Pediatric Chronic Granulomatous Disease Treatment & Management

Updated: Aug 07, 2019
  • Author: Lawrence C Wolfe, MD; Chief Editor: Cameron K Tebbi, MD  more...
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Treatment

Medical Care

Antimicrobial prophylaxis, early and aggressive treatment of infections, and interferon-gamma are the cornerstones of current therapy for chronic granulomatous disease (CGD). Hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)–compatible donor can cure chronic granulomatous disease. [10] However, this approach is fraught with clinically significant morbidity and a finite risk of death. HSCT remains a controversial therapeutic modality in this disease, even when stem cells from a matched sibling donor are available. [11, 12, 13]

Infection prophylaxis

Daily prophylaxis of bacterial infections with trimethoprim-sulfamethoxazole (TMP-SMZ; Bactrim) is indicated in chronic granulomatous disease.

TMP-SMZ prophylaxis reduces the incidence of bacterial infections in chronic granulomatous disease without increasing the incidence of fungal infections.

Although numerous other antibiotics have been used, the selective concentration of TMP-SMZ in phagocytes, its broad spectrum of microbicidal activity, and its lack of activity against anaerobic GI flora make this the antimicrobial of choice for prophylaxis in chronic granulomatous disease.

In patients with sulfa allergies, TMP alone or a cephalosporin can be used as daily prophylaxis; however, the effectiveness of this treatment has not been proven.

Ketoconazole is ineffective in reducing fungal infections in patients with chronic granulomatous disease.

Itraconazole prophylaxis against fungal infections is somewhat problematic. A prospective open-label study of long-term itraconazole prophylaxis demonstrated excellent tolerance and a significantly lowered rate of Aspergillus infections versus historical controls. [14] If Aspergillus infection occurs, consult the treatment guidelines from the Infectious Diseases Society of America. [15, 16] A randomized double-blind placebo-controlled study showed that itraconazole prophylaxis in chronic granulomatous disease prevented serious and superficial fungal infections. [17] Adverse effects included rash, increased liver-function values, and headache; these resolved after itraconazole was discontinued. Newer formulations of itraconazole may allow more reliable blood levels and more consistent prophylaxis.

Treatment of established infection

Patients with superficial or deep infections (vs those with obstructing granulomas) should receive aggressive antibiotics; the initial route is parenteral. Treatment usually requires antibiotic coverage for several weeks and should be associated with clear physical signs of resolution and systemic improvement (eg, decreased WBC count and decreased erythrocyte sedimentation rate if elevated at presentation).

Ciprofloxacin with or without additional drug for staphylococcal infection is a common first choice in patients with chronic granulomatous disease. If no response is noted within the first 24-48 hours, coverage should be broadened to include additional antistaphylococcal agents (including coverage for methicillin-resistant Staphylococcus aureus), gram-negative possibilities, and Nocardia species.

The newer antifungals (eg, voriconazole, posaconazole) should be considered for expected fungal infection instead of amphotericin because of decreased toxicity (although they require special consideration with renal dysfunction) and proven efficacy. In established fungal infection, treatment doses of antifungal agents should continue for as long as 6 months.

For poorly responsive infections leading to prolonged consolidation in the lung or large abscesses in the liver, surgical debulking or drainage should be considered. This is especially true of suspected fungal infections and even more so if the chest wall or vertebrae are affected. Prolonged postoperative antibiotics are necessary to deal with slow wound healing and the propensity for wound infection that follows major surgery in these patients.

When an infection breaks through prophylaxis and when it is life-threatening or poorly responsive to antibiotics, growth factor or dexamethasone-induced granulocyte transfusions from healthy donors may improve the outcome.

High-dose interferon-gamma during severe infectious episodes has been advocated.

Patients who present with granulomatous manifestations may have some response to intravenous antimicrobial therapy. However, low-dose corticosteroids are the treatment of choice and are cautiously used in patients who do not appear to have obvious infection, even in the absence of biopsy, especially in patients with GI or genitourinary (GU) obstruction to decrease the time of obstruction without increasing the risk of infection. Prednisone (1 mg/kg) is administered and continues for at least a week until symptoms begin to resolve. A slow taper over 4-6 weeks should be used to avoid recurrence of obstructive symptoms. Chronic treatment with low-dose prednisone or every-other-day treatment may be necessary for resistant obstructive symptoms. Treatment with corticosteroids always increases the risk of infection; thus, increased vigilance in patients throughout steroid treatment is required.

Prophylaxis to improve WBC function

Based on preliminary observations suggesting the efficacy of interferon-gamma, a multi-institutional, randomized double-blind placebo-controlled study of interferon-gamma 50 mcg/m2/dose 3 times per week in patients with chronic granulomatous disease showed that it was well tolerated and that it reduced the frequency of serious infections. [18] The relative risk of a serious infection was 67% lower in the treated group than in the untreated group. Therapy seemed to benefit the youngest children the most.

