Chronic granulomatous disease (CGD) - Causes, Pathogenesis, Symptoms, Diagnosis, Treatment

Chronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency disease. It affects the phagocytic cells mainly neutrophils and macrophages. These cells are normally used to kill the invading bacteria and fungi.

It is caused due to mutation in genes which are related with NADPH oxidase enzyme complex. Due to defect in this enzyme complex, the phagocytes cannot form reactive oxygen species (ROS). So, the organisms which are engulfed by the phagocytes are not killed properly.

In this disease, the patient suffers from repeated and severe infections. The common sites of infection are lungs, liver, lymph nodes, skin and bones. These infections may be serious and sometimes life threatening.

CGD also causes abnormal inflammatory response in the body. Due to this, clusters of immune cells are formed and these are called granulomas. The granulomas may block different organs, especially in gastrointestinal tract and genitourinary tract.

The disease mostly affects males. This is because the common form of CGD is inherited as X-linked recessive pattern. Autosomal recessive forms are also present. The symptoms usually appear in the first few years of life.

History and Discovery of CGD

Chronic granulomatous disease (CGD) was first recognized in the mid 1950s. It was described by Charles Janeway Senior and Robert Good as a separate clinical disease.
They observed this disease in young boys who had repeated bacterial infections. These boys also showed systemic tissue granulomatosis. At that time most of the affected children did not live beyond the first decade of life.

Due to its severe nature, the disease was first called fatal granulomatous disease of childhood. This name was given because the disease mainly affected children and caused severe recurrent infections.
In 1967, Robert Baehner and David Nathan developed the Nitroblue Tetrazolium (NBT) reduction test. This test was used to detect the killing defect in neutrophils. It became an important diagnostic test for CGD.
The NBT test is based on the ability of stimulated neutrophils to reduce nitroblue tetrazolium. In CGD patients, this reduction is absent or decreased. So, the test helped to identify defective neutrophil function.

Later, Bernard Babior explained the main mechanism of the disease. He showed that activated neutrophils transfer electrons from NADPH to molecular oxygen. This produces superoxide anion during respiratory burst.
In CGD, this respiratory burst is defective. Due to this, phagocytes cannot produce enough reactive oxygen species. So, bacteria and fungi are not killed properly inside the phagocytic cells.
During the 1970s, treatment of CGD started to improve. The use of antibiotic prophylaxis helped to reduce severe infections. Due to this, survival of patients also became better.

In the modern time, the life expectancy of CGD patients has improved much more. This improvement is due to azole antifungal drugs such as itraconazole, interferon-gamma therapy, and hematopoietic stem cell transplantation (HSCT).
At present, gene therapy is also being studied for CGD. It is considered as a future treatment method, because the disease is caused due to genetic defect in NADPH oxidase complex.

Genetic Basis of CGD

Chronic Granulomatous Disease (CGD) is caused by pathogenic mutation in the genes which form or help in formation of phagocyte NADPH oxidase complex. This enzyme complex is required for respiratory burst in phagocytic cells. Due to genetic defect, superoxide and reactive oxygen species are not formed properly.

The following are the important genes involved in CGD–

CYBB gene
CYBB gene is present on the X chromosome. Mutation in this gene causes X-linked recessive CGD and mainly affects male patients. It is the most common genetic defect of CGD, responsible for about 65-70% cases. This form is generally severe because gp91phox subunit of NADPH oxidase is affected.
NCF1 gene
NCF1 gene mutation is inherited as autosomal recessive form. It is the second most common cause of CGD, responsible for about 20-25% cases. This gene has a complex genetic basis because the normal gene is surrounded by almost similar pseudogenes. Most defect occurs due to two nucleotide deletion by recombination or crossing over with these pseudogenes. It affects p47phox subunit.
CYBA gene
CYBA gene mutation is also autosomal recessive type. It causes instability of p22phox protein subunit. This defect is responsible for less than 5-7% of CGD cases. Due to this mutation, normal membrane part of oxidase complex is not maintained.

