Primary Immunodeficiency Flashcards
primary immunodeficiency
conditions characterized by intrinsic defects within the immune system (caused by inherited or de novo genetic defects)
3 effects of immunoglobins/antibodies
- neutralize
- opsonize
- ADCC: antibody coats infected cell so other immune cells can bind and kill
name 4 warning signs of immunodeficiency (there are many)
- 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
T/F: most primary immunodeficiency diseases are due to de novo mutations
TRUE: most patients have no family history
3 important things for diagnosing primary immunodeficiency
- index of suspicion - frequency/severity/duration of infections, unusual infectious agents, poor response to antibiotics (“this patient is different than those I normally see”)
- initial evaluation
- specific defects
overall patterns of infections involving B cells and T cells, respectively, in patients with primary immunodeficiency
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
overall patterns of infections involving phagocytes, complement, and NK cells, respectively, in patients with primary immunodeficiency
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
SCID is a ____ deficiency (primary immunodeficiency)
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)
DiGeorge syndrome is a primary immunodeficiency disorder caused by ____ defect
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
ataxia telangiectasia is a primary immunodeficiency disorder caused by _____ defect
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)
WIskott-Aldrich syndrome
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)
selective IgA deficiency
most common primary immunodeficiency
IgA is decreased/absent —> recurrent infections, allergies, autoimmunity
usually asymptotic though
but some cases progress to Common Variable Immunodeficiency
describe Agammaglobulinemia
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)
Common Variable Immunodeficiency
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
chronic granulomatous disease
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
Leukocyte Adhesion Deficiency type 1
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)
initial evaluation of T cell primary immunodeficiencies involves (5 things)
- history - age of onset, birth history, sites/types of infections, vaccines, family
- CBC with differential, platelet count
- T cell subsets
- HIV serology
- delayed hypersensitivity (Type IV) skin test - PPD, anergy
initial evaluation of B cell primary immunodeficiencies involves (7 things)
- history
- CBC with differential, platelet count
- quantitative immunoglobins - IgG, IgA, IgM
- IgE level
- IgG subclasses
- pre/post vaccination tigers
- T cell subsets
initial evaluation of phagocytic primary immunodeficiency involves (3 things)
- CBC with differential, platelet count
- peripheral smear
- neutrophil oxidative burst test (tests if neutrophils can kill)
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?
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
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:
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
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?
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)
A patient presents with thrombocytopenia and eczema. He tells you he bruises easily, and PMH indicates several upper respiratory infections.
What are you thinking?
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
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?
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
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?
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
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?
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
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?
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)
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?
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
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
B cell primary immunodeficiency
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
T cell primary immunodeficiency
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
phagocytic primary immunodeficiency
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
primary immunodeficiency due to defective complement system
given the following manifestations, identity as either B cell, T cell, phagocytic, complement, or NK cell primary immunodeficiency:
severe or recurrent herpesvirus infections
NK cell primary immunodeficiency
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
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
which of these is a B-cell mediated primary immunodeficiency?
a. SCID
b. purine nucleoside phosphorylase deficiency
c. common variable immunodeficiency
d. DiGeorge syndrome
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
