Primary Immunodeficiency

Question 1

primary immunodeficiency

Answer 1

conditions characterized by intrinsic defects within the immune system (caused by inherited or de novo genetic defects)

Question 2

3 effects of immunoglobins/antibodies

Answer 2

1. neutralize
2. opsonize
3. ADCC: antibody coats infected cell so other immune cells can bind and kill

Question 3

name 4 warning signs of immunodeficiency (there are many)

Answer 3

• 4+ new ear infections within a year
• 2+ serious sinus infections within a year
• 2+ pneumonias within a year
• 2+ months on antibiotics with little effect
• 2+ deep-seated infections (septicemia)
• failure of infect to gain weight or grow normally
• persistent thrush in mouth or fungal infection on skin
• need for IV antibiotics to clear infection

Question 4

T/F: most primary immunodeficiency diseases are due to de novo mutations

Answer 4

TRUE: most patients have no family history

Question 5

3 important things for diagnosing primary immunodeficiency

Answer 5

1. index of suspicion - frequency/severity/duration of infections, unusual infectious agents, poor response to antibiotics (“this patient is different than those I normally see”)
2. initial evaluation
3. specific defects

Question 6

overall patterns of infections involving B cells and T cells, respectively, in patients with primary immunodeficiency

Answer 6

B cells - recurrent bacterial sino-pulmonary infections, parasitic GI infections

T cells - fungal and viral infections causing mucocutaneous candidiasis, persistent respiratory infections, chronic diarrhea, failure to thrive

Question 7

overall patterns of infections involving phagocytes, complement, and NK cells, respectively, in patients with primary immunodeficiency

Answer 7

phagocytes - recurrent skin infections of visceral abscesses, poor wound healing, periodontal disease

complement - bacterial infections (esp. Neisseria - remember MAC is important here), sepsis

NK cells - severe or recurrent herpesvirus infections

Question 8

SCID is a ____ deficiency (primary immunodeficiency)

Answer 8

T cell defect

SCID: virtually complete lack of T and B cell function, block in T cell development (associated with abnormal B and NK development), low immunoglobins

presents initially with life-threatening infection from first months of life

*remember SCID is often caused by gamma chain defect (X-SCID)

Question 9

DiGeorge syndrome is a primary immunodeficiency disorder caused by ____ defect

Answer 9

T cell defect

DiGeorge: deletion of part of chromosome 22, impacts end organs derived from 3rd/4th pharyngeal arches (cardiac, face, parathyroid, thymus)

thymus atresia —> low/absent T cells

Question 10

ataxia telangiectasia is a primary immunodeficiency disorder caused by _____ defect

Answer 10

T cell defect

ataxia telangiectasia: AR inheritance, mutated ATM gene (remember this is involved in dsB repair) —> neurological defect and telangiectasia (red spider veins)

increased susceptibility to infections (ATM also involved in B/T development dsB)

Question 11

WIskott-Aldrich syndrome

Answer 11

primary immunodeficiency due to T cell defect (also affects B cells)

X-linked recessive (XLR) defect in WASP gene —> thrombocytopenia, bruising/bleeding, eczema, infections, autoimmunity (poor prognosis)

Question 12

selective IgA deficiency

Answer 12

most common primary immunodeficiency

IgA is decreased/absent —> recurrent infections, allergies, autoimmunity

usually asymptotic though

but some cases progress to Common Variable Immunodeficiency

Question 13

describe Agammaglobulinemia

Answer 13

primary immunodeficiency due to B cell defect - Bruton tyrosine kinase defect —> maturation arrest of pre-B cells

X-linked or AR

reduction/absence of all Ig types, nearly absent B cells in peripheral blood

recurrent sinopulmonary or skin infections during infancy

can be treated with IV/subcutaneous Ig (good prognosis)

Question 14

Common Variable Immunodeficiency

Answer 14

primary immunodeficiency, B cell defect —> serum Ig levels are low despite normal number of B cells

good prognosis with IV/subcutaneous Ig replacement

appears later in life

Question 15

chronic granulomatous disease

Answer 15

primary immunodeficiency due to phagocyte defect

X-linked or AR
mutations lead to defective superoxidase production

recurrent. life-threatening bacterial infections (S. aureus) and fungi, tissue granuloma formation

