62. Immunodeficiencies Flashcards Preview

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Flashcards in 62. Immunodeficiencies Deck (16)
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1
Q

Immunodeficiency classification:

A
  • Primary (congenital): defect in immune system

- Secondary (acquired): caused by another disease

2
Q

Clinical features of an immunodeficiency

A

=> recurrent infections (normal: <6-8 URI/year for the 1st 10 years; 6 otitis media and 2 gastroenteritis/year for the 1st 2-3 years)

=> severe infections, unusual pathogens (Aspergillus, Pneumocystis), unusual sites (liver abscess, osteomyelitis)

3
Q

Expand on primary immunodefficiencies

A
  • Usually genetic
  • Infrequent but can be life-threatening

Defects in the..

  • Adaptive immune system: T and B cells
  • Innate immune system: phagocytes, complement

~ Mostly in antibodies, then T-cells, then phagocytes and then least in complements

4
Q

Examples of primary immunodeficiencies.

A

B LYMPHOCYTE DISORDERS:

  • X-linked agammaglobulinaemia (Bruton’s disease) ~ know this
  • Common variable immunodeficiency (CVID)
  • Selective IgA deficiency
  • IgG2 subclass deficiency
  • Specific Ig deficiency with normal Igs

COMBINED:
- Severe Combined ImmunoDeficiency (SCID)

PREDOMINANT T-CELL DISORDERS:

  • DiGeorge syndrome
  • Wiskott-Aldrich syndrome
  • Ataxia-telagiectasia
5
Q

X-linked Agammaglobulinaemia - What is it? investigations and treatment.

A

Defect in Bruton’s tyrosine kinase (Btk) protein block in B-cell development at pre-B stage

INVESTIGATIONS:

  • B cells absent / low; plasma cells absent
  • all Igs absent / very low
  • T cells and T cell-mediated responses normal

TREATMENT: ~ Ig replacement therapy

  • or subcutaneous Ig weekly
  • prompt antibiotic therapy (URI /LRI)
  • Do not give live vaccines
6
Q

Expand on Severe Combined ImmunoDeficiency (SCID).

- Presentaion, causes, investigations, treatment and outcome

A
  • involves both T and B
  • 50-60% X-linked; rest - autosomal recessive

PRESENTATION:

  • well at birth; problems > 1st month
  • diarrhoea; weight loss; persistent candidiasis
  • severe bacterial/viral infections
  • failure to clear vaccines
  • unusual infections (Pneumocystis, CMV)

CAUSES:
- Different causes; affect T & B cell development

INVESTIGATIONS:

  • Lymphocyte subsets: T, B, NK (% and numbers) => low total lymphocyte count => SCID sign!
  • Pattern: very low/absent T; normal/absent B, sometimes also absent NK (γ-chain defect affecting IL-15 receptor)
  • Igs low
  • T cell function ↓ (proliferation, cytokines)

TREATMENT:

  • isolation => to prevent further infections
  • Do not give live vaccines !
  • Blood products from CMV-negative donors
  • IVIg replacement
  • Treat infections
  • Bone marrow/haematopoietic stem cell transplant
  • Gene therapy (for ADA and γ-chain genes)

OUTCOME:

  • dependent on promptness of diagnosis
  • Survival >80% (early diagnosis, good donor match, no infections pre-transplant)
  • Survival <40% (late diagnosis, chronic infections, poorly matched donors)
  • Regular monitoring post BMT => engraftment
7
Q

Expand on DiGeorge syndrome

A

(thymic hypoplasia)

  • complex array of developmental defects
  • dysmorphic face: cleft palate, low-set ears, fish-shaped mouth
  • hypocalcaemia, cardiac abnormalities
  • variable immunodeficiency (absent/reduced thymus => affects T cell development)
8
Q

Expand on Wiskott-Aldrich syndrome (WAS):

A
  • X-linked
  • defect in WASP (protein involved in actin polymerisation => defect in signalling)
  • thrombocytopaenia, eczema, infections
  • progressive immunodeficiency (T cell loss)
  • progressive ↓ T cells; ↓ T cell proliferation
  • Ab production (↓ IgM, IgG; high IgE, IgA)
9
Q