NCF2 gene
NCF2 gene follows autosomal recessive inheritance pattern. Mutation in this gene causes loss of p67phox subunit. This produces classical and severe form of CGD in less than 5-7% cases. In this condition the cytosolic component cannot work properly during activation of oxidase complex.
NCF4 gene
NCF4 gene is a rare autosomal recessive cause of CGD. It affects p40phox subunit and represents less than 1% of cases. This form may show atypical clinical features. Infection may show incomplete penetrance, but inflammatory bowel disease may be severe and early onset.
CYBC1 gene
CYBC1 gene mutation is a novel and rare autosomal recessive cause of CGD. This gene encodes EROS protein. It does not form direct subunit of oxidase complex, but it acts as endoplasmic reticulum resident chaperone protein. It is required for stable assembly of NADPH oxidase complex.

Defect in Phagocyte Function in CGD

In Chronic Granulomatous Disease (CGD), the main defect is present in the killing function of phagocytic cells. The phagocytes can engulf the microorganism, but they cannot kill them properly. This defect is mainly seen in neutrophils, monocytes, macrophages and eosinophils.

The following are the important defects in phagocyte function in CGD–

Defective NADPH oxidase complex
In CGD, there is genetic defect in the multi-protein NADPH oxidase complex. This enzyme complex normally becomes active in phagocytes after ingestion of microorganism. Due to mutation, the enzyme complex become inactive or poorly functional.

Absence of normal respiratory burst
The defective NADPH oxidase cannot transfer electrons to molecular oxygen. So the normal respiratory burst does not occur. Due to this, superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂) and other reactive oxidants are not produced in proper amount.
Failure of reactive oxygen species formation
The phagocytes fail to produce sufficient reactive oxygen species (ROS). These reactive molecules are normally required inside the phagosome for killing of engulfed organisms. In CGD, this toxic oxygen dependent killing system is defective.
Impaired killing of bacteria and fungi
The phagocytes of CGD patients can ingest bacteria and fungi, but intracellular killing is poor. The phagosome cannot make a strongly toxic environment. As a result, many catalase positive bacteria and fungi survive inside the phagocyte.

Decreased NET formation
Neutrophil extracellular traps (NETs) are reduced in CGD. This happens mainly due to decreased formation of hydrogen peroxide. Normally NETs trap and kill extracellular pathogens, but in CGD this process is not formed properly.
Impaired efferocytosis
Macrophages in CGD have poor ability to remove dead and apoptotic inflammatory cells. This clean-up process is called efferocytosis. When this process is reduced, dead cells and inflammatory materials remain for longer time.
Persistent inflammation
Due to poor clearance of intracellular material and inflammatory signals, the immune reaction remains active for longer period. The phagocytes cannot degrade inflammatory chemoattractants properly. This causes exaggerated and continuous inflammation.

Granuloma formation
The persistent inflammatory response leads to formation of granulomas. These are masses of immune cells formed around un-cleared organisms or inflammatory debris. Granulomas may obstruct organs like intestine, urinary tract and other internal passages.

Pathogenesis of Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD) is a genetic disease in which phagocytic cells cannot kill the organisms after engulfment. The main defect is in NADPH oxidase complex. Due to this defect, oxygen dependent killing does not take place properly.

The following are the pathogenesis of CGD–

Genetic mutation
The disease starts due to inherited mutation in the gene of NADPH oxidase complex. The mutation may affect one of the subunit or the protein required for its assembly. So the phagocytic cell becomes defective in its killing activity.

Defective NADPH oxidase
In this condition, NADPH oxidase enzyme complex is absent or inactive. It is seen mainly in neutrophils and macrophages. These cells can take up the organism but cannot produce proper oxidants.
Failure of respiratory burst
Normally after phagocytosis, there is a sudden use of oxygen. This is called respiratory burst. In CGD, this burst is absent because electron transfer to oxygen does not occur.
No formation of ROS
Due to defective enzyme, reactive oxygen species (ROS) are not formed. Superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂) and hypochlorous acid (HOCl) are decreased. These are required for killing of microbes inside phagosome.

