NADPH oxidase: the biochemical basis of CGD

See how a mutation in any of the 5 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase component genes can lead to life-threatening bacterial and fungal infections.

Clinical Characteristics

What is chronic granulomatous disease?

Chronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency disorder where the immune system does not work properly. This primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) results from impaired killing of fungi and bacteria, which can lead to severe and recurrent infections.1,2

Inheriting CGD

Inheriting CGD

CGD can be inherited in 2 ways:

X-linked CGD is passed down from the carrier mother and is the most common form of CGD. It primarily affects male children, and symptoms usually appear early in childhood.1,3

Autosomal recessive CGD presents later in life, which can delay diagnosis. Serious infections* may be less frequent.1 Autosomal recessive CGD is passed down by 2 carrier parents and can affect both male and female children.

X-linked CGD Carriers

X-linked CGD Carriers

X-linked carriers can experience various symptoms and may be at risk for serious infections. Up to 23% of carriers may experience CGD-related, lupus-like symptoms including4-8:

  • skin rash
  • sensitivity to the sun
  • pain and swelling of the joints
  • feeling tired all the time
  • weight loss
 Identifying CGD

Identifying CGD

Knowing what to look for can aid in the diagnosis of CGD. Suspect CGD in a patient with:

  • frequent, repeat infections
  • unusually severe infections
  • infections from a specific group of pathogens
CGD lifestyle modifications

CGD lifestyle modifications

Infections caused by bacteria and fungi can occur from many places. They live in places like gardens (in mulch), playgrounds (in woodchips), and in lakes and ponds. People with CGD can still enjoy outdoor activities, but they should be cautioned to stay away from these places. Patients with CGD should also avoid the following:

  • Raking leaves or being around someone raking leaves
  • Barns, caves, and other musty places
  • Hay rides
  • Smoking or being around someone smoking
Benefits of early diagnosis and treating CGD

Benefits of early diagnosis and treating CGD

Early diagnosis and prophylactic treatment is beneficial for patients with CGD because they are more susceptible to and have a higher incidence of serious infections.1,7* Serious infections can be life threatening and result in long hospital stays.

To help protect patients with CGD against serious infections, the triple therapy regimen of ACTIMMUNE® (Interferon gamma-1b), antibiotic therapy, and antifungal therapy is recommended by the9-11:

The recommended treatment paradigm consists of an antibacterial, an antifungal, and immunomodulatory therapy with ACTIMMUNE® (Interferon gamma-1b).1,7,12,13 ACTIMMUNE® (Interferon gamma-1b) is the only FDA-approved biologic therapy indicated for reducing the frequency and severity of serious infections* associated with CGD.14,15

With the development of preventative therapies and the early recognition of infectious complications, 90% of children with CGD now survive into adulthood. This remains, however, largely dependent on several factors, including time of diagnosis, access to care, expertise of caregiver, adherence to therapy, and lifestyle modifications.7,12

*Serious infection is defined as a clinical event requiring hospitalization and intravenous antibiotics.

References: 1. Leiding JW, Holland SM. Chronic granulomatous disease. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews Washington, Seattle; 1993-2016. 2. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine. 2000;79(3):155-169. 3. Rider NL, Jameson MB, Creech CB. Chronic granulomatous disease: epidemiology, pathophysiology, and genetic basis of disease. J Pediatric Infect Dis Soc. 2018;7(suppl 1):S2-S5. 4. Battersby AC, Bruggins H, Pearce MS, et al. Inflammatory and autoimmune manifestations in X-linked carriers of chronic granulomatous disease in the United Kingdom. J Allergy Clin Immunol. 2017;140(2):628-630.e6. 5. Marciano BE, Zerbe CS, Falcone EL, et al. X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability. J Allergy Clin Immunol. 2018;141(1):365-371. 6. Magnani A, Brosselin P, Beauté J, et al. Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease. J Allergy Clin Immunol. 2014;134(3):655-662.e8. 7. Holland SM. Chronic granulomatous disease. Hematol Oncol Clin North Am. 2013;27(1):89-99. 8. Song E, Jaishankar GB, Saleh H, Jithpratuck W, Sahni R, Krishnaswamy G. Chronic granulomatous disease: a review of the infectious and inflammatory complications. Clin Mol Allergy. 2011;9(1):10-24. 9. Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-1205.e1-e78. 10. Leiding JW, Malech HL, Holland SM. Chronic granulomatous disease. Clinical Focus on Primary Immunodeficiencies. 2013;15:1-9. 11. Mendelian susceptibility to mycobacterial disease. In: Buckley RH, ed. Immune Deficiency Foundation Diagnostic & Clinical Care Guidelines for Primary Immunodeficiency Diseases. 3rd ed. Immune Deficiency Foundation; 2015:25. 12. Thomsen IP, Smith MA, Holland SM, et al. A comprehensive approach to the management of children and adults with chronic granulomatous disease. J Allergy Clin Immunol Pract. 2016;4(6):1082-1088. 13. Gallin JI, Alling DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med. 2003;348(24):2416-2422. 14. ACTIMMUNE® (Interferon gamma-1b) [prescribing information] Horizon. 15. The International Chronic Granulomatous Disease Cooperative Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med. 1991;324(8):509-516.

