What is Chronic Granulomatous Disease?
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is a complex made up of enzymes from the NOX family. This complex plays a vital role in creating a particle called superoxide anion (O-), using NADPH in the process. It’s important to note that the formation of these particles is key in destroying harmful microorganisms within certain white blood cells known as phagocytic leukocytes.
Chronic granulomatous disease (CGD), first discovered in the 1950s, is a rare and diverse condition that can lead to various severe and recurrent infections. This disease is caused by a flaw in the phagocyte NADPH oxidase. Because of this defect, phagocytes – like neutrophils, monocytes, and macrophages – cannot destroy certain microbes. This article offers updates on the clinical biochemistry and management of this phagocyte disorder.
What Causes Chronic Granulomatous Disease?
The NOX family, which includes NOX1-5, has conserved properties that allow it to be active. Each member has between six to seven domains that span across the cell membrane, and also contain two heme units and a binding site for NADPH. All these members combine to form a multi-part complex, and NOX2 is often involved in CGD.
Typically, cells called phagocytes create active oxygen species by NADPH oxidase. This powerful ROS is created within the phagocyte that has swallowed a microorganism. The NADPH oxidase includes five subunits, some located in the cytoplasmic region of the cell and the others in the membrane units. Once they are activated, they come together to form a fully formed enzyme and become active.
The gp91phox subunit plays an essential role in transferring electrons and combining them with molecular oxygen inside the phagosome. This forms a potent superoxide anion which produces a variety of other ROS, which are crucial in killing microorganisms. The rapid consumption of oxygen and production of superoxide and its metabolites is known as a respiratory burst.
When the outer membrane of the phagocytic cell merges with bacteria, it forms an intracellular vesicle. The superoxide and oxygen-derived products lead to a surge in potassium and an increased pH level within the phagosome, which activates enzymes that lead to the killing of the ingested microorganisms.
In individuals suffering from CGD, the defective production of ROS hampers the effective killing of certain pathogens. Studies have noted that these patients are not capable of enhancing neutrophil extracellular traps (NETs), which work by entrapping and killing bacteria and fungi. CGD also results in a reduction in efferocytosis, a process where phagocytes remove dying inflammation cells, contributing to the inflammation often seen in CGD patients.
CGD is caused by mutations which cause the loss or ineffective function of the NADPH oxidase complex subunits. There are various genes associated with the five components of NADPH oxidase, and mutations in these genes lead to the CGD phenotypes. Most of the CGD mutations are recessively inherited, with the exception of the NOX2 variant which is X-linked recessive.
About 70 percent of CGD patients have the CYBB variant which causes a higher occurrence of CGD in males. The p47phox gene mutation accounts for 25% of the cases and the rest is due to other mutations.
In some instances, the mutations allow the NADPH oxidase to remain partially functional, hence, the severity of the disease is reduced. However, this can vary depending on the mutated gene, the type of mutation, and the position of the mutation within the gene. Usually, mutations in the NCF1 gene result in milder forms of the disease.
Risk Factors and Frequency for Chronic Granulomatous Disease
Chronic Granulomatous Disease (CGD) happens in about 1 in every 200,000 live births in the United States. Because this condition is linked to a gene mutation on the X chromosome, around 80% of people with CGD are males. This rate is almost the same across different ethnic and racial groups. Also, one-third of these X-linked mutations happen spontaneously, not inherited from parents.
In societies where marriages between close relatives are common, a different type of CGD, which is inherited in an autosomal recessive manner, is more usual than the X-linked type, causing higher overall occurrence rates. Children who have the X-linked version of CGD usually experience the onset of the disease earlier and suffer from a more severe form of the illness compared to those with the autosomal recessive type.
Signs and Symptoms of Chronic Granulomatous Disease
Chronic granulomatous disease (CGD) primarily affects children, causing them to experience many repeated bacterial and fungal infections. Symptoms usually start within the first 2 years of life, with an average diagnosis age of 2.5 to 3 years. However, some individuals with milder forms of the disease may not be diagnosed until later in life.
The infections often affect organs that interact with the outside environment like lungs, gastrointestinal tract, skin, and lymph nodes. The infections can also spread to other organs such as the liver, bones, kidneys, and brain.
Patients also deal with other problems in organ systems that shield the body from foreign microbes. These systems most frequently involve the skin, gums, lungs, lymph nodes, digestive tract, liver, and spleen. The majority of patients begin to show symptoms within their first year of life. These symptoms can range from infections and skin inflammation to gastrointestinal complications and malnutrition. More specific issues could include:
- Liver issues, such as enlarged liver or abscesses
- Urinary tract infections
- Eye inflammation
- Gum disease and overgrowth
- Skin sensitivity to sun
- Blood vessel inflammation
- Chronic lung disease
- Low platelet count
- Juvenile arthritis
- Delay in growth
- Anemia and nervous system symptoms in case of Kell gene deletion,
- and other symptoms that can vary greatly from one patient to another.
The infections in CGD patients often come from specific organisms like Staphylococcus aureus, Burkholderia, Serratia marcescens, and Nocardia and fungi like Aspergillus. Some patients who were vaccinated against tuberculosis might have issues with the BCG vaccination and could show several kinds of infections like skin abscesses, lymph gland inflammation, blood poisoning, and more. Other common microbes causing infections include Escherichia coli, Klebsiella, and Candida.