Survival of microbes
The phagosome cannot become toxic for the organisms. So the engulfed bacteria and fungi remain alive. Especially catalase positive bacteria and fungi survive and multiply in the cell.
Defective NET formation
Neutrophil extracellular traps (NETs) are also less formed. This is because hydrogen peroxide is not produced properly. So extracellular bacteria and fungi are not trapped and killed properly.
Poor removal of dead cells
Macrophages cannot remove apoptotic cells and inflammatory debris properly. This process is called efferocytosis. Due to this, dead cells and inflammatory materials remain in the tissue.

Chronic inflammation
The retained debris and chemical signals continuously stimulate the immune system. So inflammation becomes prolonged and excessive. NLRP3 inflammasome may also become activated.
Granuloma formation
Many immune cells like lymphocytes and histiocytes come to the site. They collect together and form granuloma. These granulomas may block gastrointestinal tract and genitourinary tract.

Role of NADPH Oxidase in CGD

NADPH oxidase is present in phagocytic cells. It is required for killing of bacteria and fungi after phagocytosis. In CGD, this enzyme system is defective.

The following are the role of NADPH oxidase in CGD–

Respiratory burst
NADPH oxidase causes respiratory burst in phagocytes. In this process oxygen is rapidly used. Electron is transferred from NADPH to oxygen.
Superoxide formation
Due to this electron transfer, superoxide anion (O₂⁻) is formed. It is the first oxygen radical formed in phagocyte. Other toxic oxygen substances are formed from it.

ROS formation
Superoxide forms hydrogen peroxide (H₂O₂), hydroxyl radical and hypochlorous acid (HOCl). These are called reactive oxygen species (ROS). These are needed for microbial killing.
Killing inside phagosome
After engulfment, bacteria and fungi remain inside phagosome. ROS and granule enzymes act together there. This makes the phagosome toxic and the organism is killed.
Control of inflammation
ROS also control inflammatory reaction. It affects pathways like NF-kB and NLRP3 inflammasome. So inflammation does not continue unnecessarily.

Efferocytosis
NADPH oxidase helps in removal of dead inflammatory cells. This process is called efferocytosis. By this process dead cells and debris are removed from the tissue.
Defect in CGD
In Chronic Granulomatous Disease (CGD), mutation occurs in genes of NADPH oxidase complex or its assembly proteins. So the enzyme becomes absent or inactive. Respiratory burst is not formed properly.
Failure of killing
As ROS are not formed, phagocytes cannot kill the engulfed organisms. They can take the organism inside but killing does not occur properly. Mainly catalase positive bacteria and fungi survive.

Defective NETs
Due to low hydrogen peroxide, neutrophil extracellular traps (NETs) are also decreased. These traps normally catch extracellular organisms. In CGD, this function is weak.
Granuloma
Because organisms and debris are not cleared, inflammation remains for long time. Immune cells collect at the site. This collection forms granuloma and it may obstruct organs.

Clinical Features and Symptoms of CGD

Chronic Granulomatous Disease (CGD) mainly shows recurrent infection and chronic inflammation. The symptoms usually starts in early childhood. Some patients may show mild feature, but many cases are severe.

The following are the clinical features and symptoms of CGD–

General symptoms
Patient may have repeated fever, weakness and malaise. Severe weight loss may be present. In children, growth restriction and failure to thrive is commonly seen.
Recurrent infections
The main feature of CGD is repeated bacterial and fungal infection. Infection may become severe and life threatening. It commonly affects lungs, lymph nodes, liver, bones and skin.

Lung infection
Pneumonia is common in CGD. It may occur again and again. Fungal pneumonia may also occur and become serious.
Lymph node infection
Lymphadenitis may be present. The lymph nodes become enlarged and painful. Sometimes pus formation may also occur.
Liver and skin abscess
Liver abscess is an important feature of CGD. Skin abscess and cellulitis are also common. These infections may not heal easily.

