Immunodeficiency Syndromes

Question 1

Classification of primary immunodeficiencies

Answer 1

1. Combined immunodeficiencies
2. Well-defined syndrome with immnuodeficiencies
3. Predominantly antibody defects
4. Defects of immune dysregulation
5. Phagocytic defects
6. Defects in innate immunity
7. Autoinflammatory disorders
8. Complement deficiencies
9. Bone marrow failure
10. Phenocopies of PID

Question 2

Notes on common variable immune deficiency

Answer 2

• Most common clinically relevant PID
• Variable collection of disorders
• Diagnosis of exclusion
• Median diagnostic delay of 9 years
• Hypogammaglobulinaemia
  
  • IgG severely reduced, +/- IgA, +/- IgM
• Recurrent infections
• Absence of antibody production in response to vaccination
• Treatment → immunoglobulin replacement

Question 3

When to suspect immunodeficiency

Answer 3

Suprman

Severe infections

• Complicated/prolonged pneumonia, meningococcal disease, sepsis, osteomyelitis
• Lobar pneumonia or meningococcal disease in an otherwise healthy adult should prompt consideration of PID

Unusual infections

Persistent infections

• Extensive warts, chronic diarrhoea, chronic mucocutaneous candidiasis

Recurrent infections

Sinopulmonary infections → chest, sinus, otitis media

Herpes infections → cutaneous or invasive (zoster or simplex)

Warts (HPV)

Malignancy

Autoimmune disease

Not gaining weight

Question 4

Clinical clues suggestive of primary immunodeficiency

Answer 4

Infections

Bacterial → antibody

Fungal/viral/HPV → T cells

Stpahylococcal, fungal → phagocytes

Encapsulated organisms → complement and spleen

Immune dysregulation

Autoimmune disease

Lymphpproliferation

Haemophagocytosis

Question 5

Complications of immune dysregulation

Answer 5

Question 6

Basics of humoral immunity

Answer 6

• Lymphocytes need to develop in the bone marrow and migrate into the circulation
• T cells need to be “educated” in the thymus
• B cells mature in the bone marrow and then circulate to secondary lymphoid organs -> where they meet their target antigen. If their target antigen is recognised - T cell and B cells will respond with clonal expansion
• Upon clearance of the pathogen/antigen -> quiescence of response. Some cells survive -> memory T cells, and some persistence of plasma cells which secrete IgM at the end of this process
• Memory cells circulate - upon a secondary exposure they are reactivated and able to produce a more rapid response
• Antibodies → important role in protection against infection from encapsulated organisms
  
  • Opsonisation → IgG binding to surface of microorganism triggers phagocytosis by neutrophils and macrophages
  • Complement activation - classical pathway activated by Ag/Ab complex
• Common infections associated with antibody deficient states:
  
  • Strep pneumoniae
  • Haemophilus
  • E.Coli
  • Giardia lamblia

Question 7

Assessment of humoral immunity

Answer 7

• Serum IgG, IgA, IgM, IgE levels
  
  • +/- IgG subclasses - generally only helpful if normal IgG (IgG subclass deficiency not an indication for IVIG)
• Lymphocytes count and subsets:
  
  • Absent B-cells may indicate X-link agammaglobulinaemia (but low in 5-10% CVID)
  • Low T cell suggestive of combined immunodeficiency
• Exclude secondary causes of low IgG (serum and urine protein and albumin)
  
  • Low IgG +/- IgA but relatively normal IgM in renal or GI protein loss
  • Consider haematologic malignancy in older patients
• Functional antibodies (pre and post vaccination)
  
  • Response to polysaccharide e.g. Pneumovax - >1g or 4 fold increase ≥ 4 weeks post-vaccine
• Additional investigations
  
  • Specific antibody responses - tetanus, haemophlilus, diphtheria
  • Lymphocyte proliferation (when you suspect combined immunodeficiency) → mitrogens, anti-CD3, Candida
  • Bone marrow aspirate

Question 8

Notes on phagocyte dysfunction

Answer 8

• E.g. chronic granulomatous disease
  
  • One X-linked and 5 AR forms
• Clues:
  
  • Severe recurrent or unusual bacterial infections (staph, serratia, pneumocyctis, klebsiella, E.Coli, salmonella, proteus
  • Unusual or persistent infections → fungal (candida, aspergillus, nocardia)
  • Sites → skin, lymph node, lung, liver, bone, periodontal
  • Delayed separation of cord (LAD - leucocyte adhesion deficiency)
• Diagnosis:
  
  • Nitroblue tatrazolium test (NBT reduction test) → absence of NADPH oxidase cells do not change colour
  • Flow based assay more commonly used

Question 9

Clues to complement deficiency

Answer 9

• C1, C2, C4 → manifests as SLE-like autoimmunity (failure to clear self-antigen)
  
  • Recurrent sinopulmonary infections can be seen → particularly C2
• C3 deficiency → can’t distinguish from severe antibody defect clinically → recurrent or severe infection
• C5-C9 0> Neisseria meningitides, sepsis, gonococcal arthritis
• Alternative pathway (Factor B, properdin and Factor D deficiencies) → N. meningitides and bacterial infection