5 - Primary Immune Deficiencies (PIDs) Flashcards
What are Primary Immune Deficiencies? What about secondary immunodeficiencies?
Primary - Intrinsic defects in the immune system, usually but not always inherited.
Secondary - due to extrinsic fators that depress the immune system (HIV-1, immunosuppressive drugs)
What should you suspect PID?
- Too many infections that won’t go away (>2 pneumonias, intractable sinusitis)
- Weird infections (pneumocystic jerovecii) or infections in weird places (liver/lung)
- Early onset autoimmunity
Give examples of secondary immunodeficiencies?
- Infections - HIV, measles, mononucleosis, severe sepsis, miliary TB, leprosy
- Malnutrition
- Malignangies - lymphoma, leukemia, myeloma
- Metabolic - diabetes, liver disease
- Loss of lymphocytes/antibodies - nephrotic syndrome, protein-losing enteropathy, burns
- Immunosuppressants
- Collagen vascular disease
How do you determine the lab evaluation of PIDs needed?
- Narrow the possible types of PIDs
- Know your screening tests for types of PIDs
- Individual tests of immune function measures: number or quantity (are there enough PMNs?), function (do the PMNs work?)
What CD antigens are associated with all T cells? What about naive T cells? Memory T cells?
All T cells: CD3+
Naive T cells: CD3+ and CD45RA (A for nAive)
Memory T cells: CD3+ and CD45RO (O for memOry)
What CD antigens are associated with helper T cells and cytotoxic t cells? B cells? NK cells?
Helper T cells: CD3+ and CD4+
Cytotoxic T cells: CD3+ and CD8+
B cells: CD19 or CD20
NK cells: CD3- and CD56+
What are common manifestations of neurotrophil defects? What are examples of PMN defects?
- Onset in infancy/childhood
- Severe bacterial infections
- Abscesses (skin, internal organs-liver)
- Poor wound healing
Examples:
- Chronic granulomatous disease (CGD)
- Congenital/cyclic neutropenia
- Leukocyte adhesion deficiency
What common pathogens are seen with neutrophil defects?
Catalase + organisms
Staphylococcus
Aspergillus, nocardia, burkholderia
How would you workup a neutrophil defect?
-
CBC with differential, note absolute numbers of WBC including absolute neutrophil count (ANC)
- Test ability of PMNs to gen. oxidative burst via dihydrorhodamine test (CHR) or the older nitroblue tetrazolium (NBT) test.
- Secondary: chemotaxis
When are complement defects present? What are the two types? What type is most common?
Present at any age - “classical” pathway most common defect
- Early (C2,C4) defects: autoimmune disease most common presentation; sinopulmonary infections, sepsis, increased susceptibility to S. pneumoniae and H influenzae
- Late (C5-C9) defects: increased susceptibility to neisserial infections
What is the workup for a complement defect?
CH50 functional assay for all classical components of complement.
In complement deficiencies, CH50 is usually zero.
If CH50 is low, individual complement testing is needed. If >1, complement protein is lopw/absent, suspet complement consumption (may be lupus).
What is the most common type of PIDs? Give examples and when you would expect to see them? How does this commonly present?
B-cell/antibody deficiencies
- Agammaglobulinemias: usually present in first year or two of life
- CVID: any age
- XLA
Recurrent sinopulmonary bacterial infections by encapsulated organisms (H flu, S pneomo, mucoplasma), chronic GI infections, failure to thrive.
What is the initial workup for a B-cell/antibody defect?
Initial:
- Quantitative Immunoglobulins (IgG/A/M/E)
- Vaccine titers (Dip, tet, pneumococcus): if low, reimmunize and measures ~4wks
What are manifestations of T cell or combined T/B cell defects? What is an example?
Recurrent, severe infections: viruses, fungi, bacteria, opportunistic pathogens (jiroveci, mycobacteria)
Poor growth, failure to thrive
Combined T/B deficiency: SCID (onset first year after maternal Abs wane)
What’s the workup for T cell/combined T/B cell defects?
- CBC with differential: low absolute lymphocyte count (ALC) can be a clue
- Lymphocyte subsets via flow cytometry gives numbers of T/B/NK cells, memory and naive T cells.
- T cell proliferation: T cell prolif response to mitogens
A 3 month old male comes in with respiratory distress, nasal flaring, retractions, poor aeration, and imaging with bilateral pneumonia/ARDs. His brother died at age 4mo previously. A bronchoscopy reveals p. jiroveci. What primary immune deficiency is this and what is the underlying mechanism?
