62. Immunodeficiencies Flashcards
Immunodeficiency classification:
- Primary (congenital): defect in immune system
- Secondary (acquired): caused by another disease
Clinical features of an immunodeficiency
=> 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)
Expand on primary immunodefficiencies
- 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
Examples of primary immunodeficiencies.
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
X-linked Agammaglobulinaemia - What is it? investigations and treatment.
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
Expand on Severe Combined ImmunoDeficiency (SCID).
- Presentaion, causes, investigations, treatment and outcome
- 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
Expand on DiGeorge syndrome
(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)
Expand on Wiskott-Aldrich syndrome (WAS):
- 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)
Expand on Ataxia-Telangiectasia (AT):
- 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
Examples of defects in the innate immunity in primary immunodeficiencies
- PHAGOCYTE DEFECTS:
- quantitative (↓ number)
- qualitative
=> Chronic granulomatous disease
=> Chediak-Higashi syndrome
=> Leucocyte adhesion defects (LADs)
- COMPLEMENT DEFECTS:
Expand on chronic granulomatous disease
- 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
Expand on Chediak-Higashi syndrome
- 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
Expand on LAD (leucocyte adhesion deficiency)
- 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)
Expand on complement deficiencies in primary immunodeficiencies
- 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
Secondary Immunodeficiency
- 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
