Chronic granulomatous disease (CGD) 

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Chronic granulomatous disease (CGD)

  • Chronic granulomatous disease (CGD) is an uncommon inherited primary immunological weakness that affects particular white blood cells (neutrophils, monocytes, macrophages, eosinophils).
  • The illness is characterised by a failure to resist certain bacterial and fungal infections and a propensity to develop persistent inflammation.
  • Life-threatening recurrent fungal and bacterial infections affecting the skin, lungs, and bones may occur alongside widely dispersed granulomas, which are swelling regions of inflammatory tissues.
  • Symptoms typically manifest in infancy or early childhood. Mild variants of the illness may not manifest symptoms until adolescence or maturity.
  • Chronic granulomatous disease is a hereditary illness caused by inherited abnormalities in an essential enzyme in white blood cells that produces oxidants for killing microorganisms.
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Signs & Symptoms of CGD

Patients with chronic granulomatous illness typically have recurring infections due to their impaired immune system’s ability to combat disease-causing microbes. Their recurring infections are specific and, in decreasing order of frequency, include:

  • pneumonia
  • abscesses of the skin, tissues, and organs
  • septic arthritis
  • osteomyelitis
  • bacteremia/fungemia
  • superficial skin infections such as cellulitis or impetigo

The majority of CGD cases are diagnosed in childhood, typically before age 5 [9] Important because these individuals can be given medications to prevent infections before they occur. Due to the proximity of the two genes on the same X-chromosome, a small number of CGD patients may also be affected by McLeod syndrome.

Atypical infections

People with CGD are occasionally infected with organisms that often do not cause disease in healthy individuals. Among the most prevalent pathogens affecting CGD patients are:

Bacteria (particularly those that are catalase-positive)

  • Staphylococcus aureus.
  • Serratia marcescens.
  • Listeria species.
  • E. coli.
  • Klebsiella species.
  • Pseudomonas cepacia, a.k.a. Burkholderia cepacia.
  • Nocardia.


  • Aspergillus species. Aspergillus has a propensity to cause infection in people with CGD and of the Aspergillus species, Aspergillus fumigatus seems to be most common in CGD.
  • Candida species.

Catalase-negative bacteria are typically resistant to infection in CGD patients, but catalase-positive bacteria are susceptible to infection. In several organisms, catalase catalyses the decomposition of hydrogen peroxide. In infections caused by organisms lacking catalase (catalase-negative), a host with CGD is able to “borrow” the hydrogen peroxide produced by the organism and use it to combat the illness. This “borrowing process” fails in infections caused by organisms with catalase (catalase-positive) because the enzyme catalase first degrades any hydrogen peroxide that would be borrowed from the organism. Therefore, catalase-positive bacteria are able to infect a patient with CGD because hydrogen peroxide cannot be used to produce oxygen radicals to fight infection.

Causes of CGD

  • Chronic granulomatous disease is an inheritable condition. Mutations in any one of five distinct genes can lead to phagocyte NADPH oxidase deficiency in CGD. This enzyme is used by some white blood cells to create hydrogen peroxide, which these cells require to fight specific bacteria and fungus.
  • Two genes, one inherited from the father and one inherited from the mother, determine genetic illnesses. There is a hereditary variant of CGD that mostly affects males (X-linked recessive). The remaining instances of CGD are inherited as autosomal recessive characteristics that can affect both men and women.
  • X-linked genetic illnesses are caused by a mutated gene on the X chromosome and predominantly affect males. Females who possess a faulty gene on one of their X chromosomes are referred to be “carriers” for the disease. Males get one X chromosome from their mothers, and if they receive an X chromosome with a faulty gene, they will acquire the condition.
  • Because females have two X chromosomes and only one bears the faulty gene, women who are carriers of the X-linked form of CGD do not typically exhibit symptoms of infection. However, some X-linked CGD carriers develop inflammatory skin or gastrointestinal diseases, or, less frequently, lupus or other autoimmune disorders.
  • With each pregnancy, female carriers of an X-linked ailment have a 25% chance of having a carrier daughter like themselves, a 25% risk of having a non-carrier daughter, a 25% chance of having a son affected by the disease, and a 25% chance of having an unaffected son.
  • If a man with an X-linked illness is able to procreate, he will pass on the defective gene to all of his daughters, who will become carriers. A guy cannot transmit an X-linked gene to his kids since males always transmit their Y chromosome to male progeny instead of their X chromosome.
  • An individual develops a recessive genetic condition when he or she receives two copies of a defective gene for the same trait, one from each parent. If a person receives one normal gene and one disease-causing gene, he or she will be a carrier for the disease but will not typically exhibit symptoms.
  • With each pregnancy, two carrier parents have a 25% chance of passing on the faulty gene and having an afflicted child. Each pregnancy carries a 50% chance that the child will also be a carrier. 25% of children inherit normal genes from both parents and are genetically normal for that specific trait. The risk is identical for men and women.
  • Each individual carries at least four to five single-copies of defective genes. Consanguineous parents are more likely than unrelated parents to carry the same faulty gene, which raises the probability of having offspring with a recessive genetic condition due to the presence of two copies of the same abnormal gene.