Question 16

Leukocyte Adhesion Deficiency type 1

Answer 16

primary immunodeficiency due to phagocyte defect

rare AR, mutations in ITGb2, which makes beta-integrin on leukocyte membranes

serious bacterial and fungal infections from brith (skin, mucosal), gingivitis, delayed wound healing, leukocytes is (leukocytes cannot migrate into tissues)

Question 17

initial evaluation of T cell primary immunodeficiencies involves (5 things)

Answer 17

1. history - age of onset, birth history, sites/types of infections, vaccines, family
2. CBC with differential, platelet count
3. T cell subsets
4. HIV serology
5. delayed hypersensitivity (Type IV) skin test - PPD, anergy

Question 18

initial evaluation of B cell primary immunodeficiencies involves (7 things)

Answer 18

1. history
2. CBC with differential, platelet count
3. quantitative immunoglobins - IgG, IgA, IgM
4. IgE level
5. IgG subclasses
6. pre/post vaccination tigers
7. T cell subsets

Question 19

initial evaluation of phagocytic primary immunodeficiency involves (3 things)

Answer 19

1. CBC with differential, platelet count
2. peripheral smear
3. neutrophil oxidative burst test (tests if neutrophils can kill)

Question 20

You’re on pediatric rotation when you see a 2mo F with a life-threatening oral candidiasis infection and severe diarrhea. Workup reveals very low levels of all Ig types.

What are you thinking?

Answer 20

primary immunodeficiency

this is presenting as SCID - virtual complete lack of T and B cell function

SCID is a T cell defect immunodeficiency (diarrhea is a clue), which is associated with abnormal B and NK cell development

Question 21

During pediatric rounds, a fellow resident presents a patient with tetralogy of Fallot (cardiac defect), cleft palate, hypocalcemia (parathyroid issue), and thymic atresia. Genetic analysis reveals a deletion in chromosome 22.

The attending asks you what disease you think it is, and how this will impact their immune system. You will say:

Answer 21

DiGeorge Syndrome - primary immunodeficiency due to T cell defect (due to thymic atresia)

low/absent T cells

some patients present with recurrent infections, but in general there is wide phenotypic variability and prognosis

Question 22

You’re taking a pediatric patient’s history and collect the following information:
- progressive loss of motor function was noted ~2 years of age
- at age 7, red, spidery veins became apparent
- pt has apparent susceptibility to infections, with a history of recurrent respiratory infections
- FHx reveals a grandparent was hypersensitive to ionizing radiation and developed lymphoid cancer

what are you thinking?

Answer 22

ataxia telangiectasia - mutation in ATM gene (DSB repair and T/B cell development), autosomal recessive

primary immunodeficiency due to T cell defect

• neurological defects (early in childhood)
• telangiectasia (red spider veins, later in childhood)
• susceptible to infections, usually respiratory (poor prognosis if this)

Question 23

A patient presents with thrombocytopenia and eczema. He tells you he bruises easily, and PMH indicates several upper respiratory infections.

What are you thinking?

Answer 23

this is presenting as Wiskott-Aldrich syndrome -

primary immunodeficiency caused by T cell defect

progressive T cell defect, but also affects B cells

poor prognosis if autoimmunity and lymphoid malignancy

Question 24

in this primary immunodeficiency disease, there is a B cell defect, though affected individuals are usually asymptomatic

if symptoms occur, patients may have recurrent infections, allergies, or autoimmune diseases

inheritance is unknown

What could this be?

Answer 24

Selective IgA deficiency - B cells express IgA but cannot develop into mature IgA-secreting plasma cells (still immature, expressing IgM and IgD)

note that some cases progress to Common Variable Immunodeficiency

Question 25

An infant on your pediatric floor has had recurrent sinopulmonary infections. Workup included a blood smear that showed an absence of all types of immunoglobins or B cells. Genetic analysis revealed a defect in Bruton tyrosine kinase. The infant was treated with IV immunoglobins and has been well since.

What is going on?

