Immunodeficiency and diagnosis

Question 1

Why are some patients more susceptible to and infection than others?

Answer 1

Genetic polymorphisms of MHC molecules

Question 2

When might it be suspected that a Pt may be immunodeficient?

Answer 2

If Pt is getting recurrent infections or if the infection takes longer than usual to treat or if the infection occurs at an unusual site.

Question 3

When do most immunodeficiencies present and why?

Answer 3

An Ig deficiency has a diagnostic delay of 7 years, presenting at 30-50 years of age, as it isn’t the first differential diagnosis considered with the odd infection.

Question 4

What are the red flags for immunodeficiency?

Answer 4

An infection that doesn’t respond to normal treatment.
Recurrent infection.
Unusual site of infection.
Unusual type of infection.

Question 5

Give an example of a quantitative and qualitative diagnosis of immunodeficiency?

Answer 5

Quantitative - Inadequate production of neutrophils

Qualitative - Normal number of neutrophils but defective in function

Question 6

How does a primary ID present?

Answer 6

Attributed to inherited, recessive genes, causing EARLY presentation of overwhelming infections.
If due to polymorphisms they are usually less severe and present later in life.

Question 7

What is a secondary ID?

Answer 7

An immunodeficiency that is secondary to other diseases such as HIV and chemotherapy that cause immunosupression, disease, infection or lymphoid malignancy (myeloma, CLL). More common than primary ID.

Question 8

What are the three types of antibody deficiencies?

Answer 8

Failure to produce B cells
Failure to educate B cells
Failure to class switch

Question 9

What causes a failure to produce B cells? What condition is associated with this?

Answer 9

Absence of B cell TK prevents lymphopoiesis = X-linked agammaglobulinaemia

Question 10

What causes the failure to educate B cells?

What condition is associated with this?

Answer 10

Caused by a T cell defect, preventing production of high affinity antibodies in the germinal centres = SCID and DiGeogrge

Question 11

What causes a failure to class switch? What condition is associated with this?

Answer 11

Defective CD40 ligand expression in T cells prevents germinal centres from forming and therefore a failure to class switch. T cell help for class switching is defective = X-linked hyper-IgM syndrome

Question 12

When and how do antibody deficiencies present?

Answer 12

Does not present until 4-6 months, once the maternal IgG levels have decreased. An infant born before complete IgG placental transfer will present earlier.
Present with recurrent resp. tract infections - sinusitis, otitis media, bronchitis, pneumonia.
Usually caused by ENCAPSULATED BACTERIA e.g. strep. pneumoniae, haem. influenza B

Question 13

What is the most common form of Ig deficiency and when does it present?

Answer 13

Common Variable ID - presents in adulthood. Caused by a second mutation hit.

Question 14

How are immunoglobulin deficiencies treated?

Answer 14

Normal human Ig isolated from 5000 donors per infusion to ensure a broad, variable repertoire. Used to reduce infection rates and end organ damage.

Question 15

How are T cell deficiencies characterised?

Answer 15

Increased susceptibility to intracellular pathogens. The infections are opportunistic e.g. pneumonia or diarrhoea. Present within 1st year.
Most common infections are of the mucosa by yeast / candida.

Question 16

What condition arises due to a severe T cell deficiency?

Answer 16

SCID - Results from variety of genetic defects such as RAG genes from somatic recombination.

Question 17

What infections commonly arise secondary to T cell ID?

Answer 17

HIV and lymphoma

Question 18

How are neutrophil deficiencies characterised?

Answer 18

Result in severe invasive bacterial infections that respond poorly to antibiotics and are fatal.
Bacteria is usually gram -ve and associated with invasive fungi.

Question 19

Why might a neutrophil deficiency occur?

Answer 19

Congential neutropenia (inherited)
Cytotoxic drugs, haematological malignancy (aquired)

Question 20

Neutropenic sepsis is an emergency. How is it treated?

Answer 20

Intensive antibiotics and antifungal treatments

Question 21

What is leukocyte adhesion deficiency?

Answer 21

The inability for neutrophils to migrate across the endothelium to the site of infection due to a gene defect in the adhesion molecules. Presents with increased neutrophil levels in the blood and the absence of pus.

Question 22

What happens in chronic granulomatous disease?

Answer 22

Neutrophil function is impaired as they can’t produce superoxide radicals. Particularly susceptible to staphylococcal abscesses and fungal infections.

Question 23

What does a low C3 suggest?

Answer 23

Defect in either alternative or classical pathway, as it is a common component in both.

Question 24

What does a low C4 suggest?

Answer 24

Defect in CLASSICAL pathway

Question 25

What may be occurring in the classical or alternative pathway to cause a problem?

Answer 25

A component may be absent or the pathway may be consumed and over activated e.g. SLE

Question 26

What can be used to detect a problem in the terminal pathway?

Answer 26

Detected via the function of CH50 in the classical pathway and AP50 in the alternative pathway. The test used looks at the pt's serum ability to lyse RBC through MAC.

Question 27

What defects and infections are associated with classical pathway defects?

Answer 27

Associated with immune complex disease e.g. SLE and increased infections with encapsulated bacteria e.g. pneumococcus pneumoniae. Commonly missing one of 4 alleles making up C4 = low but not absent C4 levels. Rarely associated with C1 esterase inhibitor deficiency.

Question 28

What is C1 esterase inhibitor deficiency?

Answer 28

Reduced / absent C1 esterase inhibitor resulting in hereditary angioedema. Presents with recurrent, spontaneous angioedema attacks. May affect larynx or gut, causing abdo pain commonly mistaken for appendicitis or peritonitis.

Question 29

How is C1 esterase inhibitor deficiency diagnosed and treated?

Answer 29

Absent or reduced C1 esterase inhibitor and low C4 due to consumption. Treat with replacement or bradykinin receptor antagonist to block the angioedema pathway. May take danazol - an attenuated androgen to boost liver and upregulate C1 inhibitor production.

Question 30

What defects and infections are associated with alternative pathway deficiencies?

Answer 30

Inheritedd deficiency of C3 and control proteins (factor D). Associated with severe, recurrent bacterial infections in INFANCY. Acquired deficiency due to antibodies against C3 or C3 nephritic factor (needed to stabilise C3 convertase) resulting in excessive activation of complement.

Question 31

What complications are associated with C3 nephritic factor deficiency?

Answer 31

Can cause renal disease - glomerulonephritis and post streptococcal glomerulonephritits in children.

Question 32

How should an alternative pathway deficiency be treated?

Answer 32

With prophylactic antibiotics.

Question 33

What are the characteristics of a terminal deficiency?

Answer 33

Associated with increased risk of infection by the bacterial group Neisseria (meningitidis / gonorrhoeae).

Question 34

Which is the most severe complement cascade deficiency?

Answer 34

C3 as common component for BOTH pathways.

Question 35

What conditions increase the risk of infection and secondary ID?

Answer 35

``` Chronic diseases Arthritis CKD Asthma COPD DM >65 years Cancer AI ```

Question 36

Which medications are associated with secondary ID?

Answer 36

Immunosupressants | Steriods

Question 37

What factors of health care contribute to increased risk of secondary ID?

Answer 37

Dialysis Lines Frequent contact to health care environments Hospital infections

Question 38

Which characteristics of a Pt's phenotype contribute to risk of secondary ID?

Answer 38

Increased age Poor nutrition Sedatory lifestyle Comorbidities

Question 39

What are the four common types of immune tests used?

Answer 39

ELISA Flow cytometry Immuno fluorescence Electrophoresis