Primary immunodeficiency: Difference between revisions
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+ | * See also [[immunodeficiency]] and [[acquired immunodeficiency]] |
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+ | |||
==Clinical Manifestations== |
==Clinical Manifestations== |
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+ | |||
+ | * See also [[Immunodeficiency#Clinical Manifestations|clinical manifestations of immunodeficiency]] |
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+ | |||
+ | === Red Flags for Immunodeficiency === |
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{| class="wikitable" |
{| class="wikitable" |
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+ | ! |
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− | !Immune Defect |
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+ | !Children |
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− | !Typical Infections |
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+ | !Adults |
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− | !Typical Organisms |
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|- |
|- |
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+ | |New ear infections |
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− | |Humoural and complement |
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+ | |≥4 in 1 year |
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− | |recurrent sinopulmonary infections, chronic GI infections, [[bacteremia]], and [[meningitis]] |
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+ | |≥2 in 1 year |
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− | |[[encapsulated bacteria]], [[Giardia]], [[Cryptosporidium]], and [[Campylobacter]] |
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|- |
|- |
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+ | |Serious sinus infections |
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− | |Phagocytic |
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+ | |≥2 in 1 year |
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− | |recurrent invasive [[Skin and soft tissue infection|skin and soft tissue infections]], especially [[Abscess|abscesses]] |
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+ | |≥2 in 1 year, in the absence of allergy |
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− | |[[Staphylococcus aureus]], [[Gram-negative bacilli]], [[Aspergillus]], and [[Nocardia]] |
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|- |
|- |
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+ | |Pneumonias |
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− | |Cell-mediated |
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+ | |≥2 in 1 year |
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− | |severe or prolonged infections with common viruses, opportunistic intracellular infections, and [[fungi]] |
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+ | |≥2 in 1 year |
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− | |[[CMV]], [[EBV]], [[Human herpesviruses|other human herpesviruses]], [[mycobacteria]], [[Candida]], [[Cryptococcus]], and [[Pneumocystis]] |
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+ | |- |
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+ | |Deep skin or organ abscesses |
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+ | |Recurrent |
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+ | |Recurrent |
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+ | |- |
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+ | |Oral thrush or fungal skin infections |
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+ | |Persistent |
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+ | |Persistent |
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+ | |- |
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+ | |Family history of primary immunodeficiency |
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+ | |Any |
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+ | |Any |
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+ | |- |
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+ | |Other |
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+ | | |
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+ | * ≥2 months on antibiotics with little effect |
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+ | * Failure to gain weight or grow normally |
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+ | * Need for IV antibiotics to treat infections |
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+ | * ≥2 deep-seated infections including bacteremia |
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+ | | |
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+ | * Chronic diarrhea with weight loss |
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+ | * Recurrent need for IV antibiotics to treat infections |
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+ | * Recurrent viral infections, such as colds, [[herpes]], warts, or condylomata |
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+ | * Infection with [[non-tuberculous mycobacteria]] |
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|- |
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|[[X-linked agammaglobulinemia]] |
|[[X-linked agammaglobulinemia]] |
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+ | |BTK mutation |
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| |
| |
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+ | |X-linked, very low antibody levels |
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− | | |
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− | | |
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|- |
|- |
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|[[Common variable immunodeficiency]] (CVID) |
|[[Common variable immunodeficiency]] (CVID) |
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+ | |multiple |
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− | | |
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+ | |20-40 years |
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− | | |
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+ | |low IgG with poor antibody response |
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− | | |
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|- |
|- |
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|[[Transient hypogammaglobulinemia of infancy]] |
|[[Transient hypogammaglobulinemia of infancy]] |
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|- |
|- |
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|[[Hyper-IgM syndrome]] |
|[[Hyper-IgM syndrome]] |
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+ | |multiple |
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| |
| |
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+ | |X-linked or autosomal recessive, high IgM with poor T-cell function |
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− | | |
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− | | |
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|- |
|- |
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|[[IgA deficiency]] |
|[[IgA deficiency]] |
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+ | |decreased IgA |
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| |
| |
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+ | |low IgA, often associated with other immunodeficiencies |
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− | | |
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− | | |
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|- |
|- |
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! colspan="4" |Cell-Mediated (5%) |
! colspan="4" |Cell-Mediated (5%) |
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|near-absolute T cell deficiency |
|near-absolute T cell deficiency |
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| |
| |
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+ | |lymphopenia with hypogammaglobulinemia |
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− | | |
