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Clinical features suggestive of a primary immunodeficiency 

●Family history of immunodeficiency or unexplained early death (eg, before age 30 years)

●Failure to gain weight or grow normally (failure to thrive)

●Need for intravenous antibiotics and/or hospitalization to clear infections

●Six or more ear or respiratory tract infections within one year

●Two or more serious sinus infections or pneumonias within one year

●Four or more new ear infections within one year

●Two or more episodes of sepsis or meningitis in a lifetime

●Two or more months of antibiotics with little effect

●Recurrent or resistant oral or cutaneous candidiasis

●Recurrent deep skin or organ abscesses

●Infection caused by an unusual microbial organism and/or in an unusual location

●Complications from a live vaccine (eg, rotavirus, varicella, and Bacillus Calmette-Guérin [BCG] vaccines)

●Chronic diarrhea

●Nonhealing wounds

●Extensive skin lesions

●Persistent lymphopenia (a count of <1500 cells/uL in patients over five years and <2500 cells/uL in younger children)

●Unexplained autoimmunity or fevers


●Hemophagocytic lymphohistiocytosis (HLH)

●Lymphoma in infancy

●Features typical of syndromic PIDs (eg, cartilage-hair hypoplasia, Chediak-Higashi syndrome, ataxia-telangiectasia) 


Define recurrent infections

  • two or more severe infections in one year, three or more respiratory infections (eg, sinusitis, otitis, bronchitis) in one year, or the need for antibiotics for two months/year.
  • Severe/serious infections = persistent fever or confinement to bed for a week or more, failure to respond to oral antibiotics and/or the need for intravenous antibiotics or hospitalization, infections with an unusual pathogen, unusual complications (eg mastoiditis, pleural effusion, abscesses), or persistent laboratory abnormalities (eg, leukocytosis, elevated erythrocyte sedimentation rate [ESR]/C-reactive protein [CRP], persistent imaging abnormalities).


Primary immunodeficiencies

- incidence

- major cause


  • 1 in 10,000
  • 3/4 of the PIDs are caused by an antibody (B cell) deficiency or a combined antibody plus cellular (T cell) abnormality
  • Isolated T cell defects, phagocytic cell, complement, and other innate immune defects, are much less common.


Describe angiooedema

- definition

- typically affects which areas

- how is it different from other forms of oedema

- types of angiooedema

  • Angioedema: localised subcutaneous and submucosal swelling, extravasation of fluid into interstitial tissues
  • Can occur in isolation, or together with urticaria, or as a component of anaphylaxis.
  • Angioedema typically affects areas of loose connective tissue eg, face, lips, mouth, throat, larynx, uvual, extremities, genitalia. Bowel wall angioedema causes colicky abdominal pain
  • Clinically different from other forms of oedema: 
    • onset wihtin minutes-hours, spontaneous resolution hours-few days
    • asymmetric distribution
    • tendency NOT to involve gravitationally-dependent areas
    • involvement of face, lips, larynx, bowels
  • types of angiooedema;
    • mast cell mediated: e.g. allergic reaction. histamine mediated
    • bradykinin-induced: NOT a/w urticaria, bronchospasm, symptoms of allergic reaction. triggers include ACEi. 


Ix of angiooedema

  • isolated angiooedema: 
    • FBE, UEC, LFT, CRP, ESR, levels of C4 +/- C1 inhibitor level 
      • if depressed C4; test for C1 inhibitor deficiency (hereditary angiooedema & acquired C1 inhibitor deficiency)
      • HAE = low C4 + decreased C1INH protein/function. 2x complement tests 1 month apart. 
      • high CRP, ESR: infections, malignancies, inflammatory diseases
  • angiooedema with anaphylaxis: serum total tryptase level (high = anaphylactic event. normal does NOT exclude, given variable & transient elevations)
  • angiooedema due to a suspect allergen: IgE antibodies


Describe hereditary angiooedema (HAE)

- pathogenesis

- epidemiology

- px


  • rare disorder caused by deficiency or dysfunction of the C1 inhibitor
  • Epidemiology:
    • 1:1  men:women
    • no known racial predilections.
    • sx often begin in childhood, the disease is commonly diagnosed during puberty or early adulthood
  • Px:
    • recurrent episodes of angioedema, without accompanying hives or pruritus - most commonly affect the skin, bowel, or upper airway
    • attack: 24-72h. usually involves one site at a time (skin, viscera, or larynx)
    • prodrome: fatigue or erythematous rash is noticed by some patients. 
    • trigger: Mild trauma, including dental work, estrogens, angiotensin-converting enzyme (ACE) inhibitors, stress, H. pylori infection, and menstruation. 
    • permanent for life, however frequency of attacked reduced by therapy 


Selective IgA deficiency

- common infections & pathogens

- diagnostic testing

- mx

  • Sinopulmonary infections:
    • Streptococcus pneumoniae
    • Haemophilus influenzae
  • Diarrhea/malabsorption:
    • Giardia lamblia