Important Safety Information

INDICATIONS AND USAGE

ACTIMMUNE® (Interferon gamma-1b) is indicated:

  • For reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease
  • For delaying time to disease progression in patients with severe, malignant osteopetrosis

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

  • In patients who develop or have known hypersensitivity to interferon-gamma, E. coli derived products, or any component of the product

WARNINGS AND PRECAUTIONS

  • ACTIMMUNE should be used with caution in patients with:
    • Pre-existing cardiac conditions, including ischemia, congestive heart failure, or arrhythmia
    • Seizure disorders or compromised central nervous system function; reduce dose or discontinue
    • Myelosuppression, or receiving other potentially myelosuppressive agents; consider dose reduction or discontinuation of therapy
    • Severe renal insufficiency
    • Age <1 year
  • Monitoring:
    • Patients begun on ACTIMMUNE before age 1 year should receive monthly assessments of liver function. If severe hepatic enzyme elevations develop, ACTIMMUNE dosage should be modified
    • Monitor renal function regularly when administering ACTIMMUNE in patients with severe renal insufficiency; accumulation of interferon gamma-1b may occur with repeated administration. Renal toxicity has been reported in patients receiving ACTIMMUNE
  • Pregnancy, Lactation, and Fertility:
    • ACTIMMUNE should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus
    • Use of ACTIMMUNE by lactating mothers is not recommended. ACTIMMUNE or nursing should be discontinued dependent on the importance of the drug to the mother
    • Long-term effects of ACTIMMUNE on fertility are not known

DRUG INTERACTIONS

  • Concomitant use of drugs with neurotoxic, hematotoxic, or cardiotoxic effects may increase the toxicity of interferons
  • Avoid simultaneous administration of ACTIMMUNE with other heterologous serum protein or immunological preparations (eg, vaccines)

ADVERSE REACTIONS

  • The most common adverse experiences occurring with ACTIMMUNE therapy are “flu-like” symptoms such as fever, headache, chills, myalgia, or fatigue, which may decrease in severity as treatment continues, and may be minimized by bedtime administration of ACTIMMUNE. Acetaminophen may be used to prevent or partially alleviate the fever and headache
  • Isolated cases of acute serious hypersensitivity reactions have been observed in patients receiving ACTIMMUNE
  • Reversible neutropenia, thrombocytopenia, and elevations of AST and/or ALT have been observed during ACTIMMUNE therapy
  • At doses 10 times greater than the weekly recommended dose, ACTIMMUNE may exacerbate pre-existing cardiac conditions, or may cause reversible neurological effects such as decreased mental status, gait disturbance, and dizziness

Important Safety Information

INDICATIONS AND USAGE

ACTIMMUNE® (Interferon gamma-1b) is indicated:

  • For reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease
  • For delaying time to disease progression in patients with severe, malignant osteopetrosis
IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

  • In patients who develop or have known hypersensitivity to interferon-gamma, E. coli derived products, or any component of the product

WARNINGS AND PRECAUTIONS

  • ACTIMMUNE should be used with caution in patients with:
    • Pre-existing cardiac conditions, including ischemia, congestive heart failure, or arrhythmia
    • Seizure disorders or compromised central nervous system function; reduce dose or discontinue
    • Myelosuppression, or receiving other potentially myelosuppressive agents; consider dose reduction or discontinuation of therapy
    • Severe renal insufficiency
    • Age <1 year
  • Monitoring:
    • Patients begun on ACTIMMUNE before age 1 year should receive monthly assessments of liver function. If severe hepatic enzyme elevations develop, ACTIMMUNE dosage should be modified
    • Monitor renal function regularly when administering ACTIMMUNE in patients with severe renal insufficiency; accumulation of interferon gamma-1b may occur with repeated administration. Renal toxicity has been reported in patients receiving ACTIMMUNE
  • Pregnancy, Lactation, and Fertility:
    • ACTIMMUNE should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus
    • Use of ACTIMMUNE by lactating mothers is not recommended. ACTIMMUNE or nursing should be discontinued dependent on the importance of the drug to the mother
    • Long-term effects of ACTIMMUNE on fertility are not known

DRUG INTERACTIONS

  • Concomitant use of drugs with neurotoxic, hematotoxic, or cardiotoxic effects may increase the toxicity of interferons
  • Avoid simultaneous administration of ACTIMMUNE with other heterologous serum protein or immunological preparations (eg, vaccines)

ADVERSE REACTIONS

  • The most common adverse experiences occurring with ACTIMMUNE therapy are “flu-like” symptoms such as fever, headache, chills, myalgia, or fatigue, which may decrease in severity as treatment continues, and may be minimized by bedtime administration of ACTIMMUNE. Acetaminophen may be used to prevent or partially alleviate the fever and headache
  • Isolated cases of acute serious hypersensitivity reactions have been observed in patients receiving ACTIMMUNE
  • Reversible neutropenia, thrombocytopenia, and elevations of AST and/or ALT have been observed during ACTIMMUNE therapy
  • At doses 10 times greater than the weekly recommended dose, ACTIMMUNE may exacerbate pre-existing cardiac conditions, or may cause reversible neurological effects such as decreased mental status, gait disturbance, and dizziness
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