Infection associated with chronic granulomatous disease (CGD)

Published 24.10.21

Question:

1 years-old boy presented with growth retardation, gastric outlet obstruction, recurrent Staphylococcus aureus skin and soft tissue infection. He also had a couple of episodes of pneumonia caused by Staph aureus and Serratia marcescens.

A diagnosis of chronic granulomatous disease was made.

Which prophylaxis would be appropriate for him?

1. Cotrimoxazole and Itraconazole

2. Doxycycline

3. Cotrimoxazole

4. Voriconazole

5. Doxycycline and fluconazole

For answer see below

CGD is a rare inherited immunodeficiency disorder where the NADPH oxidase in the phagocytic cells is absent or malfunctioning. Most of the CGDs are inherited as X linked, while the rest are autosomal recessive.

Phagocytes, like neutrophils and monocytes, in the absence of NADPH oxidase, cannot kill the ingested pathogens due to the lack of oxidative burst. As a result, this patient suffers from severe, recurrent bacterial and fungal infections.

Chronic infection and inflammation lead to granuloma formation, which may cause obstructive symptoms, especially in the gastrointestinal and urinary systems. CGD most commonly manifests in childhood, but some cases manifest for the first time in adulthood.

Phagocytic cells like neutrophils and monocytes from a phagosome after ingesting the pathogen.

Inside the phagocytes, NADPH oxidase helps to for superoxide from molecular oxygen. Another enzyme, superoxide dismutase, converts the superoxide to hydrogen peroxide, which is converted to hypochlorous acid by the myeloperoxidase enzyme.

This whole process, called oxidative burst, leads to the activation of protease enzymes inside the phagosome. Protease and hypochlorous acid play an essential part in killing the pathogens inside the phagosome.

In CGD, NADPH oxidase is either absent or malfunctioning. As a result, phagocytes are unable to produce reactive oxygen species to kill the ingested pathogen.

It has been seen that the CGD patient is most affected by catalase-positive pathogens. Why?

In CGD, although phagocytes cannot produce superoxide or hydrogen peroxide, pathogens themselves produce hydrogen peroxide due to their metabolic activity.

Catalase positive pathogens produce catalase to convert hydrogen peroxide to water. This prevents the hypochlorous acid medicated killing of the pathogen.

Catalase negative organisms are unable to do this and, as a result, get destroyed. However, recent research showed Catalase production is probably not as important as it was thought before.

The five commonest organisms are –

1. Staphylococcus aureus,

2. Burkholderia cepacia complex,

3. Serratia marcescens,

4. Nocardia species,

5. Aspergillus species.

In endemic areas – Salmonella and T B should also be considered. Infection caused by Bacillus Calmette-Guérin or BCG should raise the suspicion of CGD.

Other less common pathogens are Granulobacter bethesdensis, Chromobacterium violaceum, Neisseria, Klebsiella, Actinomycetes, Francisella philomiragia etc.

• Pneumonia – is the commonest type of infection in this patient group.

• Abscess – may affect various organs, including skin and soft tissue.

• Bone and joint infection in the form of septic arthritis and osteomyelitis.

• Bacteraemia/fungaemia.

• Suppurative adenitis.

• Other skin and soft tissue infections – furuncle, cellulitis etc.

Other than infection, we may also find

• The granulomatous disease affects multiple organ systems – like gastrointestinal, genitourinary, pulmonary, eye etc. This is mainly due to chronic infection and inflammatory processes. The patient may present with oesophageal stricture or gastric outlet obstruction.

• Growth retardation in children.

• McLeod syndrome, which could be associated with X linked CGD.

The diagnosis is usually made by a neutrophil function test, such as

• the dihydrorhodamine 1 2 3 oxidation test or

• the nitroblue tetrazolium reduction test.

The result should be confirmed by genetic testing.

The principles of management include

• Lifelong antibiotic and antifungal prophylaxis – usually cotrimoxazole and itraconazole

• Prompt recognition and treatment of infection

• Immunomodulatory treatment with interferon-gamma

• Avoidance of B C G vaccine

• Cautious use of steroids or other anti-inflammatory drugs to reduce inflammation