Diagnosis of CGD

When chronic granulomatous disease (CGD) is suspected, neutrophil function testing and genotyping should be performed. Due to the fact that the p47phox mutation is caused by a pseudogene conversion, it may not be detected by conventional sequencing; in these instances, an immunoblot or gene dosage determination may be required to confirm p47phox deficiency.

Infections produced by microorganisms often linked to CGD should prompt functional or genetic screening; neonatal or early postnatal screening of potentially afflicted children with a family history of CGD is crucial.

Neutrophil function tests

  • Among them are the nitroblue tetrazolium (NBT) reduction test, the dihydrorhodamine (DHR) 123 test, the direct detection of superoxide generation, the cytochrome c reduction assay, and chemiluminescence.
  • In general, the DHR test is chosen because it is simple, objective, and able to differentiate between X-linked and autosomal types of CGD; also, it can find gp91phox carriers.

The nitroblue-tetrazolium (NBT) test

  • The first and most well-known test for chronic granulomatous illness is the nitroblue-tetrazolium (NBT) test. Negative in CGD, meaning it does not change colour to blue.
  • The greater the blue score, the more efficiently the cell produces reactive oxygen species.
  • This test relies on the direct reduction of NBT to the insoluble blue chemical formazan by superoxide produced by neutrophils stimulated in vitro; NADPH oxidase catalyses the aforementioned reaction, and NADPH is oxidised in the same reaction.
  • This test is straightforward and yields quick results, however it only indicates whether or not the PHOX enzymes are impaired, not to what extent.

Dihydrorhodamine (DHR) 123 test

  • In this test, the respiratory burst of neutrophils is induced by phorbol myristate acetate (PMA), which results in the oxidation of dihydrorhodamine 123 (a nonfluorescent derivative of rhodamine) to rhodamine 123 (a green fluorescent molecule), which may be evaluated by flow cytometry.
  • This test is abnormal in chronic granulomatous disease patients (i.e., there is no shift in fluorescence with stimulation). In addition, its quantitative nature permits differentiation between oxidase-positive and oxidase-negative phagocyte subpopulations in CGD carriers and identification of gp91phox and p47phox deficits.
  • As measured by the DHR 123 test, moderate residual generation of reactive oxygen intermediates (ROI) is associated with much less severe illness and a higher probability of long-term survival than individuals with little residual ROI production.
  • In the case of complete myeloperoxidase deficiency, however, the DHR test yields abnormal results (false positive for CGD) because the DHR signal yielded by flow cytometry is dependent on intact NADPH oxidase activity and the presence of myeloperoxidase (MPO); however, the NBT test demonstrates normal production of superoxide.

Genetic testing

  • Following the diagnosis of CGD based on faulty neutrophil function tests, genetic testing should be performed.
  • As stated previously, p47phox deficiency is typically difficult to discover genetically since it is produced by pseudogene conversion and can be missed in conventional sequencing studies; in this situation, immunoblotting or flow cytometry can demonstrate the absence of protein.

Prenatal testing

  • When a family member has already been diagnosed with CGD, it is especially beneficial. The NADPH oxidase activity of neutrophils from foetal blood can be analysed to perform this test.
  • Samples of amniotic fluid or chorionic villi give families at risk with an earlier and more accurate diagnosis.

Treatment of CGD

The management of chronic granulomatous illness centres on two objectives: 1) Identify the disease early so that antibiotic prophylaxis can be administered to prevent infection; and 2) Inform the patient on his or her condition so that prompt treatment can be administered if an infection occurs.


  • Antibiotic trimethoprim-sulfamethoxazole is frequently prescribed to prevent bacterial infections.
  • Additionally, this medication spares the usual bacteria of the digestive tract. Itraconazole is routinely used to prevent fungal infections, although the newer medicine voriconazole may be more effective.
  • The utility of this medication for this purpose is still being investigated by scientists.


  • The Food and Drug Administration has licenced interferon in the form of interferon gamma-1b (Actimmune) for the prevention of infection in CGD.
  • It has been demonstrated to lessen the incidence and severity of infections in CGD patients by 70%.
  • Although its specific mechanism is not well understood, it has the potential to improve CGD patients’ immune function and, consequently, their ability to combat infections. For numerous years, this therapy has been the conventional treatment for CGD.

Hematopoietic stem cell transplantation (HSCT)

  • Hematopoietic stem cell transplantation from a matched donor is curative, but has a high degree of risk.

How CGD may impact your immediate family

CGD is a genetic disorder, which means it is inherited. It is transmitted to a kid by the mother, who is the “carrier.”

A female carrier may have CGD symptoms, such as skin sensitivity, mouth ulcers, or lupus-like symptoms, but does not have the illness. Her offspring are able to inherit and pass on CGD. A father with CGD might potentially transmit it to his daughters, who will become carriers.

What about your children’s children?

  • If your daughter is a carrier, there is a 50% chance that her sons will get CGD. 50% possibility of being unaffected.
  • Her daughters have a fifty percent chance of being CGD carriers. 50% possibility of being unaffected
  • If your son is diagnosed with CGD, none of his sons will be affected. Each of his daughters will bear children.



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