Primary Immunodeficiencies

Question 1

List warning signs of primary immunodeficiency

Answer 1

4+ ear infections in a year
2+ sinus infections in a year
2 months of antibiotics without effect
2+ pneumonias per year
Failure to thrive
Recurrent deep abscesses
Persistent thrush or fungal infection
Need for IV antibiotics to clear infections
Two or more deep infections incl septicemia
Family history of PI

Question 2

List signs of B cell deficiency

Answer 2

Recurrent sinopulmonary infections or sepsis
Infections with encapsulated organisms
Chronic enteroviral meningoencephalitis

Question 3

What lab tests are used to work up B cell deficiencies

Answer 3

Ig levels
Specific antibody titers
Flow cytometry

Question 4

What disease states present with B cell deficiencies?

Answer 4

X linked agammaglobulinemia
Common variable immunodeficiency
Selective IgA deficiency

Question 5

List signs of T cell deficiency

Answer 5

Opportunistic infections
Recurrent and severe common infections
Failure to thrive

Question 6

List lab tests used to work up T cell deficiencies

Answer 6

CBC with differential
Flow cytometry
T cell functional study
Ig levels

Question 7

List disease states associated with T cell deficiency

Answer 7

DiGeorge syndrome
Wiskott Aldrich syndrome
SCID (B and T cell)
CID

Question 8

List signs of phagocyte deficiency

Answer 8

Soft tissue abscess or lymphadenitis
Infection with catalase + organisms (staph, serratia, aspergillus)
Poor wound healing

Question 9

List lab test used to work up phagocyte deficiency

Answer 9

CBC with differential
Neutorphil oxidative burst assay
Flow cytometry for adhesion molecules

Question 10

List disease states associated with phagocyte deficiency

Answer 10

Chronic granulomatous disease

Leukocyte adhesion defecit

Question 11

List signs of complement deficiency

Answer 11

Recurrent disseminated Neisseria infection
Autoimmune disease
Bacterial sepsis

Question 12

List lab tests used to work up complement deficiency

Answer 12

CH50 measures entire complement cascade

AH50

Question 13

List disease states associated with complement deficiency

Answer 13

Classical complement deficiency

Alternative complement defect

Question 14

List presenting signs of innate immune defects

Answer 14

Septicemia

Poor inflammatory response

Question 15

List lab tests used to work up innate immune defects

Answer 15

TLR signaling

Question 16

List disease states associated with innate immune defects

Answer 16

IRAK 4 mutation
NEMO mutation
MyD88 mutation

Question 17

The majority of primary immune deficiencies are due to deficiency in ______

Answer 17

antibodies

#2: combined cellular and antibody
#3: phagocytic
#4: cellular
#5: complement

Question 18

Describe the rationale for SCID screening on the newborn screening panel

Answer 18

• many genotypes, many mutations
• diagnosis often not apparent on exam
• treatable but life threatening
• early treatment associated with better outcomes
• cost effective

Question 19

T cell recombination in the thymus creates ______ as a byproduct. They are stable and can be detected by PCR in newly formed T cells but are diluted out as T cells undergo successive division

Answer 19

TRECs- TCRa rearrangement excision circles

Question 20

Newborn screening for SCID involves quantitative PCR to determine the number of ______ present and is confirmed with ______

Answer 20

TRECs

Flow cytometry

Question 21

What findings will be present on flow cytometry of a child with SCID?

Answer 21

Low absolute lymphocytes
Low CD3
Low CD19
Normal NK cells

Question 22

How is SCID treated?

Answer 22

immune reconstitution: bone marrow transplant, gene therapy, PEG-ADA, thymic transplant

Question 23

What is the classic triad of DiGeorge syndrome?

Answer 23

Conotruncal cardiac anomaly
Hypoplastic thymus
Hypocalcemia

Question 24

Describe the pathophysiology of DiGeorge syndrome

Answer 24

Deletions in chromosomes 22 (or 10)

teratogens that presumably inhibit neural crest cell migration at critical times during development result in chromosomal defects. Examples: accutane, EtOH, maternal diabetes.

