Overview of PID (Primary Immune Deficiencies) Flashcards
- Define Primary Immune Deficiencies
- Define Secondary Immunodeficiencies
- Intrinsic defects in the immune system
- Due to extrinsic factors that depress the immune response (HIV-1, immunosuppressive drugs)
When to suspect PID (4)
- Too many infections
- Weird infections
- Infections in weird places
- Early onset immunity
Causes of Secondary Immunodeficiencies
- Infections
- Malnutrition
- Malignancies
- Metabolic
- Loss of lymphocytes/antibodies
- Immunosuppresants
- Collagen vascular disease
Neutrophil defects (Common attributes)
- Onset early in infancy
- Severe bacterial infections
- Abscesses
- Gingival/peridontal diseases
- Poor wound healing
Common pathogens associated with neutrophil defects
- Catalase positive organisms
- Staphylococcus
- Aspergillus
- Nocardia
- Burkholderia
Examples of Neutrophil defects
Chronic Granulomatous Disease
Congenital/cyclic neutropenia
Leukocyte adhesion deficiency
Evaluating neutrophil defects (initial and secondary)
- Initial
- CBC with differential
- Oxidative burst testing
- Secondary
- Chemotaxis
- Anti-neutrophil Abs
Complement Defects
- Early (C2,C4):
- Late (C5-C9):
- C3 defects:
Complement Defects
- Early (C2,C4):
- sinopulmonary infections (S. pneumoniae)
- Autoimmune disease
- Late (C5-C9):
- Increased susceptibility to Neisseria
- C3 defects:
- Severe pyogenic infections
Complement Defects - Workup (Initial and Secondary)
- Initial
- CH50
- Secondary
- Individual component testing if CH50is low
- If > 1 complement protein is low/absent - suspect complement consumption
- AH50 useful for rare alt. pathway defects
What are the most common PIDs?
Antibody deficiencies (50%)
Agammaglobulinemias usually present at what age?
CVID?
First year or two of life
CVID at any age
B-cell/Antibody Defects - Workup (Initial and Secondary)
- Initial
- quantitative immunoglobulins (IgG/A/M/E)
- Vacine titers - measure ability to make specific Abs
- Secondary
- Flow cytometry for lymphocytes/B cell subsets
T-Cell or combined T cell/ B cell defects
- SCID - First year of life
- Recurrent, severe infections
- viruses; fungi; bacteria; opportunistic pathogens
- Poor growth/chronic diarrhea
- T cell: 22q11.2DS
T-Cell/Combined Defects - Workup (Initial)
- Initial
- Lymphocyte subset enumeration (flow cytometry
- Numbers of T-/B-/NK- cells, memory and naive T cells
- Immunoglobulins (quantitative, functional
- T-cell proliferation
Screening tests for PIDS
- Combined B-cell and T cell
- T-cell
- Antibody
- PMN
- Complement
Screening tests for PIDS
- Combined B-cell and T cell: Lymphocytes subsets by flow cytometry - T-cell proliferative response to mitogens
- T-cell: FISH (old), RT-PCR TBX1, DNA chromosome microarray
- Antibody: IgG, IgA and IgM - do not order IgG subclasses; antibody titers
- PMN: Dihydrorhodamine (DHR) test
- Complement: CH50
X-linked SCID Molecular basis
- Mutation in the common gamma chain of the IL-2 receptor
- The gamma chain is a shared component for other interleukin receptors (IL-4, IL-7, IL-15, IL-21)
- Lack T cells and NK cells; B cells present but not functional
SCID - Diagnostic studies
- Screening Test:
- Confirmatory Test:
- Other Screening?
- Screening Test: CBC; lymphopenia (<1.5k in most cases)
- Confirmatory Test: Lymphocyte enumeration (T-cells-naive/ memory, B cells, NK cells)
- Newborn screening for SCID in several states
Common feature in all forms of SCID
Absent/Non-Functional T Cells
Why do we screen newborns for SCID
- Universally fatal without treatment
- Incidence meets criteria for newborn screening
- Asymptomatic at birth
- Curative therapy is readily available for most
- Early treatment improves mortality
- Cost Efficient
What are TRECs?
Tcell Receptor Excision Circles
- Non replicating circular pieces of DNA in naive T cells generated in the process of making a T cell receptor
- Number of TRECs are a surrogate marker for numbers of normal, naive T cells
- T cell numbers and TRECs are low in all forms of SCID
How is TREC measured?
qRT-PCR
DiGeorge Syndrome genetic cause
Microdeletion in chromosome 22q11.2 - Field defect first to sixth pharyngeal pouches (Deletion of TBX1 underlies many of the abnormalities)
DiGeorge: CATCH22 mnemonic
- Cardiac defects
- Abnormal facies
- Thymic hypoplasia
- Cleft palate
- Hypocalcemia
- 22nd chromosome
DiGeorge Syndrome (Arch anomolies)
- 1st arch:
- 1st Pouch:
- 2nd Pouch:
- 3rd Pouch:
- 4th Pouch:
DiGeorge Syndrome (Arch anomolies)
- 1st arch: Facial anomalies
- 1st Pouch: Tubotympanic anomalies
- 2nd Pouch: Tonsil/thyroid anomalies
- 3rd Pouch: Inferior parathyroid and thymus deficiencies
- 4th Pouch: Superior parathyroid
Major Phenotypic features in DiGeorge Syndrome (DGS1)
- Immunodeficient
- Cardiac Defects
- Palate abnormalities
- Autoimmune disorders
DGS Immune Abnormalities
- Recurrent/chronic infection and autoimmunity
- T cells abnormalities (30% have low T cell counts)
- Antibody deficiency
- Autoimmunity up to 30% (Abnormal thymic function)
Recommended Tests and Diagnostic Tests for DGS
- Recommended Testing
- All infants with significant heart defects; unexplained lymphoma
- Diagnostic Tests
- FISH - most commonly used test but false negatives 15% of the time
- Chromosome microarray/DNA duplication deletion test (Preffered test)
- RT-QPCR for haploinsufficiency (TBX1)
X-linked agammaglobulimenia (XLA)
Characterized by recurrent _____, ______ and _____
Early diagnosis to prevent _________
Otitis, sinusitis and pneumonia
Bronchiectasis
XLA
Onset?
