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FPP Weeks 1 & 2 > Overview of PID (Primary Immune Deficiencies) > Flashcards

Overview of PID (Primary Immune Deficiencies) Flashcards

1
Q
  1. Define Primary Immune Deficiencies
  2. Define Secondary Immunodeficiencies
A
  1. Intrinsic defects in the immune system
  2. Due to extrinsic factors that depress the immune response (HIV-1, immunosuppressive drugs)
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2
Q

When to suspect PID (4)

A
  1. Too many infections
  2. Weird infections
  3. Infections in weird places
  4. Early onset immunity
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3
Q

Causes of Secondary Immunodeficiencies

A
  • Infections
  • Malnutrition
  • Malignancies
  • Metabolic
  • Loss of lymphocytes/antibodies
  • Immunosuppresants
  • Collagen vascular disease
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4
Q

Neutrophil defects (Common attributes)

A
  • Onset early in infancy
  • Severe bacterial infections
  • Abscesses
  • Gingival/peridontal diseases
  • Poor wound healing
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5
Q

Common pathogens associated with neutrophil defects

A
  • Catalase positive organisms
    • Staphylococcus
    • Aspergillus
    • Nocardia
    • Burkholderia
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6
Q

Examples of Neutrophil defects

A

Chronic Granulomatous Disease

Congenital/cyclic neutropenia

Leukocyte adhesion deficiency

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7
Q

Evaluating neutrophil defects (initial and secondary)

A
  • Initial
    • CBC with differential
    • Oxidative burst testing
  • Secondary
    • Chemotaxis
    • Anti-neutrophil Abs
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8
Q

Complement Defects

  • Early (C2,C4):
  • Late (C5-C9):
  • C3 defects:
A

Complement Defects

  • Early (C2,C4):
    • sinopulmonary infections (S. pneumoniae)
    • Autoimmune disease
  • Late (C5-C9):
    • Increased susceptibility to Neisseria
  • C3 defects:
    • ​Severe pyogenic infections
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9
Q

Complement Defects - Workup (Initial and Secondary)

A
  • 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
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10
Q

What are the most common PIDs?

A

Antibody deficiencies (50%)

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11
Q

Agammaglobulinemias usually present at what age?

CVID?

A

First year or two of life

CVID at any age

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12
Q

B-cell/Antibody Defects - Workup (Initial and Secondary)

A
  • Initial
    • quantitative immunoglobulins (IgG/A/M/E)
    • Vacine titers - measure ability to make specific Abs
  • Secondary
    • Flow cytometry for lymphocytes/B cell subsets
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13
Q

T-Cell or combined T cell/ B cell defects

A
  • SCID - First year of life
  • Recurrent, severe infections
    • viruses; fungi; bacteria; opportunistic pathogens
  • Poor growth/chronic diarrhea
  • T cell: 22q11.2DS
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14
Q

T-Cell/Combined Defects - Workup (Initial)

A
  • Initial
    • Lymphocyte subset enumeration (flow cytometry
    • Numbers of T-/B-/NK- cells, memory and naive T cells
    • Immunoglobulins (quantitative, functional
    • T-cell proliferation
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15
Q

Screening tests for PIDS

  • Combined B-cell and T cell
  • T-cell
  • Antibody
  • PMN
  • Complement
A

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
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16
Q

X-linked SCID Molecular basis

A
  • 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
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17
Q

SCID - Diagnostic studies

  • Screening Test:
  • Confirmatory Test:
  • Other Screening?
A
  • 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
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18
Q

Common feature in all forms of SCID

A

Absent/Non-Functional T Cells

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19
Q

Why do we screen newborns for SCID

A
  1. Universally fatal without treatment
  2. Incidence meets criteria for newborn screening
  3. Asymptomatic at birth
  4. Curative therapy is readily available for most
  5. Early treatment improves mortality
  6. Cost Efficient
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20
Q

What are TRECs?

A

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
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21
Q

How is TREC measured?

