Medical Care
Early diagnosis and treatment can significantly improve the prognosis. [27] Modern therapy for chronic granulomatous disease (CGD) includes aggressive and prolonged administration of antibiotics and prednisone. [28] Treatment for inflammatory and autoimmune complications in patients with CGD is problematic because most agents are immune suppressive and immunity is already impaired in patients with CGD. Many patients respond well to corticosteroids, but they might require prolonged courses.
Sulfasalazine and azathioprine are useful steroid-sparing agents. Tumor necrosis factor-α (TNF-α) inhibitors such as infliximab are effective anti-inflammatory agents but might significantly increase the risk of severe and even fatal infections. The risk of infection needs to be weighed carefully against the risks of uncontrolled mucosal inflammation or surgery that might be further complicated by persistent inflammation, abscesses, and fistulae formation at surgical sites. If TNF-α inhibitors are used, augmented prophylaxis and enhanced vigilance regarding exposures are mandatory.
Methotrexate and hydroxychloroquine (Plaquenil) can be effective in those with arthritides or lupuslike problems.
Conventional treatment consists of lifelong anti-infectious prophylaxis with antibiotics such as trimethoprim-sulfamethoxazole (TMP-SMZ), antimycotics such as itraconazole, and/or interferon (INF)–gamma.
Long-term antibiotic therapy may be helpful. All infections should be treated with broad-spectrum systemic antibiotics. Aggressive treatment should be initiated at the first signs of infection. Every episode of fever must be treated promptly by an aggressive use of drugs able to cross the phagocyte cell membrane and accumulate within the phagocytic cells. Initial empirical therapy should include at least two antibiotics against gram-positive and gram-negative bacteria. In case of failure to respond within 48 hours, empirical changes in antibiotic coverage may be needed before definitive pathogen identification, including the administration of an antifungal drug, if not administered from the beginning. Treatment should be continued for weeks or months, even when there is significant improvement in the inflammatory index and the patient’s clinical condition in order to eradicate the infection completely. [23]
If a fungal invasive infection is identified or strongly suspected, intravenous voriconazole is recommended as initial treatment. Voriconazole serum concentrations present great variability, and drug monitoring is recommended to document bioavailability and efficient blood levels. Severe photosensitivity leading to squamous cell carcinoma and melanoma has been reported with long-term voriconazole treatment. Therefore, voriconazole should be used carefully for durations longer than 6-9 months, particularly among patients with risk factors for skin cancer. In patients requiring prolonged voriconazole, diligent skin examinations, avoidance of excess sunlight, and liberal use of ultraviolet protectants are advisable. [23] When infections are refractory to voriconazole or when there is intolerance, intravenous liposomal amphotericin B and caspofungin have been shown effective. Posaconazole, an orally well-tolerated broad-spectrum triazole antifungal agent, has proven efficacy as prevention of and salvage therapy for invasive fungal infection. When the fungal cause is uncertain, combined antifungal therapy can be considered. The most common combinations are voriconazole and caspofungin combination or caspofungin and liposomal amphotericin B. Amphotericin B should be added to the therapeutic regimen of CGD patients with established invasive aspergillosis. Aspergillus and other fungal infections of the lung typically require prolonged treatment (3-6 mo). [29]
In case of multidrug refractoriness, life-threatening infections (eg, aspergillosis), hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning represents a valid curative option. [30]
Alternatively, a combination of sequential granulocyte transfusions (GTs), leading to a transitory beneficial effect on preexisting infections, and HSCT have been proposed. [23]
Gene editing is being studied. [31]
INF-gamma therapy subcutaneously appears to be a promising way of improving neutrophil and monocyte function and may prove to be of particular value in the prevention or treatment of deep fungal infections. INF-gamma is now recommended as life-long therapy for infection prophylaxis in persons with CGD. [32, 33]
HSCT may be considered as an early treatment option for CGD. Since the beginning of the 21st century, there have been many reports on HSCT in patients with CGD and the encouraging results obtained with regard to survival rate, engraftment, and graft versus host disease (GVHD). In particular, it is notable that HSCT can cure CGD and reverse organ dysfunction. There is continuing controversy about indications and optimum timing of HSCT in CGD. Patients with absent NADPH oxidase activity and poor prognosis have been recommended for early HSCT. Present HSCT indication criteria in children are as follows: (1) one or more life-threatening infection, (2) noncompliance with antimicrobial prophylaxis, or (3) steroid-dependent autoinflammation. Indication criteria in adolescents and young adults are more difficult to apply because organ dysfunction is frequent and transplant-related mortality after HSCT has been high. [23, 34]
Bone marrow transplantation (BMT), as a last resort, can be undertaken. This treatment has been partially successful. Transplantations with other than perfectly matched donors are presently discouraged. [35, 36]
Recurrent impetigo, frequently in the perinasal area and caused by S aureus, usually requires prolonged courses of oral and topical antibiotics to clear.
Noninfectious granulomas may resolve spontaneously, and they rarely require systemic corticosteroid therapy unless vital organs are compromised.
Gene therapy for CGD
Gene therapy for hematopoietic cells (GT-HSC) represents an attractive alternative to HSCT as therapy for CGD patients without a matched donor. The observation that XR-CGD carriers in whom 10% or greater of normal neutrophils were healthy suggested that a minor functional correction of neutrophils would be sufficient to restore a normal phenotype in GT-HSC–treated patients. Nevertheless, GT-CGD is difficult to perform because corrected HSCs do not have a selective growth advantage compared with deficient cells, and, at the same time, a large number of cells needs to be corrected to ensure a good restoration of neutrophil activity. Thus, myeloablative conditioning is necessary to ensure an efficient engraftment of progenitor cells. [23, 37, 38, 39, 40]
Surgical Care
In addition to systemic antifungal treatment, surgical debridement or excision of consolidated infection is advised when possible, [23] including surgical drainage of abscesses and resection (when possible) of granulomas.
Consultations
Gastrointestinal manifestations include perineal abscesses; fistulae; and, characteristically, obstructive lesions associated with granulomatous infiltration; thus consultation with a surgeon may be necessary.
An internist consultation may be necessary because pyrexia should be carefully investigated to reveal the site of the causative infection and the responsible microorganism. Pulmonary disease (eg, recurrent pneumonia, empyema, lung abscess formation) should be treated.
Prevention
Chronic granulomatous disease (CGD) in adults may be more common than previously assumed. Because timely treatment, infection prophylaxis, and genetic counseling for affected families are possible, CGD should be excluded in any patient with unexplained infections or granulomas. Patients with the disease should be counseled about prophylaxis for bacterial and fungal disease and avoidance of unnecessary exposure to mold and nonchlorinated water. Prophylactic therapy is based on daily doses of trimethoprim/sulfamethoxazole and itraconazole.
Long-Term Monitoring
Skin hygiene is an important element of further outpatient care for chronic granulomatous disease (CGD). The skin should be washed twice daily with a disinfectant soap. The fingernails should be cut short. The patient should be monitored for the results of antibacterial and antifungal prophylaxis.
-
Scanning electron micrograph of Aspergillus species.