Answer 25

Agammaglobulinemia - primary immunodeficiency due to B cell defect (X linked or AR)

Bruton tyrosine kinase defect leads to maturation arrest of pre-B cells

absent B cells/ Ig
recurrent sinopulmonary or skin infections during infancy

IV or subcutaneous treatment with Ig gives good prognosis most of the time

Question 26

Pt is a 28yo M presenting with a sinopulmonary infection for the 2nd time this year. PMHx and FHx is unremarkable. Workup shows low levels of all Ig types.

What are you thinking and how will you treat?

Answer 26

Common Variable Immunodeficiency - primary B cell immunodeficiency

no pattern of inheritance, recurrent infections may not develop until 2nd/3rd decade of life or later

normal number of B cells but do not mature normally

—> treat with IV or subcutaneous Ig replacement, usually good prognosis

Question 27

You’re doing rounds on the pediatric floor when you encounter a 4yo patient that is presenting with their 3rd S.aureus infection, all of which have been life-threatening. On PE, you note a large granuloma in their neck.

What are you thinking, and what mutation is causing this issue?

Answer 27

Chronic Granulomatous Disease - primary phagocytic immunodeficiency, X-linked or AR

mutated phagocyte oxidase complex (could be 4 different genes) —> defective superoxide production

onset variable, but usually childhood

recurrent life-threatening bacterial infections (S. aureus most common) and fungi and granuloma formation

can be fair prognosis if just pulmonary, cutaneous, lymphatic, hepatic infections (most common)

Question 28

At 1 week old, patient developed a serious fungal infection on their skin and in their mouth. The infection caused open blisters on their skin which were noted to heal poorly. Further, delayed separation of the umbilical cord was noted. It was determined the infant has leukocytosis.

What is going on?

Answer 28

Leukocyte Adhesion Deficiency Type 1 - primary phagocytic immunodeficiency

rare AR, mutation in ITGb2 —> reduced beta-2 integrins on leukocyte membranes —> leukocytes cannot migrate into tissues

serious bacterial and fungal infection from birth on skin and mucosal membranes

gingivitis, delayed wound healing, delayed umbilical cord separation

Question 29

given the following manifestations, identity as either B cell, T cell, phagocytic, complement, or NK cell primary immunodeficiency:

recurrent sinopulmonary infections, chronic or recurrent gastroenteritis, septic arthritis

Answer 29

B cell primary immunodeficiency

Question 30

given the following manifestations, identity as either B cell, T cell, phagocytic, complement, or NK cell primary immunodeficiency:

opportunistic infections (fungal, viral, mycobacterial), chronic diarrhea

Answer 30

T cell primary immunodeficiency

Question 31

given the following manifestations, identity as either B cell, T cell, phagocytic, complement, or NK cell primary immunodeficiency:

skin abscesses, poor wound healing, periodontal disease

Answer 31

phagocytic primary immunodeficiency

Question 32

given the following manifestations, identity as either B cell, T cell, phagocytic, complement, or NK cell primary immunodeficiency:

recurrent Neisseria infections, pyrogenic bacterial infections, autoimmune disease

Answer 32

primary immunodeficiency due to defective complement system

Question 33

given the following manifestations, identity as either B cell, T cell, phagocytic, complement, or NK cell primary immunodeficiency:

severe or recurrent herpesvirus infections

Answer 33

NK cell primary immunodeficiency

Question 34

Which of these is a T-cell primary immunodeficiency?
a. Common Variable Immunodeficiency
b. X-linked lympho-proliferative syndrome
c. SCID
d. leukocyte adhesion deficiency

Answer 34

c. SCID: T cell primary immunodeficiency

T cell immunodeficiencies present with: opportunistic infections, chronic diarrhea

important tests: HIV serology (just in case!), delayed hypersensitivity skin test (like PPD), T cell subsets

Question 35

which of these is a B-cell mediated primary immunodeficiency?
a. SCID
b. purine nucleoside phosphorylase deficiency
c. common variable immunodeficiency
d. DiGeorge syndrome

Answer 35

c. common variable immunodeficiency: B cell immunodeficiency

B cell immunodeficiencies present as: recurrent sino-pulmonary infections, chronic or recurrent gastroenteritis, septic arthritis

these are T cell immunodeficiencies:
a. SCID
b. purine nucleoside phosphorylase deficiency
d. DiGeorge syndrome