encouraging. While the resolution of gastrointestinal disease in CGD following transplant has been appreciated for some time, the problematic inflammatory lung disease with progressive dyspnea that can develop in older CGD patients also appears to be reversible to a remarkable degree with successful HSCT.
Finally, gene therapies aimed at correcting the defective gene in bone marrow (BM) stem cells hold promise for the future if obstacles can be solved to achieve effective and safe gene delivery and their transplantation. Observations on female carriers of X-linked CGD with skewed X-inactivation and preclinical studies in murine CGD models suggest that complete correction of NADPH oxidase activity in 10% of circulating neutrophils will lead to clinically relevant improvements in host defense, although inflammatory complications may still be problematic if only partial correction is achieved.
