Feature

Q&A: Raising awareness of chronic granulomatous disease

Photo of Niraj Patel
Niraj C. Patel

Primary immunodeficiencies are a group of over 350 rare and chronic conditions in which genetic defects cause the immune system to function improperly.

Chronic granulomatous disease (CGD) is an example of a primary immunodeficiency disease that receives little attention but is nonetheless a deficiency of which pediatricians should be aware, according to Niraj C. Patel, MD, MS, an associate professor of pediatric infectious disease and immunology at Levine Children’s Hospital, Atrium Health in Charlotte, North Carolina. Although the disease is rare — the incidence is approximately one in 200,000 children — it can have life-threatening complications and a significant patient-caregiver burden.

Infectious Diseases in Children asked Patel about the need for an increased focus on CGD, how it impacts the body’s response to infections and what pediatricians and researchers need to know to combat the disease. – by Joe Gramigna

Q: Of the rare diseases affecting children in the United States, why focus on CGD?

A: There are more than 7,000 rare diseases, and 350 million people worldwide live with a rare disease. Over half of rare diseases present during childhood, including CGD. It often takes years to diagnosis CGD correctly after the onset of symptoms. Active treatment for CGD has shown to significantly improve patient outcomes, and earlier diagnosis and intervention can lead to patients living longer and healthier lives. There is even a cure for CGD, but patients must be diagnosed early and treated aggressively to be suitable candidates.

Q: What do pediatricians need to know about CGD?

A: Because people with CGD often become sick during childhood, pediatricians need to know how to recognize signs and symptoms that can lead to an early diagnosis and improved outcomes for patients. Children with CGD are often healthy at birth. The most common form of CGD, called X-linked, occurs in boys and accounts for about two-thirds of all CGD cases. Infections in children with CGD may often mimic common childhood infections, and the most common infections in infancy include skin, lymph node or bone infections. Unusual infections such as liver abscesses occur in about one-third of patients with CGD. Infections may rupture and drain, often requiring surgery with delayed wound healing and scarring. Five organisms cause more than 90% of infections in CGD (Serratia marcescens, Aspergillus, Staphylococcus aureus, Burkholderia cepacia complex and Nocardia), and their presence should prompt testing for CGD.

Q: What is the relationship between CGD and bacterial and fungal infections?

A: Phagocytes (from the Greek, phagein, “to eat”) primarily work by surrounding and ingesting bacteria and fungi. They have compartments called phagosomes, which contain hydrogen peroxide and bleach that are toxic to microorganisms. The phagocytes of patients with CGD can go to the site of infection but do not make hydrogen peroxide and bleach because of a lack of the proteins needed to generate bleach. As a result, the bacteria and fungi are not killed, leading to recurrent and often severe infections. The most accurate diagnostic test for CGD is the dihydrorhodamine reduction, which measures hydrogen peroxide in phagoctyes.

Infectious microorganisms are most commonly acquired by patients with CGD from the environment. Risk factors for CGD-related infections include the handling of garden mulch, potting soil or decaying plant matter; contact with manure or compost piles; mold in houses; dusty conditions where inhalation is likely; handling marijuana; and swimming in brackish water.

Q: What treatment options are currently available for children with CGD?

A: The treatment of infections in patients with CGD requires prompt and aggressive use of antibiotics, along with surgical drainage when needed. Empiric antibiotics are initially aimed at the most common organisms until a specific infectious cause is identified.

The cornerstone of long-term management of CGD includes antibiotic and antifungal prophylaxis taken daily to prevent infections, usually with trimethoprim/sulfamethoxazole and itraconazole. The introduction of antimicrobial prophylaxis significantly reduced the rates of serious infections and mortality in CGD. Prophylaxis treatment including interferon gamma subcutaneous injections helps to boost macrophage activity and reduces the rates of serious infection about 70%. Additionally, infections that occur while taking interferon gamma may also be less serious. The cure for CGD is a bone marrow transplantation, but there are a lot of risks and this option currently is not widely available. Gene therapy is a promising new treatment for CGD that may avoid many of the risks of a bone marrow transplant and is currently available in research clinical trials only.

Q: Where should future CGD research focus?

A: The average life expectancy for patients currently living with CGD is between 30 to 40 years, which is far less than the average for the normal population. Infection is the most common cause of early mortality, and earlier diagnosis and hence earlier intervention can lead to a longer life. An area of active investigation should include strategies for earlier diagnosis in children, including education and improved access to diagnostic tools in the pediatrician’s office. Secondly, early evidence suggests that interferon gamma injections may help treat certain infections that plague CGD patients, and not just reduce the number of infections. Further research is needed to characterize this potential benefit because use of interferon gamma during an active infection could provide an additional arm to treat patients. Finally, clinical trials are underway to investigate cures for CGD, including gene therapy. This may have advantages over bone marrow transplantation, given gene therapy does not require long-term immunosuppressive medications. Likewise, with gene therapy, there is no need to identify a matched donor, and many of the post-transplant complications, such as graft-versus-host disease, are not an issue.

Q: Is there anything else that is important to know about CGD and current issues with its diagnosis and treatment?

A: Over the past 60 years, patients with CGD are living longer with a better quality of life, often living into adulthood. However, infections remain the biggest risk for morbidity and mortality for patients with CGD, making early diagnosis imperative. Prophylactic antibiotics, antifungals and interferon gamma reduce infections and increase healthy periods for patients and are important for reducing hospitalizations for infections and the need for intravenous antibiotics.

References:

Arnold DE, et al. Adv Ther. 2017;doi:10.1007/s12325-017-0636-2.

Winkelstein JA, et al. Medicine (Baltimore). 2000;doi:10.1097/00005792-20005000-00003.

Disclosure: Patel reports no relevant financial disclosures.

