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Flashcards in Immunodeficiencies Deck (56)
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Define primary immunodeficiencies

>400 disorders characterised by abnormal immune response to infections, to self (autoimmune disease), or spontaneous inflammation (autoinflammatorydisease)


Example of rare, early onset primary immunodeficiency

 Severe Combined Immune Deficiency

(SCID-X-linked and autosomal recessive) 


Common Variable Immune Deficiency (CVID –autosomal recessive, autosomal dominant, polygenic) vary in ___ and are associated with ___ and susceptibility to ___

Common Variable Immune Deficiency (CVID –autosomal recessive, autosomal dominant, polygenic) vary in age of onset and are associated with autoimmune disease and susceptibility to malignancy 


Classification of primary immunodeficiencies in the order of prevalence


  • Predominant antibody disorders
  • Combined T & B cell deficiencies
  • Phagocyte disorders
  • Other well defined PIDs
  • Complement deficencies
  • Autoimmune/ Immune dysregulation syndromes
  • Autoinflammatory disorders
  • Unclassified PIDs


Prevalence of primary immunodeficiency


PIDs are underdiagnosed

•Selective IgA deficiency (~1:400)

•CVID 1:10,000 –1:25,000

•SCID 1:50,000 (prior to newborn screening <1:100,000)

•Delay in diagnosis is associated with increased morbidity and mortality

•Overall prevalence of clinically significant PID is estimated at 1:1000 to 1:5000 


Describe common variable immune deficiency

  • Most common clinically relevant PID in Australia and worldwide
  • Genetically heterogenious; onset, presentation 
  • Clinically variable collection of disorders
  • Diagnosis of exclusion
  • Hypogammaglobulinemia (IgG severely reduced, +/-IgA, +/-IgM)
  • Recurrent infections
  • Absence of antibody production in response to vaccination
  • Treatment immunoglobulin replacement;  however does not treat other manifestations of disease e.g. lymphoproliferative & autoimmune
  • usually 9 years of delay from onset of symptoms till diagnosis. often have symptoms at 20yo


When to suspect immunodeficiency

- infections

- immune dysregulation 


  • Infections
    • Bacterial (antibody)
    • Fungal/viral/HPV (T cells)
    • Staphylococcal, fungal (phagocytes)
    • Encapsulated organisms (complement and spleen)
  • Immune dysregulation
    • Autoimmune disease
    • lymphoproliferation
    • haemophagocytosis
  • Don’t forget the family history!!



Severe Infections; complicated/prolonged pneumonia, meningococcal disease, sepsis, osteomyelitis 

Unusual Infections

Persistent Infections; extensive warts, chronic diarrhoea, chronic mucocutaneous candidiasis

Recurrent infections; sinopulmonary infections (chest, sinus, otitis media), herpes infections, warts

•Malignancy - esp rare, unusual ones 

•Autoimmune disease

Not gaining weight


How to localise the immune defect; i.e. which infections would point to which immune defects


  • Bacterial (antibody)
  • Fungal/viral/HPV (T cells)
  • Staphylococcal, fungal (phagocytes)
  • Encapsulated organisms (complement and spleen)


Recurrent infections with fungal/viral/HPV would mean... what defect

T cells


Recurrent infections with encapsulated organisms would mean... what defect

complement & spleen


Recurrent infections with bacterial would mean... what defect

antibody defect


Recurrent infections with Staphylococcal, fungal would mean... what defect



Describe humoral immunity

- against what class of organisms

- mechanisms

- examples of organisms targeted

  • encapsulated organisms e.g. 
    • Streptococcuspneumoniae
    • Haemophilus influenzae
    • E.Coli
    • Giardia lamblia
  • protect via: 
    • Opsonisation–IgG + surface of microorganism -> phagocytosis by neutrophils & macrophages
    • Complement activation– Ag/Ab complex -> classical pathway activation

lymphocytes develop in bone marrow. T cells maturated in Thymus, B cells mature in Bone marrow -> circulate to secondary lymphoid organs. If target antigen recognised, B & T cells go through clonal expansion. Once antigen cleared, they undergo quiescence. Some cells survive, and have short lived plasma cells releasing IgM. The memory cells circulate and upon secondary exposure ,reactivated and more rapidyl able to produce immunoglobulin response. Varied population of cell types & ig and have long lived plasma cells & long lived memory T cells. 


i.e. 1st exposure; short lived memory. 2nd exposure; stronger & quicker response to antigens + long lived memory. 


