Chronic granulomatous disease
Overview
 
Chronic granulomatous disease (CGD) (also known as Bridges–Good syndrome, Chronic granulomatous disorder, and Quie syndrome) is a diverse group of hereditary diseases
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

 in which certain cells of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 have difficulty forming the reactive oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

 compounds (most importantly, the superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...

 radical) used to kill certain ingested pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s. This leads to the formation of granuloma
Granuloma
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...

ta in many organs. CGD affects about 1 in 200,000 people in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, with about 20 new cases diagnosed each year.

This condition was first discovered in 1950 in a series of 4 boys from Minnesota, and in 1957 was named "a fatal granulomatosus of childhood" in a publication describing their disease.
Encyclopedia
Chronic granulomatous disease (CGD) (also known as Bridges–Good syndrome, Chronic granulomatous disorder, and Quie syndrome) is a diverse group of hereditary diseases
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

 in which certain cells of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 have difficulty forming the reactive oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

 compounds (most importantly, the superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...

 radical) used to kill certain ingested pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s. This leads to the formation of granuloma
Granuloma
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...

ta in many organs. CGD affects about 1 in 200,000 people in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, with about 20 new cases diagnosed each year.

This condition was first discovered in 1950 in a series of 4 boys from Minnesota, and in 1957 was named "a fatal granulomatosus of childhood" in a publication describing their disease. The underlying cellular mechanism that causes chronic granulomatous disease was discovered in 1967, and research since that time has further elucidated the molecular mechanisms underlying the disease. In 1986, the x-linked form of CGD was the first disease for which positional cloning was used to identify the underlying genetic mutation.

Classification

Chronic granulomatous disease is the name for a genetically heterogeneous group of immunodeficiencies. The core defect is a failure of phagocytic cells to kill organisms that they have engulfed because of defects in a system of enzymes that produce free radicals and other toxic small molecules. There are several types, including chronic X-linked disease, chronic b-negative disease, X-linked cytochrome b-positive disease, x-linked variant disease, and atypical granulomatous disease.

Symptoms

Classically, patients with chronic granulomatous disease will suffer from recurrent bouts of infection due to the decreased capacity of their immune system to fight off disease-causing organisms. The recurrent infections they acquire are specific and are, in decreasing order of frequency:
  • pneumonia
    Pneumonia
    Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

  • abscess
    Abscess
    An abscess is a collection of pus that has accumulated in a cavity formed by the tissue in which the pus resides due to an infectious process or other foreign materials...

    es of the skin, tissues, and organs
  • suppurative arthritis
  • osteomyelitis
    Osteomyelitis
    Osteomyelitis simply means an infection of the bone or bone marrow...

  • bacteremia
    Bacteremia
    Bacteremia is the presence of bacteria in the blood. The blood is normally a sterile environment, so the detection of bacteria in the blood is always abnormal....

    /fungemia
    Fungemia
    -Pathogens:The most commonly known pathogen is Candida albicans, causing roughly 70% of fungemias, followed by Candida glabrata with 10%, Aspergillus with 1% and Saccharomyces as the fourth most common. However, the frequency of infection by C. glabrata, Saccharomyces boulardii, Candida tropicalis,...

  • superficial skin infections such as cellulitis
    Cellulitis
    Cellulitis is a diffuse inflammation of connective tissue with severe inflammation of dermal and subcutaneous layers of the skin. Cellulitis can be caused by normal skin flora or by exogenous bacteria, and often occurs where the skin has previously been broken: cracks in the skin, cuts, blisters,...

     or impetigo
    Impetigo
    Impetigo is a highly contagious bacterial skin infection most common among pre-school children. People who play close contact sports such as rugby, American football and wrestling are also susceptible, regardless of age. Impetigo is not as common in adults. The name derives from the Latin impetere...



Most people with CGD are diagnosed in childhood, usually before age 5. Early diagnosis is important since these people can be placed on antibiotics to ward off infections before they occur.

Atypical infections

People with CGD are sometimes infected with organisms that usually do not cause disease in people with normal immune systems. Among the most common organisms that cause disease in CGD patients are:
  • bacteria (particularly those that are catalase
    Catalase
    Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...

    -positive)
    • Staphylococcus aureus
      Staphylococcus aureus
      Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...

      .
    • Serratia marcescens
      Serratia marcescens
      Serratia marcescens is a species of Gram-negative, rod-shaped bacterium in the family Enterobacteriaceae. A human pathogen, S. marcescens is involved in nosocomial infections, particularly catheter-associated bacteremia, urinary tract infections and wound infections, and is responsible for 1.4% of...