Expand on Ataxia-Telangiectasia (AT):

A
  • progressive cerebellar ataxia (abnormal gait)
  • typical telangiectasia (ear lobes, conjunctivae)
  • immunodeficiency
  • increased incidence of tumours later in life
  • combined immunodeficiency (B & T)
  • defects in production of switched Abs (IgA/G2)
  • T cell defects (less pronounced) <= thymic hypoplasia
  • upper & lower respiratory tract infections
  • autoimmune phenomena, cancer
10
Q

Examples of defects in the innate immunity in primary immunodeficiencies

A
  • PHAGOCYTE DEFECTS:
  • quantitative (↓ number)
  • qualitative

=> Chronic granulomatous disease
=> Chediak-Higashi syndrome
=> Leucocyte adhesion defects (LADs)

  • COMPLEMENT DEFECTS:
11
Q

Expand on chronic granulomatous disease

A
  • Defective oxidative killing of phagocytosed microbes; mutation in phagocyte oxidase (NADPH) components

DIAGNOSIS:
Tests that measure oxidative burst:
=> NBT test (nitroblue tetrazolium reduction)
=> Flow cytometry assay dihydrorhodamine

12
Q

Expand on Chediak-Higashi syndrome

A
  • rare genetic disease
  • defect in LYST gene (regulates lysosome traffic)
  • neutrophils have defective phagocytosis
  • repetitive, severe infections
    ~ Defect phagosome-lysosome fusion => defective killing of phagocytosed microbes => recurrent infections

DIAGNOSIS:

  • decreased number neutrophils
  • neutrophils have giant granules
13
Q

Expand on LAD (leucocyte adhesion deficiency)

A
  • defect in β2-chain integrins (LFA-1, Mac-1)
  • defect in sialyl-Lewis X (selectin ligand)
  • delayed umbilical cord separation => diagnosis defect in β2-chain integrins (LFA-1, Mac-1)

PRESENTATION:
- skin infections, intestinal + perianal ulcers

INVESTIGATIONS:

  • ↓ neutrophil chemotaxis
  • ↓ integrins on phagocytes (flow cytometry)
14
Q

Expand on complement deficiencies in primary immunodeficiencies

A
  • can affect different complement factors severe/fatal pyogenic infections (C3 deficiency)
  • predisposition to infection with different pathogens
  • symptoms differ depending on C factor affected
  • recurrent infections (Neisseria) - deficiency terminal complex (MAC): C5, C6, C7, C8 & C9
  • severe/fatal pyogenic infections (C3 deficiency)
  • SLE-like syndrome (C1q, C2, C4 deficiency)
  • hereditary angioneurotic oedema: failure to inactivate complement (deficiency in C1 inhibitor); intermittent acute oedema skin/mucosa => vomiting, diarrhoea, airway obstruction

INVESTIGATIONS

  • complement function: CH50 (haemolysis)
  • measure individual components
15
Q

Secondary Immunodeficiency

A
  • Infections: viral, bacterial
  • Malignancy
  • Extremes of age
  • Nutrition (anorexia, iron deficiencies)
  • Chronic renal disease
  • Splenectomy
  • Trauma/surgery, burns, smoking, alcohol
  • Immunosuppressive drugs

EXTREMES OF AGE:
=> Prematurity
- infants < 6 months => maternal IgG
- premature delivery: interrupts placental transfer of IgG => infant Ig deficient

=> Old age
- decline in normal immune function

16
Q

Give examples of secondary immunodeficiency infections and malignancy

A

INFECTIONS:

  • viral: HIV, CMV, EBV, measles, influenza
  • chronic bacterial: TB, leprosy
  • chronic parasitic: malaria, leishmaniasis
  • acute bacterial: septicaemia

MALIGNANCIES:

  • Myeloma
  • Lymphoma (Hodgkin’s, non-Hodgkin’s)
  • Leukaemia (acute or chronic)

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