Bone infection
Osteomyelitis may occur in some patients. It is infection of bone. It causes pain, swelling and difficulty in movement.
Gastrointestinal symptoms
Inflammation and granuloma may affect intestine. Patient may develop inflammatory bowel disease (IBD) or colitis. Frequent diarrhoea, bloody diarrhoea, abdominal pain and fistula may occur.
Obstruction in gastrointestinal tract
Granuloma may cause blockage in digestive tract. It may cause delayed gastric emptying. Dysphagia and vomiting may also be present.

Genitourinary symptoms
Granuloma may form in urinary system. It may produce bladder pseudotumor and ureteric obstruction. Recurrent urinary tract infection may also occur.
Abnormal wound healing
Wound healing is not proper in CGD. Excessive granulation tissue may form. Surgical wound or drainage wound may gape or break open, this is called wound dehiscence.
Skin manifestations
Different skin lesions may occur. Papulopustular dermatitis, photosensitivity and lupus like lesions may be seen. Skin infection and abscess also occur repeatedly.

Liver complications
Patient may develop enlarged liver and spleen, called hepatosplenomegaly. Nodular regenerative hyperplasia and portal hypertension may also occur. Liver abscess is also an important complication.
Oral manifestations
Mouth involvement may be present. Gingivitis, mouth ulcers and stomatitis may occur. Gingival hypertrophy may also be seen.
Eye manifestations
Inflammatory eye disease may occur in CGD. Keratitis, uveitis and chorioretinal lesions may be present. These may affect vision also.

Autoimmune features
Due to continuous immune activation, autoimmune diseases may occur. Immune thrombocytopenia (ITP) and juvenile idiopathic arthritis may be seen. Some patients may also develop severe hyperinflammatory condition called hemophagocytic lymphohistiocytosis (HLH).
McLeod syndrome
Some male patients with X-linked CGD may have McLeod neuroacanthocytosis syndrome. It occurs due to contiguous gene deletion. It may cause neurological, muscular and blood related symptoms.

Common Microorganisms Associated with CGD Infections

In Chronic Granulomatous Disease (CGD), infection is commonly caused by catalase positive bacteria and fungi. These organisms survive inside phagocytes because ROS are not formed properly. So infection becomes repeated and severe.

The following are the common microorganisms associated with CGD infection-

Bacterial infections
- a. Staphylococcus aureus
  Staphylococcus aureus is one of the most common bacteria causing infection in CGD. It commonly affects skin, lymph nodes and liver. It may cause abscess formation.
- b. Burkholderia species
  Burkholderia cepacia complex is important in CGD. It may cause severe pneumonia. It can also cause sepsis and may become life threatening.
- c. Serratia species
  Serratia marcescens is another important organism. It commonly causes osteomyelitis and soft tissue infection. Bone infection may become recurrent.
- d. Nocardia species
  Nocardia species causes pneumonia in CGD. It may also cause osteomyelitis and brain abscess. This infection may be serious.
- e. Salmonella species
  Salmonella species may cause infection in CGD patients. It is frequently noted in some patient groups. It may cause systemic infection also.
- f. Klebsiella species and Escherichia coli
  Klebsiella species and Escherichia coli are catalase positive Enterobacteriaceae. These organisms may infect CGD patients. They may cause different bacterial infections.
- g. Mycobacteria
  Mycobacterium tuberculosis may cause severe infection in CGD. BCG vaccine strain may also cause disease. It may be localized or disseminated.
- h. Rare specific bacteria
  Some rare bacteria are strongly associated with CGD. These include Granulibacter bethesdensis, Chromobacterium violaceum and Francisella philomiragia. These organisms are uncommon but highly suggestive for CGD.
Fungal infections
- a. Aspergillus species
  Aspergillus species is the most common fungal infection in CGD. It is also an important cause of death. Aspergillus fumigatus is most common. Aspergillus nidulans causes very severe and difficult to treat infection in CGD.
- b. Candida species
  Candida species are common yeasts. Candida albicans may cause soft tissue infection, sepsis and liver abscess. It may occur when immunity is weak.
- c. Paecilomyces species
  Paecilomyces species may cause pneumonia and osteomyelitis in CGD patients. It is a rare fungal cause but important.
- d. Other molds and fungi
  Other fungi may also cause infection. These include Phellinus species, Trichosporon species, Rhizopus species and Geosmitha argillacea. These are less common but may cause severe disease.

