eMedicine Specialties > Pediatrics: General Medicine > Hematology

Chronic Granulomatous Disease: Treatment & Medication

Author: Lawrence C Wolfe, MD, Professor, Department of Pediatrics, Tufts University School of Medicine; Chief of Transfusion Service, Chief, Division of Pediatric Hematology/Oncology, New England Medical Center, Floating Hospital for Infants and Children
Contributor Information and Disclosures

Updated: Apr 13, 2009

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.3 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.

  • 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.4 If Aspergillus infection occurs, consult the treatment guidelines from the Infectious Diseases Society of America.5 A randomized double-blind placebo-controlled study showed that itraconazole prophylaxis in chronic granulomatous disease prevented serious and superficial fungal infections.6 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.7 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 2001.8 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.
    • 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.
    • 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.
  • 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.9  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.

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

Medication

Antimicrobials

These agents are used prophylactically to prevent infections in susceptible individuals or to treat active infections.


Trimethoprim-sulfamethoxazole (TMP-SMZ, Cotrimoxazole, Septra, Bactrim)

Antimicrobial drug of choice administered prophylactically to prevent infections in patients with CGD.

Adult

Dose based on TMP component
5 mg/kg/d PO divided bid; not to exceed 1 double-strength tab (ie, TMP 160 mg/SMZ 800 mg) bid
Alternative: 5 mg/kg/dose IV bid

Pediatric

Administer as in adults

May increase the PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both; coadministration of diuretics increases the incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine

Documented hypersensitivity; megaloblastic anemia due to folate deficiency; age <2 mo

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients with G-6-PD deficiency or hepatic or renal dysfunction

Biologic response modifiers

These agents regulate the immune system by various mechanisms, including enhancing activity of macrophages and cytotoxic actions of T lymphocytes.


Interferon gamma 1b (Actimmune)

Indicated in CGD to reduce frequency and severity of bacterial infections (50 mcg = 1 million IU).

Adult

50 mcg (1 million IU)/m2/dose SC 3 times per wk

Pediatric

BSA <0.5 m2: 1.5 mcg/kg/dose SC 3 times per wk
BSA >0.5 m2: Administer as in adults

May inhibit cytochrome P450 (CYP) isoenzymes; coadministration with other myelosuppressive agents (eg, antineoplastic agents) may increase risk of neutropenia, anemia, or thrombocytopenia

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause CNS toxicity (eg, decreased mental status, gait disturbance, dizziness), myelosuppression, or exacerbate existing cardiovascular disease; causes fertility impairment

Antifungal agents

The mechanism of action may involve increasing the permeability of the cell membrane, which, in turn, causes intracellular components to leak.


Itraconazole (Sporanox)

Continuous antifungal therapy effective in preventing infection due to Aspergillus species. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP–dependent synthesis of ergosterol, vital component of fungal cell membranes.

Adult

200 mg PO qd; not to exceed 400 mg/d

Pediatric

<50 kg: 5 mg/kg/d PO; not to exceed 100 mg/d

Antacids may reduce absorption; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses used; rhabdomyolysis may occur with coadministration of 3-HMG-CoA reductase inhibitors (lovastatin or simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death
May increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (may alter phenytoin metabolism)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic insufficiencies


Voriconazole (VFEND)

Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.

Adult

Loading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses
Maintenance: 4 mg/kg IV q12h infused over 2 h, when able to tolerate PO may switch to 200 mg PO q12h
Note: For inadequate response, may increase to 300 mg PO q12h; <40 kg administer oral maintenance dose of 100 mg PO q12h (may increase to 150 mg PO q12h)

Pediatric

Not established

CYP450 2C19 (highest affinity), 2C9, and 3A4 (minor) substrate and inhibitor; CYP450 inducers (eg, rifampin) have shown to decrease steady state peak plasma levels by up to 93%; may increase serum levels of drugs metabolized by CYP450 2C19 or 2C9, of which some are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids), other may need more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG CoA inhibitors, benzodiazepines, calcium channel blockers)

Documented hypersensitivity; do not administer IV form with CrCl <50 mL/min (decreased excretion of IV vehicle); coadministration with rifampin, rifabutin, carbamazepine, barbiturates, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Decrease maintenance dose with hepatic dysfunction; common adverse effects include visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, rash (including Stevens-Johnson Syndrome and phototoxicity), and respiratory disorder; rare cases of severe hepatotoxicity have been reported; administer PO 1 h ac or pc


Posaconazole (Noxafil)

Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

Adult

200 mg (5 mL) PO tid with food or liquid nutritional supplement to enhance absorption

Pediatric

<13 years: Not established
>13 years: Administer as in adults

Metabolized via UDP glucuronidation; P-gp efflux substrate; CYP3A4 inhibitor
UDP-G inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk)
Inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers (eg, nifedipine, bepridil), HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin), ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, or vinca alkaloids (eg, vincristine, vinblastine)

Documented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates likely to result in serious toxicities (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver function impairment; caution with preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon provided in package; avoid if breastfeeding

Immunomodulators

These agents suppress an overactive immune system that leads to formation of granulomas.


Prednisone (Deltasone, Orasone)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) activity.

Adult

5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve

Pediatric

1-2 mg/kg PO qd or divided bid/qid; taper over 2 wk as symptoms resolve

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI bleeding or ulceration

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

More on Chronic Granulomatous Disease

Overview: Chronic Granulomatous Disease
Differential Diagnoses & Workup: Chronic Granulomatous Disease
Treatment & Medication: Chronic Granulomatous Disease
Follow-up: Chronic Granulomatous Disease
Multimedia: Chronic Granulomatous Disease
References
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Further Reading

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Keywords

chronic granulomatous disease, fatal granulomatosis of childhood, chronic granulomatous disease of childhood, progressive septic granulomatosis, CGD, X-linked CGD, X-CGD, X91 CGD, A22 CGD, A47 CGD, A67 CGD,  hypergammaglobulinemia, hepatosplenomegaly, lymphadenopathy, Pseudomonas aeruginosa, Burkholderia cepacia, treatment, diagnosis, osteomyelitis, septicemia, dysphagia, nausea, vomiting, abdominal pain, obstruction, granulomatous colitis, Crohnlike inflammatory bowel disease, IBD, GI obstruction, hypoalbuminemia, discoid lupus erythematosus, photosensitivity, Raynaud phenomenon, aphthous ulcers

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Contributor Information and Disclosures

Author

Lawrence C Wolfe, MD, Professor, Department of Pediatrics, Tufts University School of Medicine; Chief of Transfusion Service, Chief, Division of Pediatric Hematology/Oncology, New England Medical Center, Floating Hospital for Infants and Children
Lawrence C Wolfe, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association of Blood Banks, American Society of Hematology, Children's Oncology Group, and Eastern Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Sharada A Sarnaik, MB, BS, Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan
Sharada A Sarnaik, MB, BS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

 
 
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