Interferon-gamma does not correct or enhance phagocyte superoxide production in the vast majority of patients with chronic granulomatous disease. The exact mechanisms underlying the beneficial effect of interferon-gamma is not completely understood but most likely includes augmentation of oxidant-independent antimicrobial pathways. In a subset of patients with X91–chronic granulomatous disease, an increase in functional gp91 was produced.

Data have suggested that interferon-gamma partially corrects the oxidative burst defect in circulating phagocytes from patients with variant X-linked chronic granulomatous disease (X-CGD) or recessive chronic granulomatous disease. Induction of a dose-dependent increase in neutrophil aspergillicidal activity and FcgR1 expression are additional possible explanations for the beneficial role of interferon-gamma in chronic granulomatous disease.

Long-term interferon-gamma therapy was safe in a 9-year open-label study that concluded in 2001. [19] In that study, 76 patients (accounting for 328.4 patient-years) had no life-threatening event or delay in growth or development related to interferon-gamma. Adverse effects were reported by 38% of patients and included fever (most common event; treated with acetaminophen), headache, myalgias, fatigue, irritability, and flulike syndrome. Three (4%) of 76 patients withdrew from the study because of adverse effects. The study showed no increase in proinflammatory symptoms, such as granuloma formation or inflammatory bowel disease (IBD).

Interferon-gamma is now recommended as life-long therapy for infection prophylaxis in chronic granulomatous disease.

Curative approaches (HSCT)

HSCT is the only curative therapeutic modality currently available for this disease.

At least 24 patients who have undergone HSCT for chronic granulomatous disease were reported to the International Bone Marrow Transplant Registry of the Center for International Blood and Marrow Transplant Research (CIBMTR). Several case reports of successful HSCTs are published in the literature. [20]

Because of the paucity of transplantations performed to date, meaningful assessment of the likelihood of successful outcome after HSCT in chronic granulomatous disease cannot be made.

A study by Yonkof et al for the United States Immunodeficiency Network reported that transplant-related survival improved in patients with chronic granulomatous disease who underwent allogeneic HSCT at age 14 years or younger (93% vs 82% at 60 months posttransplant). In the total patient group, however, the procedure was not found to improve overall survival. [21]

Anecdotal experience suggests that engraftment of 10-20% normal donor phagocytes may be sufficient for a clinically significant benefit.

Transplantation with matched sibling bone marrow or cord blood is likely to be most successful if performed in infancy or early childhood, when the risk of death from infection or graft versus host disease is minimal. However, even under these circumstances, a small but finite risk of mortality from HSCT is noted. This risk has led to reluctance among treating physicians in recommending or using this therapeutic procedure.

A study by Marsh et al indicated that allogeneic hematopoietic stem cell transplantation (HSCT) is curative for IBD associated with chronic granulomatous disease (CGD). The investigators reported that by 2 years posttransplant, IBD had resolved in all surviving evaluable patients in the study with a history of the condition. [22]

Gene therapy

Gene therapy for chronic granulomatous disease is attractive for numerous reasons. The exact genetic defect can usually be identified. The cells lacking the functional gene product and their precursors are accessible in blood or bone marrow. Because carriers of X-CGD are rarely symptomatic, unless less than 10% of phagocytes express the normal gene for gp91, stable correction of only 5-10% of circulating phagocytes may be adequate to substantially improve the clinical outcome.

The primary disadvantage of chronic granulomatous disease as a candidate disease for gene therapy is that the gene-modified cells do not have a selective advantage over defective host cells. This is because the phox genes are required only in the terminally differentiated phagocyte.

Published results of gene therapy in chronic granulomatous disease have come from animal studies, in vitro studies of cells derived from human bone marrow, and a reports of adoptive transfer of ex vivo modified cells into human patients. A report in two patients who underwent reduced-intensity transplant conditioning and gene transfer led to improvement in phagocyte superoxide generating activity. [23] Long-term follow up studies are required to document the safety of the gene insertion and the possibility of deleterious effects.

With current techniques, partial temporary correction of the phagocyte defect may be possible as an adjunct to medical therapy of acute or chronic infection. However, durable clinically significant correction of chronic granulomatous disease with gene therapy awaits improved methods for gene transfer, targeting of hematopoietic stem cells, and control of genetic expression. When these problems are solved, safe practical gene therapy will become the treatment of choice for chronic granulomatous disease.

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Surgical Care

Despite the increased risk of wound healing associated with surgical intervention, surgery is still an important tool for these patients.

Surgery may be required to relieve obstruction of ureters from large granulomas, drainage of abscesses, and aggressive removal of established infection, especially in the lung and liver.

Patients who require surgery are at risk for postoperative wound infections and sepsis due to catalase-producing organisms, especially S aureus.

A retrospective study by Feingold et al of patients with chronic granulomatous disease found that those undergoing thoracic surgery (stemming from persistent pulmonary infections) was accompanied by significant morbidity and a relatively poor long-term survival rate, with the hazard ratio for death rising to 3.71. In the study, 35 out of 258 patients required thoracic surgery, with overall survival probabilities at 5- and 10-year follow-up calculated at 75% and 62%, respectively. Negative prognostic factors included chest wall resection and an estimated blood loss of over 500 mL. [24]

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