Granuloma Formation in Chronic Granulomatous Disease

Granuloma formation is an important feature of Chronic Granulomatous Disease (CGD). It is formed because inflammatory signals are not controlled properly. The immune cells remain activated and collect at the affected site.

The following are the granuloma formation in CGD–

Mechanism of formation
In CGD, defective immune cells cannot shut off inflammatory and chemotactic signals. These chemical signals are not degraded properly. So activated lymphocytes and histiocytes are recruited again and again. These cells clump together and form large mass of immune cells called granuloma.
Sterile and non-caseating granuloma
Many granulomas in CGD are sterile. It means they are not always due to active localized infection. They are mainly produced by exaggerated inflammation. These granulomas are usually non-caseating granulomas.

Microscopic features
Under microscope, granuloma shows sharply defined aggregates of histiocytes. Around it lymphocytic inflammation is present. Tissue eosinophilia may also be seen. Brown pigmented epithelioid cells may be present in some lesions.
Gastrointestinal obstruction
Granuloma commonly affect hollow organs. In gastrointestinal tract, it may cause obstruction from mouth to anus. Colon is the most common site. Infiltration may start at pylorus and it may look like pyloric stenosis. It can cause delayed gastric emptying, stomach narrowing, dysphagia, vomiting and malabsorption.
Genitourinary complications
Urinary system is another important site of granulomatous inflammation. Bladder granuloma, ureteral obstruction, inflammatory pseudotumor and eosinophilic cystitis may occur. Severe obstruction may later cause kidney problem like post-renal azotemia.

Other organs affected
Granulomatous masses may also block biliary tract and bronchus. They may develop in lungs, liver, bones and skin. In the eye, it may present as chorioretinal lesions with pigment clumping. These eye lesions are usually asymptomatic.
Response to treatment
Granulomas in CGD are often due to sterile hyperinflammation. They are not always related to active infection. So they usually respond rapidly to oral corticosteroids and other immunomodulators.

Diagnosis of Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD) is diagnosed by clinical features and special blood tests. The main aim is to check whether phagocytes can produce reactive oxygen species (ROS) or not. Genetic test is then used to confirm the exact defect.

The following are the diagnosis of CGD–

Clinical evaluation
First the history of patient is taken. There may be repeated bacterial and fungal infection from childhood. Family history is also important, especially in male child with severe infection. Physical examination may show abscess, pneumonia, lymphadenitis or granuloma.
Dihydrorhodamine test
Dihydrorhodamine (DHR) 123 test is the preferred test for CGD. It is done by flow cytometry. In this test, stimulated neutrophils are checked for production of oxidants like hydrogen peroxide. In CGD, the fluorescence is decreased or absent.
Use of DHR test
DHR test is very sensitive. It can detect different severity of CGD. It can also identify female carriers of X-linked CGD. So it is used as the most important initial diagnostic test.

Nitroblue tetrazolium test
Nitroblue tetrazolium (NBT) test is the older test for CGD. In this test, stimulated neutrophils should reduce yellow dye into dark blue or black precipitate. In normal person, colour change occurs. In CGD patient, colour change does not occur because oxidants are not formed.
Other neutrophil function tests
Other tests may also be used to check respiratory burst. Cytochrome C reduction assay measures superoxide production by colour change. Luminol-enhanced chemiluminescence assay also measures oxidant production from immune cells. These tests are used in some laboratories.
Genetic testing
After abnormal neutrophil function test, genetic testing is done. It confirms the exact molecular defect. Mutation may be found in CYBB, NCF1, CYBA, NCF2, NCF4 or CYBC1 gene.