Best screening test (for all Ab deficiencies)?
- Onset: infancy or early childhood in most
- IgG, IgA, IgM
XLA genetic and molecular cause
Mutations in Bruton’s Tyrosine Kinase Gene (BtK) results in failure in the differentiation of B cells
Most mutations result in absence of BtK protein which can by diagnosed by flow cytometry
What is the most common primary immune deficiency?
Common Variable Immunodeficiency (CVID)
CVID
Onset:
Infections:
Cause of Death:
CVID
Onset: any age
Infections: RTI/GI common
Cause of Death: Pulmonary Disease (bronchiectasis and interstitial lung disease); Cancer; Autoimmune complication; Liver disease
Common non-infectious Cxns of CVID
- Lung Disease
- Neoplasia
- Autoimmunity
- GI Disease
- Liver Disease
CVID Diagnosis
- Decrease in IgG and a low IgA and or IgM
- Onset > 2 years
- Absent isohemagglutinins and poor response to vaccines
- Exclude primary Ab deficiency (XLA)
- Exclude secondary Ab deficiency
- Drugs; protein losing enteropathy; B-cell lymphomas
What is the most common Ab deficiency?
IgA deficiency (1:400 live births)
IgA deficiency charactersitcs
- Rarely associated with IgG subclass deficiency and or CVID
- Normal T cell function
- Vast majority subjects are normal (no phenotype)
- Increased incidence of atopic disease, celiac disease and autoimmune disease
IgA deficiency and false negative and false positive tests (Heterophile Abs)
- False negative tests due to lack of IgA
- Iga Ab to transglutaminase and celiac disease
- False positive results due to increased incidnce of heterophile antibodies: ELISA assays
Heterophile antibodies
Antibodies that recogize an antigen different than the antigen that originally induced the antibody response
Frequently, specificity for serum immunoglobulins of another species
Which disease is characterized by an “abnormal” antibody response to immunization - especially polysaccharide (PS) antigens?
Specific Antibody Deficiency
Specific Antibody Deficiency
What parts of the immune system are normal?
Diagnosis?
Normal IgG, IgA and IgG
Normal T Cell function
Measure Ab response pre and post vaccination
Lab Tests for Antibody Deficiencies
Screening for XLA and CVID?
- Serum IgG, IgA, IgM: best screening test
- XLA: profound decrease in all isotypes
- CVID: Decrease in two of three major isotypes including IgG
- Both XLA and CVID: Poor specific Ab response to vaccines
DO NOT use serological assays (measuring antibodies) in patients with _____
Diagnosis of infectious disease must be done by _____, ____ or other direct methods to directly test the presence of the pathogen
CVID
culture; PCR
Chronic Granulomatous Disease (CGD) - Common characteristic
- Functional absence of respiratory burst in neutrophils and monocytes - imparied bactericidal killing
CGD and NADPH oxidase
NADPH oxidase is essential for respiratory burst. Four subunits - defects in any leads to CGD
gp91phox (x-linked) - 76%
Common clinical findings in CGD
Pneumonia (70%)
Adenopathy/abscesses
Sepsis
Osteomyelitis
Infection with catalse + bacteria
CGD Diagnosis
Dihydrorhodamine test (DHR - preferred) or Nitroblue Tetrazolium test
CGD treatment?
Signs of CGD in infants/young children?
- Treatment: TM-Sulfa prophylaxis (staph); Itraconazole prophylaxis (fungi); prednisone for granulomas
- Bone Marrow transplantation
- Signs: Liver abscess in infant or young child - think CGD until proven otherwise
Describe the DHR test
Dihydrorhodamine123 (DHR) is oxidized when the PMNs are stimulated to undergo the oxidative burst with myristate acetate. The oxidized form of DHR exhibits increased fluorescence
Leukocyte Adhesion
Rolling Adhesion components:
Tight Adhesion components:
- Rolling adhesion: mediated by selectin/CD62P and E-selectin/CD6-E on the endothelium
- Tight adhesion; result of interactions with LFA-1(CD18/CD11a) with ICAM-1/2
Leukocyte adhesion disease (LAD) 1:
LAD2:
- LAD-1: mutation in common β2 chain (CD18)
- LAD-2: Mutation in GDP-fucose transporter leads to absence of sialyl Lewis x (Needed for adhesion)
LAD-1
- Clinical signs:
- Deficiency:
- Impairment:
- Treatment:
LAD-1
- Clinical signs: Recurrent pyogenic infections, delayed umbilical detachment, leucocytosis inability to form pus
- Deficiency: LFA-1/Mac-1; integrins
- Impairment: impaired leucoyte chemotaxis, phagocytosis and margination
- Treatment: Agressive Rx infection, BM transplant in severe cases
Late Complement Deficiency (C5-C9) associated infection
Neisseria
Early complement deficiencies (C2)
Characteristics:
Best Screening Test:
- Characteristics: Most common deficiency (autosomal recessive)
- Associated with collagen vascular diseases
- Recurrent bacteremia; pneumococcus, H influenzae…
- Best screening test for ALL classical complement deficiencies: CH50