      .
    • Salmonella
      Salmonella
      Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...

       species.
    • Klebsiella
      Klebsiella
      Klebsiella is a genus of non-motile, Gram-negative, oxidase-negative, rod-shaped bacteria with a prominent polysaccharide-based capsule. It is named after the German microbiologist Edwin Klebs...

       species.
    • Pseudomonas cepacia, a.k.a. Burkholderia cepacia.
    • Nocardia
      Nocardia
      Nocardia is a genus of weakly staining Gram-positive, catalase-positive, rod-shaped bacteria. It forms partially acid-fast beaded branching filaments . It has a total of 85 species. Some species are non-pathogenic while others are responsible for nocardiosis. Nocardia are found worldwide in soil...

      .
  • fungi
    • Aspergillus
      Aspergillus
      Aspergillus is a genus consisting of several hundred mold species found in various climates worldwide. Aspergillus was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli...

       species. Aspergillus has a propensity to cause infection in people with CGD and of the Aspergillus species, Aspergillus fumigatus
      Aspergillus fumigatus
      Aspergillus fumigatus is a fungus of the genus Aspergillus, and is one of the most common Aspergillus species to cause disease in individuals with an immunodeficiency....

       seems to be most common in CGD.
    • Candida
      Candida (genus)
      Candida is a genus of yeasts. Many species are harmless commensals or endosymbionts of animal hosts including humans, but other species, or harmless species in the wrong location, can cause disease. Candida albicans can cause infections in humans and other animals, especially in immunocompromised...

       species.

Patients with CGD can usually resist infections of catalase-negative bacteria. Catalase is an enzyme that catalyzes the breakdown of hydrogen peroxide in many organisms. In organisms that lack catalase (catalase-negative), normal metabolic functions will cause an accumulation of hydrogen peroxide which the host's immune system can use to fight off the infection. In organisms that have catalase (catalase-positive), the enzyme breaks down any hydrogen peroxide that was produced through normal metabolism. Therefore hydrogen peroxide will not accumulate, leaving the patient vulnerable to catalase-positive bacteria.

Genetics

Most cases of chronic granulomatous disease are transmitted as a mutation on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...

 and are thus called an "X-linked trait
Sex linkage
Sex linkage is the phenotypic expression of an allele related to the chromosomal sex of the individual. This mode of inheritance is in contrast to the inheritance of traits on autosomal chromosomes, where both sexes have the same probability of inheritance...

". The affected gene on the X chromosome codes for the gp91 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 p91-PHOX (p is the weight of the protein in kDa
KDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...

; the g means glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

). CGD can also be transmitted in an autosomal recessive fashion (via CYBA
Cytochrome b-245, alpha polypeptide
Cytochrome b-245 light chain is a protein that in humans is encoded by the CYBA gene involved in superoxide production and phagocytosis.-Further reading:...

 and NCF1
NCF1
Neutrophil cytosol factor 1 is a protein that in humans is encoded by the NCF1 gene.p47 is vital to the activation of NADPH oxidase. P47 becomes heavily phosphorylated-Interactions:...

) and affects other PHOX proteins. The type of mutation that causes both types of CGD are varied and may be deletions, frame-shift, nonsense, and missense.

A low level of NADPH, the cofactor required for superoxide synthesis, can lead to CGD. This has been reported in women who are homozygous for the genetic defect causing glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate dehydrogenase , a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency is...

 (G6PD), which is characterised by reduced NADPH levels.

Pathophysiology

Phagocytes (i.e., neutrophils
Neutrophil granulocyte
Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They are generally referred to as either neutrophils or polymorphonuclear neutrophils , and are subdivided into segmented neutrophils and banded neutrophils...

, monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s, and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s) require an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 to produce reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

 to destroy bacteria after they ingest the bacteria in a process called phagocytosis, a process known as the respiratory burst
Respiratory burst
Respiratory burst is the rapid release of reactive oxygen species from different types of cells....

. This enzyme is termed "phagocyte NADPH oxidase
NADPH oxidase
The NADPH oxidase is a membrane-bound enzyme complex. It can be found in the plasma membrane as well as in the membrane of phagosome.-Subunits:It is made up of six subunits...

" (PHOX). The initial step in this process involves the one-electron reduction of molecular oxygen to produce superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...

 anion, a free radical. Superoxide then undergoes a further series of reactions to produce products such as hydrogen peroxide (through the action of superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...

), hydroxyl radical and hypochlorite (bleach - through the action of myeloperoxidase
Myeloperoxidase
Myeloperoxidase is a peroxidase enzyme that in humans is encoded by the MPO gene. Myeloperoxidase is most abundantly expressed in neutrophil granulocytes . It is a lysosomal protein stored in azurophilic granules of the neutrophil...

 on hydrogen peroxide). The reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

 this enzyme produces are toxic to bacteria and help the phagocyte kill them once they are ingested. Defects in one of the four essential subunits of this enzyme can all cause CGD of varying severity, dependent on the defect. There are over 410 known possible defects in the PHOX enzyme complex that can lead to chronic granulomatous disease.