Examples of encapsulated organisms


•Streptococcus pneumoniae

•Haemophilus influenzae


•Giardia lamblia


What is opsonisation


IgG binding to surface of microorganism triggers phagocytosis by neutrophils and macrophages


Ix of primary immunodeficiency

How do you interprete antibody, lymphocyte count/subsets lab results


  • Serum IgG, IgA, IgM, (IgE) levels +/- IgG subclasses
    • IgG subclasses only helpful if total IgG is normal. subclass deficiency is not an indication of IVIG. need to still demonstrate lack of response to vaccines, or lack of Ig switching. 
  • Lymphocyte count and subsets:
    • Absent B-cells may indicate X-linked agammaglobulinaemia esp in a man (but low in 5-10% CVID)
    • Low T cells = combined immunodeficiency
  • Exclude secondary cause of low Ig (serum and urine protein and albumin):
    • Low IgG+/-IgA but relatively normal IgM in renal or GIT protein loss
    • Consider haematologic malignancy in older patients
  • Functional antibodies (titres of antibody pre and post vaccination)
    • Response to polysaccharide (eg Pneumovax) 
    • >1g/L or 4-fold increase >=4weeks post-vaccination
  • Specific antibody responses:
    • Tetanus (protein conjugated)
    • Haemophilus influenzae B
    • Diphtheria
  • Lymphocyte proliferation if suspicious of combined immunodeficiency
    • Mitogens (strong stimulus, could consider quantiferonas a surrogate)
    • anti-CD3 (weaker stimulus)
    • Candida (specific stimulus)
  • +/- Bone marrow aspirate to exclude haematological malignancy.


Case 1: 32 year old man

  • Infectious history:
  • Age 2 -fungal pneumonia (required lobectomy)
  • Age 3 -osteomyelitis 
  • Age 6 -staphylococcal pneumonia
  • Other complications:
  • Granulomatous colitis and severe perianal disease

?likely immune deficit

?what investigation would you like to order 


  • Phagocyte (neutrophil) defect 
  • Ix:
    • Neutrophil function tests; e.g. neutrophil oxidative burst testing
    • Dihydrorhodamine flow assay (DHR)
    • Nitroblue tetrazolium(NBT)
  • Mx of chronic granulomatous disease:
    • Cotrimoxazole and itraconazole prophylaxis
    • IFNg from age 12 to 28
    • Age 28 started anakinra (interleukin-l receptor antagonist) for severe granulomatous colitis and perianal disease –good response for 1 year
    • Underwent HSCT age 30 (matched unrelated donor)


Features suggestive of a phagocyte defect

bacterial + fungal in skin, LN, lung 

•severe, recurrent or unusual bacterial infections (staph, serratia marescens, pneumocystis, 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)



  • Streptococcal septicaemia after ENT surgery
  • Past History:
    • Recurrent discharging otitis media and tonsillitis
    • 8,14,16 months –strep. pneumoniae, haemophilus influenzae  
    • Adenotonsillectomy at 11 months 
    • Failure to thrive
    • <3% ht and wt at 8 months
  • Family History
    • Maternal uncle -‘CREST’ died age 9
    • Paternal uncle -pneumonia in childhood
  • Immunoglobulins: normal 
  • Vaccine responses 
    • 9 months: HiB and Tetanus –normal 
    • No response to MMR ( thought due to age and malnutrition)
    • 5 years:  Pneumovax –response to 11/23 serotypes
  • Lymphocyte subsets:  normal
  • Neutrophil Oxidative Burst (DHR): normal

?further Ix


Ix of Complement pathway

C3, C4

classical pathway: CH50

Alternative pathay: AH50


Dx: complement deficiency


What do you order when testing complements?


  • Measurement of C3/C4 levels
  • 'haemolytic' assays ;
    • CH50; for classical pathway
    • CH100
    • AH50; for alternative pathway
    • lectin pathway complement activation 
  • Measure of specific complement factor
  • Measurement of regulation proteins
    • C1 Inhibitor antigenic level/functional assay
    • Factor H
    • Factor I
  • Haemolytic/ELISA Assays:
    • Main function of complement is lysis of cell, therefore can assess function by looking at ability of serum to lyse cells


Features suggestive of complement deficiency

- c1, c4, c2 deficiency

- c3 deficiency

- c5-c9 deficiency


  • C1, C4 and C2 deficiency: typically manifest as SLE-like autoimmunity (failure to clear self antigen)
    • but recurrent sinopulmonary infections are seen esp. in C2deficiency
    • presents like CVID
  • C3 (significant role in antibody) deficiency = indistinguishable from severe antibody defect. clinically-recurrent or severe infections
  • C5-C9: Neisseria meningitidis, sepsis, gonococcal arthritis (encapsulated organisms)
  • Alternative pathway (factor B, properdinand Factor D deficiencies) result in Neisserial and bacterial infections


Mx of complement deficiency e.g. C2

  • prophylactic penicillin 
  • Vaccinate for meningococcus, haemophilus, pneumococcus