A

qRT-PCR

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22
Q

DiGeorge Syndrome genetic cause

A

Microdeletion in chromosome 22q11.2 - Field defect first to sixth pharyngeal pouches (Deletion of TBX1 underlies many of the abnormalities)

23
Q

DiGeorge: CATCH22 mnemonic

A
  • Cardiac defects
  • Abnormal facies
  • Thymic hypoplasia
  • Cleft palate
  • Hypocalcemia
  • 22nd chromosome
24
Q

DiGeorge Syndrome (Arch anomolies)

  • 1st arch:
  • 1st Pouch:
  • 2nd Pouch:
  • 3rd Pouch:
  • 4th Pouch:
A

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
25
Q

Major Phenotypic features in DiGeorge Syndrome (DGS1)

A
  1. Immunodeficient
  2. Cardiac Defects
  3. Palate abnormalities
  4. Autoimmune disorders
26
Q

DGS Immune Abnormalities

A
  • Recurrent/chronic infection and autoimmunity
  • T cells abnormalities (30% have low T cell counts)
  • Antibody deficiency
  • Autoimmunity up to 30% (Abnormal thymic function)
27
Q

Recommended Tests and Diagnostic Tests for DGS

A
  • 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)
28
Q

X-linked agammaglobulimenia (XLA)

Characterized by recurrent _____, ______ and _____

Early diagnosis to prevent _________

A

Otitis, sinusitis and pneumonia

Bronchiectasis

29
Q

XLA

Onset?

Best screening test (for all Ab deficiencies)?

A
  • Onset: infancy or early childhood in most
  • IgG, IgA, IgM
30
Q

XLA genetic and molecular cause

A

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

31
Q

What is the most common primary immune deficiency?

A

Common Variable Immunodeficiency (CVID)

32
Q

CVID

Onset:

Infections:

Cause of Death:

A

CVID

Onset: any age

Infections: RTI/GI common

Cause of Death: Pulmonary Disease (bronchiectasis and interstitial lung disease); Cancer; Autoimmune complication; Liver disease

33
Q

Common non-infectious Cxns of CVID

A
  • Lung Disease
  • Neoplasia
  • Autoimmunity
  • GI Disease
  • Liver Disease
34
Q

CVID Diagnosis

A
  • 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
35
Q

What is the most common Ab deficiency?

A

IgA deficiency (1:400 live births)

36
Q

IgA deficiency charactersitcs

A
  • 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
37
Q

IgA deficiency and false negative and false positive tests (Heterophile Abs)

A
  • 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
38
Q

Heterophile antibodies

A

Antibodies that recogize an antigen different than the antigen that originally induced the antibody response

Frequently, specificity for serum immunoglobulins of another species

39
Q

Which disease is characterized by an “abnormal” antibody response to immunization - especially polysaccharide (PS) antigens?

A

Specific Antibody Deficiency

40
Q

Specific Antibody Deficiency

What parts of the immune system are normal?

Diagnosis?

A

Normal IgG, IgA and IgG

Normal T Cell function

Measure Ab response pre and post vaccination

41
Q

Lab Tests for Antibody Deficiencies

Screening for XLA and CVID?

A
  • 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
42
Q

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

A

CVID

culture; PCR

43
Q

Chronic Granulomatous Disease (CGD) - Common characteristic

A
  • Functional absence of respiratory burst in neutrophils and monocytes - imparied bactericidal killing
44
Q

CGD and NADPH oxidase

A

NADPH oxidase is essential for respiratory burst. Four subunits - defects in any leads to CGD

gp91phox (x-linked) - 76%

45
Q

Common clinical findings in CGD

A

Pneumonia (70%)

Adenopathy/abscesses

Sepsis

Osteomyelitis

Infection with catalse + bacteria

46
Q

CGD Diagnosis

A

Dihydrorhodamine test (DHR - preferred) or Nitroblue Tetrazolium test

47
Q

CGD treatment?

Signs of CGD in infants/young children?

A
  • 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
48
Q

Describe the DHR test

A

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

49
Q

Leukocyte Adhesion

Rolling Adhesion components:

Tight Adhesion components:

A
  • 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
50
Q

Leukocyte adhesion disease (LAD) 1:

LAD2:

A
  • 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)
51
Q

LAD-1

  • Clinical signs:
  • Deficiency:
  • Impairment:
  • Treatment:
A

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
52
Q

Late Complement Deficiency (C5-C9) associated infection

A

Neisseria

53
Q

Early complement deficiencies (C2)

Characteristics:

Best Screening Test:

A
  • 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

FPP Weeks 1 & 2 (18 decks)

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