  • Undetectable (severe deficiency) or low (partial deficiency) IgA level with normal IgG and IgM levels


  • Vaccination against S. pneumoniae
  • Prophylactic antibiotics are controversial


Common variable immunodeficiency

- common infections & pathogens

- diagnostic testing

- mx

  • Sinopulmonary infections:
    • S. pneumoniae
    • H. influenzae
    • Mycoplasma pneumoniae
  • Respiratory viruses
  • Diarrhea:
    • Norovirus
    • Campylobacter
    • G. lamblia
  • Urethritis:
    • Mycoplasma
    • Ureaplasma


  • IgG level and either IgA or IgM ≤2 standard deviations below the mean PLUS impaired humoral response to vaccination


  • Immune globulin replacement therapy
  • Immunization with inactivated vaccines
  • Prophylactic antibiotics are controversial


Complement deficiency

- 2 types

- common infections & pathogens

- diagnostic testing

- mx

  • Early components (C2-C4): Similar to CVID
  • Late components (C5-C9): Recurrent infections with Neisseria gonorrhoeae or Neisseria meningitidis

Ix: Decreased level of total hemolytic complement (CH50)


  • Same as CVID for C2-C4 complement deficiency
  • Quadrivalent meningococcal conjugate and serogroup B meningococcal vaccines for C5-C9 complement deficiency


Patients with selective IgA deficiency may be asymptomatic, present with ___ or ___ infections, or experience ___ to blood products due to ___ antibodies.

Patients with selective IgA deficiency may be asymptomatic, present with sinopulmonary or gastrointestinal tract infections, or experience anaphylaxis to blood products due to anti-IgA antibodies.


Common variable immunodeficiency (CVID) is a heterogenous syndrome associated with decreased ____ levels and impaired ___  response to antigens. Diagnosis is usually delayed until _____, although a history of ___ throughout childhood may often be elicited.

Common variable immunodeficiency (CVID) is a heterogenous syndrome associated with decreased quantitative immunoglobulin levels and impaired humoral response to antigens. Diagnosis is usually delayed until adolescence or adulthood, although a history of recurrent infection throughout childhood may often be elicited.


What other conditions apart from infections are pts with CVID at higher risk? 

  • autoimmune disease 
  • inflammatory bowel disease
  • granulomatous disease (noncaseating granuloma in lymphoid/ solid organs)
  • bronchiectasis
  • and malignancy.


What should be avoided in CVID?

Live vaccines


Early component complement deficiency is associated with an increased rate of ____ and risk of infection with ___ organisms; terminal complement defects can result in recurrent ___ infections.

Early component complement deficiency is associated with an increased rate of systemic lupus erythematosus (especially C4) and risk of infection with encapsulated organisms;

terminal complement defects can result in recurrent Neisseria infections.


3 pathways of complement activation

alternative pathway: activation of innate activity. C3 + FB + FD -> C3 convertase activated. 

classical pathway: activated by inmune complexes. IgM, IgG. 

lectin pathway 


via activation of complements: 

anaphylatoxins released important in inflammation, non immune cell activation. 

complements also important in opsonisation, phagocytosis.

interaction with adaptive immunity  


Absence of C1 inhibitor leads to what

hereditary angiooedema 


due to its role in firbinolytic pathway

inhibition gone -> bradykinin leads to increased vascular permeability -> angiooedema


Mx of hereditary angiooedema

Hereditary angioedema caused by absence of C1 inhibitor; can be replaced. 

Absence of C1inhibitor leads to bradykinin response via kallikrein pathway. i.e. can block kallikrein. 

mx: plasma derived C1 inhibitor (IV or subcut): danazol 


BCX7353; oral synthetic kallikrein inhibitor 

Lanadelumab; humanised antibody inhibitor of kallikrein 


How is hereditary angiooedema different from allergic angiooedema?

lack of urticaria

angiooedema can be post procedure (clotting activation)



Defects of complement classical pathway can lead to what

clasical pathway: activated by immune complexes + clears apoptotic cells

if affected, increased self antigens and can lead to autoimmune conditions e.g. lupus 


i.e. defects of C1q, C1r, C1s, C4, C2 


Defects of complement alternative & terminal pathway leads to what

C3, clearance of bacterial infections esp Neiserria

If missing properdin, C3, properdin, C5, C9, factor B, factor B -> meningococcal meningitis 


Defect of complement regulatory proteins leads to what

Lack of Factor H, MCP, Factor H, factor I

reduced regulatory proteins -> increased complement deposition -> renal diseases aHUS, complement 3 glomerulopathy


Lack of CD55, CD50 (found on endothelial cells) ->  Paroxysmal nocturnal hemoglobinuria (PNH), early onset inflammatory bowel diseases

PNH is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system