SCID: severe combiend immunodeficiency. Most commonly X-linked.
Caused by mutation in common gamma chain (Yc) of the IL-2 receptor (IL2RG-19%). Yc is shared with other IL receptors (4, 7, 15, 21).
Causes lack of T cells and NK cells; B cells present but non-functional
What are the clinical manifestations of SCID?
Onset in infancy: P jirovecii, otitis media, thrus, intractable diarrhea, failure to thrive.
100% mortality without BM transplant
How would you screen and confirm SCID? What is reduced in all forms of SCID?
Screen: CBC, look for lymphopenia (<3000/mm3)
Confirm: lymphocyte enumberation (T cells-naive/memory, B cells, NK cells)
*Absent/Non-functional T cells is a common feature in all types of SCID*
What is the screening test for SCID?
T cell receptor excision circles (TRECs)
- Nonreplicating circular pieces of DNA in naive T cells generated in the process of making a TCR.
TRECs and T cell # low in ALL types of SCID
What are TRECs? When do they occur and what are they a marker of?
During T cell receptor chain recombination - they are made by ~70% of a/B T cells.
Number of TRECs measures with RT-PCR is a marker for the # of normal, naive T cells.
A 3yo male presents with recurrent thrus, otitis media, and a 4 CXR documented npeumonias. Mom notes problems swalloing. He also had a VSD in infancy and is dysmorphic on PE. What is the diagnosis?
Digeorge syndrome (DGS) - 22q11.2 deldetion syndrome (22qDS)
What is Digeorge syndrome caused by?
Microdeletion in chrom 22q11.2 causing a field defect in the first to sixth pharyngeal puches - deletion of TBX1 underlies the abnormalities.
What is the clinical manifestation of Digeorge Syndrome?
CATCH22:
Cardiac defects
Abnormal faces
Thymic hypoplasia
Cleft Palate
Hypocalcemia
22nd chrom
What physical characteristics are associated with the 1st arch and 1-4th pharyngeal pouches in Digeorge syndrome?
1st arch: facial anomolies
1st pouch: tubotympanic anomolies
2nd pouch: tonsil/thyroid anomalies
3rd pouch: inferior parathyroid and thymus deficiencies
4th pouch: superior parathyroid
What are the most common clinical findings seen with Digeorge syndrome?
- Immune abnormalities
- Cardiac defects
- PAlate abnormalities
- Autoimmune disorders
What immune abnormalities are seen with Digeorge syndrome?
- T cell abnormalities: up to 50% have low T cell counts
- Antibody deficiency: 5-10% require monthly IVIg (B cells need T cells to function)
- Autoimmunity up to 30%
- Abnormalties in thymic function likely leading to autoimmunity
Who should be tested for Digeorge syndrome? What test should be done?
All infants with significant heart defects of unexplained lymphopenia
Test with:
- FISH for microdeletion: 5-15% false negative result
- Chromosome microarray/DNA duplication deletion test (preferred because almost 100% specific and sensitive)
- RT-PCR for haploinsuff in TBF1
What is X-linked agammaglobulinemia (XLA)? What are the clinical manifestations? Which bugs?
Most common form of agammaglobulimenia (80%): 1 in 100,000 live births.
Recurrent otitis, sinusitis, pneumonia. Early Dx to prevent bronchiectasis (widening of airway).
Encapsulated bacteria: S pneumo, H influ; mycoplasma; severe enteroviral infections.
What is the onset of XLA? What is the best screening test for ALL Ab deficiencies?
Onset of XLA: infancy or early childhood
IgG, IgA, IgM best screening test for all Ab deficiencies
Mutations in what results in failure in the differentiation of B cells? How are these mutations diagnosed?
Mutations in Bruton’s Tyrosine Kinase Gene (BTK); BTK is needed to turn on NFkB, which is needed for B cell differentiation. This is seen in XLA.
Most mutations that result in the absence of BTK protein and can be diagnosed via flow cytometry.
What is the age of onset of Common Variable Immunodeficiency (CVID)? What is the most common presentation? What is the most typical cause of death in those with CVID?
Onset at any age.
Respiratory trat infections most common; inflamm bowel disease, enteropathy, and pulmonary disease (bronchietasis and interstital lung disease)
Autoimmunity (cytopenias)
Cause of death: Pulmonary disease or other non-infectious complications
What is the most common pulmonary abnormality in CVID?
Bronchiectasis - widening of the bronchi
How would you diagnose CVID? What is the age of onset?
Decrease in IgG AND low IgA and/or IgM (IgA absent in >80%)
Onset >2 yo
How would you treat an Ab deficiency such as XLA or CVID?
Gammaglobulins: IgG pooled from >1000 donars treated to inactivate all known infectious agents.
Given via vein or subQ
What are characteristics of an IgA deficiency? How common is it? What shouldnt you treat this with?
Most common Ab deficiency (1:400)
Extremely low IgA, normal IgG and IgM, normal T cell function
Most people are normal w/ no phenotype, some may have increased sinopulm infections of GI infections (giardia)
DO NOT TREAT WITH IVIg
What are characteristics of specific antibody deficiency?
Recurrent sinpulmonary infections
Normal IgG, IgA, and IgM, normal T cell function
Abnormal specific antibody response to immunization –esp polysacch antigens
What lab test is needed for antibody deficiences? What will XLA and CVID show on this test? What will both show?
Serum IgG, IgA, IgM
XLA will show decrease in all isotypes
CVID will show decrease in two of the three major isotypes, including IgG
Both will show poor antibody response to vaccine
Why shouldnt you use serological assays in pts with CVID or other panhypogammaglobulinemias? What should be used instead to diagnose?
Serological assays measure Abs in gammaglobulin in pts receiving IVIg. Pts with these disorders aren’t making Abs so the test is stupid and pointless.
Diagnosis of infectious disease MUST be done by culture, PCR, or other direct methods to directly test the presence of the pathogen.
What is chronic granulomatous disease (CGD)?
In all genetic forms: functional absence of respiratory burst in PMNs and monocytes - impaired bactericidal killing
NAPH oxidase: essential for resp burst. Four subunits, and a defect in any of them can cause CGD.
What are the four subunits of NADPH oxidase and defects in which one is the most common cause of CGD?
- gp91 phox (X-linked) - 76%
- Aut recessive: p47 phox - 35%
- Aut recessive p22 and p67 - 5% each
Hepatic abcesses without obvious source in young child is _____ until proven otherwise? What are other common clinical finding associated with this disease?
Chronic granulomatous disease (CGD)
Pneumonia, adenopathy/adenitis/abcesses, sepsis, osteomyelitis, infection with catalase + bacteria
- S. aureas, serratia, salmonella, nocardia, klebsiella, burkholderia, and fungi-aspergillus, candida
How would you diagnose chronic granulomtous disease (CGD)? How would you treat it?
Dihydrorhodamine test (DHR-preferred) or Nitroblue tetrazolium (NBT-older)
Previously: TMP/SMX
Now: bone marrow transplantation is more common
How does the Dihydrothodamine (DHR) test for CHD work?
Normal neutrophils activate NADPH oxidase to make light in the presence of phorbol myristate acetate.
CGD is from a defect in NADPH oxidase, which prevents the oxidative burst > no light and no change in the flow cytometry graph.
Why might a child with chronic granulomatous disease have a mother whos Dihydrorhodamine (DHR) test looks like this picture? Why is this finding important?
The mother is a carrier of CGD; in female carriers of Xlinked disoders, inactivation of one X chrom occurs in each cell. This means 50% of her PMNs express normal NADPH oxidase and 50% express defective NADPH oxidase. This is the cause for the two peaks on DHR.
Important b/c carriers are more prone to autoimmuna disease than non-carriers
What is the age of onset, genetic risk group, and clinical presentation of Late complement deficiencies? What do late components of complement do?
Age of onset: first infection ~17 years
Genetic risk group: homozygotes
Presentation: recurrent meningococcal disease (neisseria)
Late components of complement form MAC.
Why is it that neisseria infections are more serious in those WITHOUT late complement deficiencies?
If bacteria gets to CNS, complement is highly inflammatory. Activation of complement in the CNS will kill you (if you’re healthy)
People with late complement deficiencies can’t generate that respone so they don’t get the fatal inflammation; ie their fatality rate is lower than an immune-competent person
What is the most common early complement deficiency? What is it associated with clinically?
C2 deficiency: 1:10,000-28,000 (aut recess)
Associated with collagen vascular disease and recurrent bacteremia (pneumo, H influ, enteric bacteria, strep)
What is the best screening test for ALL classical complement deficienies?
CH50
What is the initial screening test that should be done in ALL cases of primary immunodeficiences?
CBC with differential
