Chronic granulomatous disease

Definitions & Key takeaways

Chronic granulomatous disease (CGD) is a genetic condition, in which neutrophils and macrophages cannot create superoxide radicals to kill engulfed germs. There is a mutation in NADPH oxidase genes. People with CGD have problems fighting infections because they don't have enough neutrophils to fight bacteria and other germs.

People with CGD often get recurrent and severe infections, especially in their lungs, ears, and sinuses. They may also develop skin abscesses or sores that don't heal properly. People with CGD struggle to fight off infections caused by catalase-positive bacteria, such as S. aureus, Serratia, Klebsiella, Aspergillus, and Burkholderia.

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Introduction0:00–0:29

With chronic granulomatous disease, granulomatous refers to the development of small nodules called granulomas. Granulomas are collections of immune cells, especially phagocytes, which cluster together when they can't kill invading pathogens, like bacteria or fungi.
So chronic granulomatous disease is an immunodeficiency where phagocytes are unable to kill pathogens, and instead they form granulomas throughout the body.

Physiology0:29–2:02

Normally, when a pathogen invades the body, phagocytes, like neutrophils and macrophages, are the first on the scene. When a phagocyte detects a pathogen, it stretches itself out as if it had two little arms.
These arms wrap around the pathogen and seal themselves back up, forming a vesicle inside the phagocyte called a phagosome.
Because the phagosome is lined by what was previously part of the phagocyte's surface membrane, whatever structures were previously surface-bound, like this protein complex called NADPH oxidase, end up inside the phagosome.
The phagocyte also has other organelles, like lysosomes, which are full of digestive enzymes that can destroy a pathogen.
When a lysosome fuses with a phagosome, it forms a phagolysosome, and lysosomal enzymes start to destroy the pathogen. The lysosomal enzymes also activate NADPH oxidase, which came from the phagosome, causing NADPH to undergo oxidation, and lose two of its electrons.
Nearby oxygen molecules can grab these electrons to form superoxide ions, or O2- ions. Another enzyme, superoxide dismutase, can take these ions and combine them with hydrogen ions to form hydrogen peroxide, or H2O2.
This process of producing superoxide ions and hydrogen peroxide is called the respiratory burst. These ions and molecules destroy pathogens by breaking down their cell membranes and damaging their proteins.

Pathophysiology2:02–4:21

In chronic granulomatous disease, there’s a mutation in the genes that code for NADPH oxidase, so the enzyme is less functional.
One common mutation is an autosomal recessive mutation, which is where both copies of a chromosome need to possess the same mutation for the disease to occur.
Another common mutation is an X-linked recessive mutation, and since men only have one X chromosome, they get the disease, whereas because women have two X chromosomes, they only get the disease if both of their X chromosomes are affected which is much less likely.
Regardless of the underlying mutation, when there’s a decrease in the amount of functioning NADPH oxidase, it's bad news for phagocytes.
Now, when they swallow up a pathogen and eventually form a phagolysosome, there are fewer superoxide ions and less hydrogen peroxide, so the respiratory burst is weaker.
This makes it difficult for individuals with chronic granulomatous disease to kill certain pathogens - specifically fungi and bacteria that have an enzyme called catalase, and are therefore called catalase-positive pathogens.
Catalase breaks down hydrogen peroxide, into water and oxygen, before it gets a chance to damage the pathogen. Normally, there's enough hydrogen peroxide being produced that catalase positive pathogens can only break down some of it, but in the case of chronic granulomatous disease, there's already so little hydrogen peroxide, that catalase-positive pathogens can break down all of it.
That's why the most pathogens that cause disease in chronic granulomatous disease are catalase positive -- Burkholderia, Nocardia, Pasteurella, Listeria, Aspergillus, Candida, E.
coli, Staphylococcus, and Serratia, which you can remember with the handy mnemonic “CATs have BeeN PLACESS". Pathogens which don't get killed linger within phagocytes and occasionally break free, and over time that attracts even more phagocytes that engulf the pathogens, as well as other immune cells like T lymphocytes.
Over time, the immune cells gather up to stop the pathogen from spreading, forming little clusters called granulomas with phagocytes with living pathogens within them at the center.

Symptoms4:21–4:46

In terms of symptoms, chronic granulomatous disease can cause recurrent pneumonia, or recurrent skin and soft tissue infections like cellulitis and abscesses, as well as bone and joint infections like osteomyelitis and septic arthritis.
It's also common to see bacteremia or fungemia, which is when the pathogens that don't get killed find their way into the bloodstream and kind of just hang out.

Diagnosis4:46–5:36

The most common way to diagnose chronic granulomatous disease is by testing neutrophil function in a blood sample. A very old test is the nitroblue tetrazolium test, which is when a colorless dye called nitroblue tetrazolium is added to the blood sample.
If the respiratory burst is working properly, superoxide ions are produced and react with the dye, changing its color to a deep blue.
A newer test is the dihydrorhodamine 123 test, which is where dihydrorhodamine 123 is added to the blood sample. If levels of NADPH oxidase are normal, then the enzyme will oxidize dihydrorhodamine 123, causing it to fluoresce, or shine.
How much or how little it shines is directly proportional to the amount of functional NADPH oxidase. Treatment of chronic granulomatous disease involves prophylactic antibiotics and antifungals that target the most common infectious organisms, typically that includes trimethoprim-sulfamethoxazole and itraconazole.

Treatment5:36–6:08

In addition, interferon gamma can be given because it stimulates the production of superoxide in phagocytes. In some cases, a hematopoietic stem cell transplantation can be done to wipe out the non-functional immune cells and to introduce new immune cells that don’t have the genetic mutation.
All right, as a quick recap… chronic granulomatous disease is an autosomal recessive or X-linked recessive disease that causes a mutation in NADPH oxidase.

Review6:08–6:54

As a result, phagocytes are unable to create superoxide, hydrogen peroxide, or hypochlorite ions, and so they struggle to kill catalase-positive pathogens which can be remembered with the mnemonic “CATs have BeeN PLACESS": Burkholderia, Nocardia, Pasteurella, Listeria, Aspergillus, Candida, E.
coli, Staphylococcus, and Serratia.