Methods of genetic test
Different methods are used for genetic confirmation. Multigene panel and whole-exome sequencing may be used. For complex gene like NCF1, special method like droplet digital PCR (ddPCR) may be required.
Prenatal diagnosis
If the disease causing mutation is already known in family, prenatal testing can be done during pregnancy. It helps to know whether the fetus is affected or not. This is useful for families with previous child having CGD.

Treatment and Management of CGD

Chronic Granulomatous Disease (CGD) treatment is done to prevent infection, treat active infection and control inflammation. Some treatment are lifelong. Curative treatment is also present in selected patients.

The following are the treatment and management of CGD–

Antibacterial prophylaxis
Daily antibiotic is given to prevent bacterial infection. Trimethoprim-sulfamethoxazole (TMP-SMX) is most commonly used. It is usually given lifelong.
Antifungal prophylaxis
Daily antifungal drug is used to prevent fungal infection. Itraconazole is commonly used. Posaconazole and voriconazole may also be used in some patients.
Interferon-gamma therapy
Interferon-gamma (IFN-γ) injection may be given regularly. It helps to improve immune response. It can reduce frequency and severity of serious infections.

Treatment of acute infection
When infection occurs, treatment should be started early. Long course of targeted antibiotics or antifungal drugs are needed. These may be given by oral or intravenous route according to severity.
Surgical drainage
Deep abscess may not improve by drug only. Liver abscess, lymph node abscess or deep tissue abscess may need drainage. Surgical excision or percutaneous drainage may be done.
Granulocyte transfusion
In very severe infection, donor granulocytes may be given. It is used when infection is life threatening and not responding to usual treatment. It gives temporary support only.

Corticosteroids for inflammation
Corticosteroids like prednisone are used to control excessive inflammation. They are given with antimicrobials when required. They help in granuloma blockage and CGD-associated colitis.
Stem cell transplantation
Allogeneic hematopoietic stem cell transplantation (HSCT) is the established curative treatment for CGD. It is also called bone marrow transplantation. It can stop disease progression and may improve old inflammatory complications also.
Gene therapy
Gene therapy is a newer and promising treatment. It is useful for patients who do not have suitable stem cell donor. In this method, patient stem cells are taken, genetic defect is corrected and then cells are given back to the patient. Lentiviral vectors or newer editing methods may be used.

Avoid decayed organic matter
Patients should avoid compost, mulch, decayed leaves, gardening and hayrides. These materials contain fungal spores. Inhalation may cause severe lung reaction called mulch pneumonitis.
Avoid unsafe water
Swimming should be done only in chlorinated pool. Fresh water, salt water and brackish water should be avoided. Lakes and ponds may contain atypical bacteria.
Avoid marijuana smoking
Marijuana smoking should be strictly avoided. It may contain viable Aspergillus spores. This can cause severe fungal infection in CGD.

Avoid live bacterial vaccines
Live bacterial vaccines should be avoided. BCG vaccine and live Salmonella typhi vaccine may cause disease in CGD patients. So these are not given.

Complications and Prognosis of CGD

Chronic Granulomatous Disease (CGD) is a disease with repeated infection and long continued inflammation. The complications are mainly due to poor killing of bacteria and fungi. Some complications are also due to granuloma and abnormal immune reaction.

A. Complications of CGD

Severe recurrent infections
Repeated infection is the main complication of CGD. The infection may be bacterial or fungal. It commonly causes pneumonia, liver abscess, skin abscess, infected lymph nodes and osteomyelitis. These infections may become severe and life threatening.

