Innate Immune System - Case Study

A 4-year-old boy, Liam, presents to the pediatric clinic with a history of recurrent infections, including pneumonia, skin abscesses, and lymphadenitis. His parents report that these infections have required frequent hospitalizations and intravenous antibiotics. Recently, Liam developed a persistent fever, cough, and weight loss. Physical examination reveals enlarged cervical lymph nodes and hepatosplenomegaly. Blood tests show elevated inflammatory markers, anemia, and neutrophilia. A chest X-ray reveals patchy infiltrates in both lungs, and a culture from a skin lesion grows Staphylococcus aureus. Further testing confirms the diagnosis of CGD.

What is the function of the NADPH oxidase enzyme complex in the innate immune response?

Pump in oxygen into the pathogen to cause respiratory burst.

How do mutations in the NADPH oxidase genes lead to the clinical manifestations of CGD?

Prevents phagocytes from producing ROS (reactive oxygen species) causing the failure to cause respiratory burst to kill various pathogens 

Describe the types of infections commonly seen in patients with CGD and explain why these infections occur.

Pneumonia: A common lung infection that can be caused by fungi like Aspergillus

Abcesses on the Liver and Skin: a pus-filled mass in the liver/on the skin that can be  caused by a bacterial or fungal infection

Cellulitis: a bacterial infection of the skin that can cause pain, redness, swelling, and  fever

Osteomyelitis: a bone infection that can be acute or chronic. It's usually caused by bacteria, but can also be caused by fungi or other germs

These infections often occur because of the patient’s inability to fight bacterial and fungal infections. This is caused by their neutrophils not being able to produce sufficient reactive oxygen species during respiratory bursts which is crucial in killing pathogens.

What are granulomas, and why do they form in patients with CGD?

Granulomas are masses of neutrophils and other immune cells that gather at the site of infection. These form in patients with CGD because of a genetic defect that causes the patient’s immune system to not fight infection properly leading to an excess of immune cells gathering in an attempt to contain the infection.

Explain the role of phagocytes in pathogen clearance and how their function is impaired in CGD

Without the ROS, phagocytes will not be able to kill certain pathogens after engulfing them. Dead and live pathogens accumulate, which can lead to granuloma formation, which can also cause damage and blockage to tissues. Phagocytes engulf and destroy pathogen cells, the CGD impairment will cause the phagocytes to not make certain chemicals like hydrogen peroxide needed to kill pathogens

Why are patients with CGD particularly susceptible to infections with catalase-positive organisms?

Catalase positive - microbe that produces enzyme catalase 

Patients with CGD are particularly susceptible because they cannot neutralize all of the enzymes produced, therefore not being able to trigger the NADPH pathway and therefore induce respiratory bursts of pathogenic cells.

What laboratory tests can be used to diagnose CGD, and what results are characteristic of the disease

Some laboratory tests that can be conducted are neutrophil function tests (dihydrorhodamine 123 (DHR)), genetic testing, prenatal testing. 

Neutrophil function tests are the leading way for providers to diagnose CGD to see how the white blood cell is functioning. Genetic testing may also be tested to confirm genetic alterations to CGD. Prenatal testing can also be a way to test CGD if one or more of your children have CDG. 

The results of this disease are frequent infections in multiple organ systems, such as the GI tract, which can lead to diarrhea and abdominal pain

Discuss the genetic inheritance patterns of CGD and the implications for family members

CGD is an X-linked genetic disorder and is inherited when mutations occur in 1 of 5 genes. This means it can be passed down from parent to child. This makes the disease sex-linked and also makes it more common in men than in women. It can also be passed down in an autosomal recessive manner but that is much less common.