Question 25

How can DiGeorge syndrome be diagnosed?

Answer 25

FISH

Question 26

How can DiGeorge syndrome be treated?

Answer 26

Immunologic monitoring Guidance re: live vaccines Thymic transplantation if complete syndrome

Question 27

_______ is the most common humoral immune deficiency but is poorly understood at the molecular level.

Answer 27

Common variable immunodeficiency

Question 28

What is the main defect in CVID?

Answer 28

Primarily a defect in B cell differentiation or function | Also often involves autoimmunity

Question 29

What age is most commonly affected by CVID?

Answer 29

Bimodal age of onset- first and third decades of life

Question 30

Lis three diagnostic criteria for CVID

Answer 30

Male or female with marked decrease in IgG, IgM, IgA PLUS 1. Onset greater than 2 years of age 2 .Absence of isohemagglutinins or poor response to vaccines 3. Defined causes of hypogammaglobulinemia have been excluded

Question 31

There is increased incidence of _____, _____, and ___ in CVID

Answer 31

lymphoid malignancy, autoimmune disease, atopy

Question 32

List some autoimmune manifestations of CVID

Answer 32

``` Hematologic: autoimmune cytopenias GI: pernicious anemia,celiac, IBD Rheumatologic: SLE, RA, JRA, vasculitis Endocrine: Hashimoto’s, Type 1 DM Dermatologic: vitiligo, alopecia Neurologic: Guillain-Barre ```

Question 33

What treatments are used for CVID?

Answer 33

Gammaglobuline therapy Aggressive antibiotics for bacterial infections Immunosuppression ofr autoimmunity BMT????

Question 34

Wiskott Aldrich Syndrome shows ________ inheritance and typically presents with recurrent infections, thrombocytopenia, and eczema

Answer 34

X linked

Question 35

What is the normal role of the Wiskott Aldrich protein

Answer 35

actin cytoskeleton modulation

Question 36

Describe lab findings in WAS

Answer 36

Low platelets with low volume Lymphopenia Increased IgA, IgE and normal- low IgM and IgG

Question 37

List treatments of WAS

Answer 37

- possible prophylactic antibiotics against PCP - acyclovir to prevent HSV - gammaglobulin replacement therapy - curative options: HSCT, gene therapy trials underway

Question 38

_________ is a primary immune deficiency characterized by severe immune dysregulation after EBV infection.

Answer 38

X linked lymphoproliferative disorder, XLP

Question 39

Describe the clinical phenotype of XLP

Answer 39

fatal mononucleosis, hemophagocytic lymphohistiocytosis, lymphoma, aplastic anemia

Question 40

What is the genetic defect in XLP?

Answer 40

Genetic mutation in SH2D1A gene which encodes intracellular signaling protein, SLAM associated protein. SAP is necessary for NK cell development, CD8 response to EBV

Question 41

How is XLP treated?

Answer 41

Bone marrow transplant | B cell depletion early in EBV infection course

Question 42

Chronic granulomatous disease shows _____ inheritance and involves disruption of NADPH oxidase complex formation

Answer 42

X linked

Question 43

What are the clinical manifestations of chronic granulomatous disease?

Answer 43

Recurrent abscess, pneumonia, osteomyelitis, gingivitis, poor wound healing, colitis, GI obstruction. Susceptibility to catalase positive organisms

Question 44

How is chronic granulomatous disease treated

Answer 44

``` Antibacterial and antifungal prophylaxis Interferon gamma prophylaxis Steroid therapy for dysregulated inflammatory responses Bone marrow transplant Gene therapy ```

Question 45

Summarize the genetics of the diseases presented in lecture

Answer 45

X linked: WAS, XLP, CGD SDID: various, can be X linked, AR, mitochondrial DiGeorge: chromosomal deletion CVID: