Tom Fleischer on "The Diagnostic Work-Up of Primary Immunodeficiency Including the Role of Genomics that can Translate into new Therapeutic Options".
Frequency of primary immunodeficiency depends on how you define PID - eg, is low IgA without symptoms really PID?
PID work-up starts with good history with attention to family history going beyond siblings and parents, freq of infxns/organisms/treatments. Exam can be helpful esp cutaneous findings, dysmorphic features, lymphoid tissue (tonsils, spleen).
General approach to evaluate immune function: https://twitter.com/MatthewBowdish/status/955988176425795584
Age-related difference are significant and must be considered for each evaluation (essential to use age-specific ranges).
Total immunoglobulin level is the net of production, consumption, and loss.
Primary immunodeficiency disorders (PIDD) (click to enlarge the image).
Ability to mount an immune response to vaccines is probably more important than IgG subclass levels. Use unconjugated 23 serotype pneumococcal vaccine after age 24 months. The conjugated 13 serotype pneumococcal vaccine does not facilitate eval of normal immune response to polysaccharide antigens but it's a critical vaccine clinically.
Level of protection in pneumococcal polysaccharide vaccine:
- Invasive disease (hematogenous): 0.15 ug/mL
- Colonization & infection (eg pneumonia): 1.3 ug/mL
In flow cytometry, looking at immune cell identification, the absolute number is as important as the percentage.
Hypo/agammaglobulinemia with low or absent B cells:
-Infancy/early childhood: XLA, AR agammaglobulinemia
-Agammaglobulinemia with thymoma (Good syndrome - adults)
Assessment of T cells - recurrent opportunistic infections often associated with failure to thrive. Must rule out secondary defects such as HIV.
Methods for T cell proliferation: https://twitter.com/MatthewBowdish/status/955992305231585280
Lymphocyte proliferation is good at detecting normal or SCID, but not great at mild immunodeficiencies. If a normal prolif is 100K and SICD is 1000, what does a level of 50K mean? A little immunodeficiency? No one can answer that.
You have to do multiple neutrophil counts because one test will not rule out phagocytic defects (eg cyclic neutropenia).
Evaluation of phagocytic cells:
1. PMN counts (multiple)
2. Adhesion molecule
3. Oxidative Burst (NBT, DHR, flow assay)
-chemotaxis & phagocytosis not likely helpful
Recurrent viral infections typically involving herpes virus family suggest NK cell defects.
NK cell evaluation:
1. NK cell quantitation: CD56, CD16, CD57
2. NK cell functional testing: cytotoxicity assays using susceptible target cells (K562), CD107a expression by NK cells using flow cytometry.
Assessment of complement: https://twitter.com/MatthewBowdish/status/955995491837263872
Newborn screening using TREC assay: https://twitter.com/MatthewBowdish/status/955997397657698304
PIDs to date involve defects in more than 300 genes, most result from loss of function but at least six have different disorder with either loss or gain of function.
10-12% of our genome is dedicated to the immune system, which translates into ~2150 genes, most of which (1500 genes) are in the innate immune system.
Sanger method of direct sequencing is the traditional method for direct sequencing. It's simple, but high cost and can only choose so many genes based on history/labs. Next Generation Sequencing offers high throughput with lower costs. Three types of Next Generation Sequencing: https://twitter.com/MatthewBowdish/status/955999241385656320
Why evaluate for genomic changes in PIDD?
-opportunity to screen at risk pts
-identify potential therapeutic targets
-increases understanding specific disorders and mechanisms
-define potential contributions of environmental factors (epigenetics) on human disease
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