Diagnosis

The nitroblue-tetrazolium
Nitro blue tetrazolium chloride
Nitro blue tetrazolium is a chemical compound composed of two tetrazole moieties. It is used in immunology for sensitive detection of alkaline phosphatase . NBT serves as the oxidant and BCIP is the AP-substrate ....

 (NBT) test is the original and most widely-known test for chronic granulomatous disease. It is positive in CGD, meaning that it does not turn blue (a "positive" test result indicates that the disease in question is present). The higher the blue score, the better the cell is at producing reactive oxygen species. This test depends upon the direct reduction of NBT by superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...

 free radical to form an insoluble formazan. This test is simple to perform and gives rapid results, but only tells whether or not there is a problem with the PHOX enzymes, not how much they are affected. A similar test uses dihydrorhodamine (DHR) where whole blood is stained with DHR, incubated, and stimulated to produce superoxide radicals which reduce DHR to rhodamin in cells with normal function. An advanced test called the cytochrome C reduction assay tells physicians how much superoxide a patient's phagocytes can produce. Once the diagnosis of CGD is established, a genetic analysis may be used to determine exactly which mutation is the underlying cause.

Treatment

Management of chronic granulomatous disease revolves around two goals: 1) diagnose the disease early so that antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

 prophylaxis can be given to keep an infection from occurring, and 2) educate the patient about his or her condition so that prompt treatment can be given if an infection occurs.

Antibiotics

Physicians often prescribe the antibiotic trimethoprim-sulfamethoxazole to prevent bacterial infections. This drug also has the benefit of sparing the normal bacteria of the digestive tract. Fungal infection is commonly prevented with itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...

, although a newer drug of the same type called voriconazole
Voriconazole
Voriconazole is a triazole antifungal medication that is generally used to treat serious, invasive fungal infections. These are generally seen in patients who are immunocompromised, and include invasive candidiasis, invasive aspergillosis, and certain emerging fungal infections.-Invasive...

 may be more effective. The use of this drug for this purpose is still under scientific investigation.

Immunomodulation

Interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...

, in the form of interferon gamma-1b (Actimmune) is approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 for the prevention of infection in CGD. It has been shown to prevent infections in CGD patients by 70% and to reduce their severity. Although its exact mechanism is still not entirely understood, it has the ability to give CGD patients more immune function and therefore, greater ability to fight off infections. This therapy has been standard treatment for CGD for several years.

Hematopoietic stem cell transplantation (HSCT)

Hematopoietic stem cell transplantation from a matched donor is curative although not without significant risk.

Prognosis

There are currently no studies detailing the long term outcome of chronic granulomatous disease with modern treatment. Without treatment, children often die in the first decade of life. The increased severity of X-linked CGD results in a decreased survival rate of patients, as 20% of X-link patients die of CGD-related causes by the age of 10, in contrast to an approximate age of 35 in autosomal recessive patients.

Epidemiology

CGD affects about 1 in 200,000 people in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, with about 20 new cases diagnosed each year.

Chronic granulomatous disease affects all people of all races, however, there is limited information on prevalence outside of the United States. One survey in Sweden reported an incidence of 1 in 220,000 people,, while a larger review of studies in Europe suggested a larger 1 in 250,000 people.

History

This condition was first described in 1954 by Janeway, who reported five cases of the disease in children. In 1957 it was further characterized as "a fatal granulomatosus of childhood". The underlying cellular mechanism that causes chronic granulomatous disease was discovered in 1967, and research since that time has further elucidated the molecular mechanisms underlying the disease. Use of antibiotic prophylaxis, surgical abscess drainage, and vaccination lead to the term "fatal" being dropped from the name of the disease as children survived into adulthood. The oldest person to suffer from Chronic Granulomatos Disease was Mr. Jackie Ray Johnson of Fredericksburg, Virginia who died in 2002 at the age of 63.

Research

Gene therapy is currently being studied as a possible treatment for chronic granulomatous disease. CGD is well-suited for gene therapy since it is caused by a mutation in single gene which only affects one body system (the hematopoietic system). Viruses have been used to deliver a normal gp91 gene to rats with a mutation in this gene, and subsequently the phagocytes in these rats were able to produce oxygen radicals.

In 2006, two human patients with X-linked chronic granulomatous disease underwent gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...

 and blood cell precursor stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

 transplantation to their bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...

. Both patients recovered from their CGD, clearing pre-existing infections and demonstrating increased oxidase activity in their neutrophils. However, long-term complications and efficacy of this therapy are unknown.

External links

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