Photo of Niraj Patel
Niraj C. Patel

Primary immunodeficiencies are a group of over 350 rare and chronic conditions in which genetic defects cause the immune system to function improperly.

Chronic granulomatous disease (CGD) is an example of a primary immunodeficiency disease that receives little attention but is nonetheless a deficiency of which pediatricians should be aware, according to Niraj C. Patel, MD, MS, an associate professor of pediatric infectious disease and immunology at Levine Children’s Hospital, Atrium Health in Charlotte, North Carolina. Although the disease is rare — the incidence is approximately one in 200,000 children — it can have life-threatening complications and a significant patient-caregiver burden.

Infectious Diseases in Children asked Patel about the need for an increased focus on CGD, how it impacts the body’s response to infections and what pediatricians and researchers need to know to combat the disease. – by Joe Gramigna

Q: Of the rare diseases affecting children in the United States, why focus on CGD?

A: There are more than 7,000 rare diseases, and 350 million people worldwide live with a rare disease. Over half of rare diseases present during childhood, including CGD. It often takes years to diagnosis CGD correctly after the onset of symptoms. Active treatment for CGD has shown to significantly improve patient outcomes, and earlier diagnosis and intervention can lead to patients living longer and healthier lives. There is even a cure for CGD, but patients must be diagnosed early and treated aggressively to be suitable candidates.

Q: What do pediatricians need to know about CGD?

A: Because people with CGD often become sick during childhood, pediatricians need to know how to recognize signs and symptoms that can lead to an early diagnosis and improved outcomes for patients. Children with CGD are often healthy at birth. The most common form of CGD, called X-linked, occurs in boys and accounts for about two-thirds of all CGD cases. Infections in children with CGD may often mimic common childhood infections, and the most common infections in infancy include skin, lymph node or bone infections. Unusual infections such as liver abscesses occur in about one-third of patients with CGD. Infections may rupture and drain, often requiring surgery with delayed wound healing and scarring. Five organisms cause more than 90% of infections in CGD (Serratia marcescens, Aspergillus, Staphylococcus aureus, Burkholderia cepacia complex and Nocardia), and their presence should prompt testing for CGD.

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Q: What is the relationship between CGD and bacterial and fungal infections?

A: Phagocytes (from the Greek, phagein, “to eat”) primarily work by surrounding and ingesting bacteria and fungi. They have compartments called phagosomes, which contain hydrogen peroxide and bleach that are toxic to microorganisms. The phagocytes of patients with CGD can go to the site of infection but do not make hydrogen peroxide and bleach because of a lack of the proteins needed to generate bleach. As a result, the bacteria and fungi are not killed, leading to recurrent and often severe infections. The most accurate diagnostic test for CGD is the dihydrorhodamine reduction, which measures hydrogen peroxide in phagoctyes.

Infectious microorganisms are most commonly acquired by patients with CGD from the environment. Risk factors for CGD-related infections include the handling of garden mulch, potting soil or decaying plant matter; contact with manure or compost piles; mold in houses; dusty conditions where inhalation is likely; handling marijuana; and swimming in brackish water.

Q: What treatment options are currently available for children with CGD?

A: The treatment of infections in patients with CGD requires prompt and aggressive use of antibiotics, along with surgical drainage when needed. Empiric antibiotics are initially aimed at the most common organisms until a specific infectious cause is identified.

The cornerstone of long-term management of CGD includes antibiotic and antifungal prophylaxis taken daily to prevent infections, usually with trimethoprim/sulfamethoxazole and itraconazole. The introduction of antimicrobial prophylaxis significantly reduced the rates of serious infections and mortality in CGD. Prophylaxis treatment including interferon gamma subcutaneous injections helps to boost macrophage activity and reduces the rates of serious infection about 70%. Additionally, infections that occur while taking interferon gamma may also be less serious. The cure for CGD is a bone marrow transplantation, but there are a lot of risks and this option currently is not widely available. Gene therapy is a promising new treatment for CGD that may avoid many of the risks of a bone marrow transplant and is currently available in research clinical trials only.

Q: Where should future CGD research focus?

A: The average life expectancy for patients currently living with CGD is between 30 to 40 years, which is far less than the average for the normal population. Infection is the most common cause of early mortality, and earlier diagnosis and hence earlier intervention can lead to a longer life. An area of active investigation should include strategies for earlier diagnosis in children, including education and improved access to diagnostic tools in the pediatrician’s office. Secondly, early evidence suggests that interferon gamma injections may help treat certain infections that plague CGD patients, and not just reduce the number of infections. Further research is needed to characterize this potential benefit because use of interferon gamma during an active infection could provide an additional arm to treat patients. Finally, clinical trials are underway to investigate cures for CGD, including gene therapy. This may have advantages over bone marrow transplantation, given gene therapy does not require long-term immunosuppressive medications. Likewise, with gene therapy, there is no need to identify a matched donor, and many of the post-transplant complications, such as graft-versus-host disease, are not an issue.

PAGE BREAK

Q: Is there anything else that is important to know about CGD and current issues with its diagnosis and treatment?

A: Over the past 60 years, patients with CGD are living longer with a better quality of life, often living into adulthood. However, infections remain the biggest risk for morbidity and mortality for patients with CGD, making early diagnosis imperative. Prophylactic antibiotics, antifungals and interferon gamma reduce infections and increase healthy periods for patients and are important for reducing hospitalizations for infections and the need for intravenous antibiotics.

References:

Arnold DE, et al. Adv Ther. 2017;doi:10.1007/s12325-017-0636-2.

Winkelstein JA, et al. Medicine (Baltimore). 2000;doi:10.1097/00005792-20005000-00003.

Disclosure: Patel reports no relevant financial disclosures.