In some cases, CGD patients do not show typical signs of infection but rather develop chronic inflammation that forms granulomas. Granulomas are typical for CGD and can cause blockages in organs like the bile duct, bladder, digestive tract, uterus, or bronchus. Gastrointestinal and urinary tract issues are the most common, but other areas can be affected as well including retina, liver, lungs, and bone. The exact cause for granulomas in CGD is uncertain, but they are believed to be due to the body’s inability to turn off the inflammatory response.
Testing for Chronic Granulomatous Disease
Chronic Granulomatous Disease (CGD) can be detected at the microscopic level by measuring white blood cells’ ability to produce certain substances, known as superoxide or hydrogen peroxide. These substances help fight against infections. Generally, a type of white blood cell called neutrophilic granulocytes is used to identify if the cells are effectively fighting against infections.
A couple of ways to measure this include the cytochrome c reduction assay and the nitroblue tetrazolium slide assay. Both of these tests measure the production of superoxide. There are also tests to measure hydrogen peroxide production, such as the dihydrorhodamine-123 (DHR) assay and the Amplex Red assay.
While a patient’s medical history may hint at their genetic inheritance pattern, genetic testing can identify specific genetic changes that may be causing the disease.
Treatment Options for Chronic Granulomatous Disease
Chronic granulomatous disease (CGD) used to be a fatal condition in children, but today, children diagnosed with this disease can live fulfilling lives thanks to advancements in treatments. The management of CGD revolves around three main principles: taking antibiotics and antifungal medicines for life, early detection of infections, and immediate treatment of any infectious complications.
Globally, a combination of two medicines, trimethoprim-sulfamethoxazole and itraconazole, is used to manage the condition. Some places also incorporate a third treatment known as interferon-gamma therapy, though this isn’t always universally accepted. Together, these treatments have drastically reduced severe infections in patients from nearly once per year to once per decade. It’s important to note that live bacterial vaccines should typically be avoided.
When acute infections occur, quick action is crucial. Start treatment early with antibiotics or antifungal therapies, and work to identify the specific infectious agent causing the problem. If an infection doesn’t improve with treatment after a day or two, additional testing may be necessary. For fungal infections in particular, starting antifungal treatment should be a priority, even before confirming the diagnosis. In some cases, surgery may be needed to remove fungal infections that don’t respond to medication. Doctors often prescribe oral glucocorticoids to handle inflammatory aspects of CGD, but using tumor necrosis factor-alpha inhibitors can lead to risky infections and is typically not recommended.
Hematopoietic cell transplantation (HCT) is currently the only treatment proven to cure CGD. Swift diagnosis is key to determining whether HCT is a feasible option for a patient. Success rates are highest in young patients who are disease-free at the time of the transplant. A patient’s prognosis, available donors, access to transplantation facilities, and patient preference all factor into the decision to proceed with HCT.
If a patient doesn’t have a compatible donor for HCT, gene therapy could be a potential alternative, particularly since CGD often originates from single genetic defects. Gene therapy involves using retroviral vectors to deliver healthy genes into stem and progenitor cells. This approach reestablishes normal activity in cells deficient in NADPH oxidase, an enzyme associated with CGD. To date, gene therapy has seen limited success, and has sometimes led to severe complications due to abnormalities caused by vector integration. But as gene repair technology advances, newer methods such as CRISPR/Cas9 could be used to correct defective genes in cases of CGD linked to the X chromosome. This method has been shown to restore NADPH oxidase activity in the lab.
What else can Chronic Granulomatous Disease be?
When doctors are considering if a patient has Chronic Granulomatous Disease (CGD), they also think about other medical conditions like:
- Cystic Fibrosis (CF)
- Hyperimmunoglobulin E syndrome
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency
- Glutathione synthase (GS) deficiency
- Crohn’s Disease
People with CF usually get multiple infections, but these are generally found only in the lungs with a special condition called bronchiectasis, which isn’t usual in people with CGD.
Those with hyperimmunoglobulin E syndrome usually get a specific lung infection called Aspergillus, but only when there are lung cysts. These cysts are typically not seen in CGD patients. Additionally, these patients have high levels of a protein called IgE, which isn’t seen in CGD patients.
G6PD and GS deficiencies affect a certain process in white blood cells and can increase the risk of bacterial infections. However, G6PD deficiency is associated with a type of anemia called hemolytic anemia. In contrast, GS deficiency is characterized by symptoms such as hemolytic anemia, acidic urine with increased organic compounds, acid build-up in the body, mental developmental issues, and other neurological problems which are not common in CGD.
Both G6PD and GS deficiencies can be confirmed by checking the enzyme levels in the cells. Crohn’s disease can look similar to CGD as it can affect the intestine. However, Crohn’s doesn’t cause severe infections, and the cells in the intestine don’t contain fat, which are a big part of CGD.
Finally, since the symptoms of CGD can vary greatly, it can also look like other conditions like pyloric stenosis (a condition affecting the valve at the end of the stomach), food allergies, or anemia due to lack of iron.
What to expect with Chronic Granulomatous Disease
The future outlook for Chronic Granulomatous Disease (CGD) is increasingly positive due to advancements in treatment. By maintaining good skin hygiene and using antifungals and antibiotics, patients can prevent infections.
Those with the autosomal recessive form of CGD generally have a better outlook compared to those with the X-linked version of the disease. With proper lifelong preventive treatments, CGD patients can live for 40 years on average.
However, severe bacterial or fungal infections can be life-threatening. Aspergillus, a common type of fungus, often causes respiratory infections and is the leading cause of death in CGD patients.
Improved preventive measures, along with advances in Hematopoietic Stem Cell Transplant (HSCT) and other treatments that modulate the immune system, will likely continue to reduce the death and illness rates associated with CGD.