Granuloma and obstruction
In CGD, inflammatory cells collect and form granuloma. These are mass like collections of immune cells. They may block hollow organs. It may cause gastric outlet obstruction, delayed gastric emptying, urinary tract obstruction and ureteral blockage.
Gastrointestinal disease
Many patients develop bowel inflammation. It may look like inflammatory bowel disease (IBD) or Crohn’s like colitis. Patient may have bloody diarrhoea, abdominal pain and malabsorption. Perianal fistula may also occur.
Liver and spleen problems
Liver abscess is common in CGD. Liver and spleen may become enlarged, called hepatosplenomegaly. Nodular regenerative hyperplasia may occur. Non-cirrhotic portal hypertension may also develop.

Autoimmune disorders
Autoimmune disease may occur because immune regulation is abnormal. Immune thrombocytopenic purpura (ITP) may occur. Juvenile idiopathic arthritis (JIA), discoid lupus erythematosus and IgA nephropathy may also be seen.
Hyperinflammatory condition
Some patients develop excessive inflammatory reaction. Infection may trigger hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome. Inhalation of mulch or decayed organic matter may also cause severe lung inflammation.
Growth restriction
Children with CGD may have poor growth. It is due to repeated infection, chronic inflammation and intestinal disease. Failure to thrive may be seen in early childhood.

Late problems after transplant
After HSCT, some late problems may occur. Graft-versus-host disease (GVHD) may occur. Sensory problem, skeletal growth problem, anxiety and learning difficulty may also be seen. These may be related with chemotherapy and long hospital stay.

B. Prognosis of CGD

Improved survival
Previously CGD was often fatal in childhood. Now survival is much better. This is due to regular antibiotic, antifungal prophylaxis and better treatment. Many patients survive for 40 years or more.
Residual enzyme activity
Prognosis depends on residual superoxide production. If some NADPH oxidase activity is present, disease is usually less severe. NCF1 mutation often gives milder disease. Severe CYBB mutation usually gives poor course.

Main cause of death
Invasive fungal infection is the main cause of death. Aspergillus species is very important. It may cause severe pneumonia and spread infection.
Effect of HSCT
Allogeneic hematopoietic stem cell transplantation (HSCT) is the curative treatment of CGD. If successful, it stops further disease progression. It can also improve colitis and other inflammatory complications. Survival after successful HSCT is very good in children.

Clinical Significance of Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD) is clinically important because it shows failure of phagocytic killing. It also shows the importance of respiratory burst in innate immunity. In this disease, infection and inflammation both are important.

The following are the clinical significance of CGD–

Model of innate immune failure
CGD is an important example of innate immune defect. It shows that phagocytes need respiratory burst for killing of microbes. When reactive oxygen species (ROS) are not formed, engulfed pathogens are not destroyed properly.
Specific pathogen susceptibility
CGD patients are more susceptible to some specific organisms. Mainly catalase positive bacteria and fungi cause infection. Common organisms are Staphylococcus aureus and Aspergillus species. Rare organisms like Granulibacter bethesdensis and Chromobacterium violaceum are highly suggestive for CGD.
Relation of ROS with immune regulation
ROS are not only used for killing of microbes. They also help in controlling immune response. In CGD, absence of ROS causes uncontrolled inflammation. This leads to granuloma, Crohn’s like colitis and delayed wound healing.

High morbidity and mortality
Previously CGD was known as fatal granulomatous disease of childhood. It is a serious and life threatening disease. Even with modern treatment, invasive fungal infection is still the main cause of death. Aspergillus infection is especially important.
Importance in diagnosis
CGD needs special tests for diagnosis. Routine blood test may not show the main defect. Dihydrorhodamine (DHR) flow cytometry test is used to measure oxidant production by neutrophils. It also helps to detect carrier state in X-linked CGD.
Importance in genetic disease study
CGD is a single gene disorder in many cases. So it is important for understanding inherited immune deficiency. Genetic testing can identify mutation in genes of NADPH oxidase complex.

Target for advanced treatment
CGD is important for curative treatment research. Allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. It is also an important disease for gene therapy studies. Lentiviral vectors and newer Prime Editing methods are studied for correcting the genetic defect.

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Chronic granulomatous disease (CGD) – Causes, Pathogenesis, Symptoms, Diagnosis, Treatment