Features suggestiev of antibody or combined defect

- infection sites

- infection types

- other cx

  • Infection sites: Typically mucosal–sinuses, lung, gastrointestinal tract
  • Infection types
    • Lung 
      • Streptococcus pneumoniae
      • Haemophilus influenzae
    • Gastrointestinal 
      • diarrhoea in 25% often due to persistent infection 
      • especially giardia but also enterovirus, campylobacter, salmonella, shigella
  • Other complications
    • Autoimmune cytopaenias
    • Chronic diarrhoea due to villous atrophy, exocrine pancreatic insufficency, lymphocytic enterocolitis


CLTA4 deficiency/mutations

- px

- similar defects

- mx

  • autosomal dominant immune dysregulation syndrome 
  • susceptibility to autoimmune disease & immunodeficiency
  • Similar to LRBA (allows CTLA to be on the surface) deficiency/mutation
  • CTLA4; cell surface molecule presented on T cells after stimulation, puts break on immune system. 
  • Px; e.g. chronic diarrhoea, autoimmuen enteropathy, megaloblastic anaemia, autoimmune hepatitis
  • At risk of malignancy e.g. melanoma 


Name some conditions with defects of immune dysregulation 

  • ALPS: autoimmune lymphoproliferative syndrome
    • px; lymphadenopathy, splenomegaly, autoimmune haemolytic anaemia/ thrombocytopaenia, high risk lymphomas
    • flow analysis: increased double negative alphabeta T-cells in peripheral blood
  • IPEX; immune dysregulation polyendocrinopathy enteropathy X linked
    • defect in FoxP3 (critical for development & function of regulatory T cells, CD4+ CD25+)
    • px; severe and early onset autoimmune enteropathy, T1DM, eczema, hypothyroidism
  • autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (aka. autoimmune polyglandular syndrome)
    • defect in AIRE gene (autoimmune regulator; controls exprsesoin of self antigens)
    • px; hypoparathyroidism, Addison's disease, chronic mucocutaneous candidiasis and other autoantibodies 
  • Haemophagocytic lymphohistiocytosis
    • defective NK & T cell cytotoxicity
    • triggered by viruses esp ESB, CMV, malignancy 
    • px; fever, hepatosplenomegaly, high ferritin, cytopaenias
    • high LDH, triglycerides and bilirubin
    • haemophagocytosis on histology. soluble CD25/IL-2 receptor. NK function testing
  • Familial haemophagocytic lymphohistiocytosis (FHL) syndromes
  • X-linked lymphoproliferative syndrome (XLP)


Name some well-defined syndrome with immunodeficiency


  • Wiskott–Aldrich syndrome (WASP gene defect)
    • XL: Triad of eczema, thrombocytopenia, Immune-dysfunction
  • Ataxia–telangiectasia: defect in the ATM gene–impaired DNA repair
  • DiGeorge anomaly/VCFS (chromosome 22q11.2 deletion)
    • Thymic defect (defect of T cell-mediated response) with congenital anomalies: cardiac, cleft plate, hypoparathyroidism, facial dysmorphism


Conditions with phagocyte defects


  • Cyclic Neutropenia
  • Leukocyte adhesion deficiency(AR): Impaired adhesion of neutrophils to endothelium due to mutations in CD18 LADI/CD15 LADII
  • Chronic granulomatous disease(CGD): Defects of respiratory burst
  • Neutrophil G-6PD deficiency
  • Myeloperoxidase deficiency


Conditions with defects in innate immunity & their relevant infections


  • TLR3 deficiency: herpes simplex encephalitis
  • CARD9 deficiency: invasive fungal diseases
  • Mendelian susceptibility to mycobacterial disease: 
    • IL-12  & IL-23 receptor b1 chain deficiency
    • STAT1 deficiency
    • IFN-gamma receptor, autoantibodies to IFN gamma 
  • GATA2 deficiency (mono MAC syndrome) 


(3) Broad approach to immunodeficiency

  • Anatomic lesions (congenital/acquired) and disorders affecting the function of specific organs 
  • Primary immunodeficiencies (uncommon to present in adulthood)
    • Humoral immunodeficiency; Agammaglobulinaemia, CVID, IgA deficiency, hyperIgM, IgG subclass deficiency 
    • severe combined immunodeficiency 
    • T cell immunodeficiency
    • phagocyte disorders
  • Secondary immune disorders
    • diabetes, HIV, cirrhosis, nephrotic syndrome
    • protein losing states, malnutrition
    • haemoglobinopathy, AI disease, splenectomy
    • medications 


Causes of secondary immunodeficiency

  • Splenectomy
  • Malignancy
  • Medications: glucocorticoids, rituximab, etanercept etc.
  • Diabetes
  • HIV
  • Cirrhosis
  • Nephrotic syndrome
  • Protein losing states (enteropathies, PD)
  • Malnutrition
  • Haemoglobinopathy
  • IBD/RA receiving immunosuppressive therapies
  • Autoimmune disease