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|- |
|- |
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|[[Wiskott-Aldrich syndrome]] |
|[[Wiskott-Aldrich syndrome]] |
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+ | |WASP mutation |
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| |
| |
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+ | |X-linked, [[eczema]], [[thrombocytopenia]], low IgM with high IgA |
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− | | |
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− | |[[eczema]], [[thrombocytopenia]] |
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|- |
|- |
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|[[Ataxia-telangiectasia]] |
|[[Ataxia-telangiectasia]] |
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+ | |ATM mutation |
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| |
| |
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+ | |autosomal recessive, with low IgA, CD3, and CD4, and malignancies |
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− | | |
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− | | |
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|- |
|- |
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|[[X-linked lymphoproliferative disease]] |
|[[X-linked lymphoproliferative disease]] |
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+ | |SAP mutation |
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| |
| |
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+ | |X-linked, low EBNA antibodies |
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− | | |
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− | | |
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|- |
|- |
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|[[CD40 ligand deficiency]] |
|[[CD40 ligand deficiency]] |
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|STAT3 mutation |
|STAT3 mutation |
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| |
| |
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− | |eczema, pneumatoceles, mucocutaneous candidiasis, recurrent cutaneous and respiratory infections, and elevated IgE |
+ | |[[eczema]], [[Pneumatocele|pneumatoceles]], [[mucocutaneous candidiasis]], recurrent cutaneous and respiratory infections, and elevated IgE |
|- |
|- |
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! colspan="4" |Phagocytic (10%) |
! colspan="4" |Phagocytic (10%) |
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− | |- |
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− | |Phagocyte deficiencies |
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− | | |
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− | | |
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− | | |
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|- |
|- |
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|[[Chronic granulomatous disease]] (CGD) |
|[[Chronic granulomatous disease]] (CGD) |
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|- |
|- |
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|[[Leukocyte adhesion deficiency]] |
|[[Leukocyte adhesion deficiency]] |
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+ | |multiple types |
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| |
| |
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+ | |autosomal recessive |
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+ | |- |
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+ | |TLR3 deficiency |
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| |
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| |
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+ | |recurrent [[Herpes simplex encephalitis|HSV encephalitis]] |
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|- |
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! colspan="4" |Complement (5%) |
! colspan="4" |Complement (5%) |
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|- |
|- |
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− | |[[C2 deficiency]] |
+ | |[[C2 deficiency]] and other classical complement deficiencies |
+ | |classical complement pathway |
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− | | |
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− | | |
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| |
| |
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+ | |low CH<sub>50</sub>, autoimmune disease in C1-C4, bacteremia and meningitis |
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|- |
|- |
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|[[Properdin deficiency]] |
|[[Properdin deficiency]] |
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+ | |alternative complement pathway |
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| |
| |
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+ | |more severe than classical complement deficiencies |
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− | | |
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− | | |
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|- |
|- |
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! colspan="4" |Immune Dysregulation |
! colspan="4" |Immune Dysregulation |
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!Disease |
!Disease |
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!Arm of Immune System |
!Arm of Immune System |
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+ | !Notes |
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|- |
|- |
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− | ! colspan=" |
+ | ! colspan="3" |Adult-Onset Common |
|- |
|- |
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|[[IgA deficiency]] |
|[[IgA deficiency]] |
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|Humoural |
|Humoural |
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+ | | |
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|- |
|- |
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|[[Common variable immunodeficiency]] |
|[[Common variable immunodeficiency]] |
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|Humoural |
|Humoural |
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+ | | |
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|- |
|- |
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|[[IgG subclass deficiency]] |
|[[IgG subclass deficiency]] |
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|Humoural |
|Humoural |
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+ | | |
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|- |
|- |
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|[[Complement deficiencies]] |
|[[Complement deficiencies]] |
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|Complement |
|Complement |
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+ | | |
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+ | |- |
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+ | |[[Good syndrome]] |
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+ | |Combined humoural and cell-mediated |
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+ | |Very rare. Associated with thymoma and autoimmune diseases |
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|- |
|- |
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− | ! colspan=" |
+ | ! colspan="3" |Delayed Presentation Possible |
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|- |
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|[[Adenosine deaminase deficiency]] |
|[[Adenosine deaminase deficiency]] |
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|Combined |
|Combined |
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+ | | |
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|- |
|- |
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|[[Wiskott-Aldrich syndrome]] |
|[[Wiskott-Aldrich syndrome]] |
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|Combined |
|Combined |
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+ | | |
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|- |
|- |
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|[[X-linked agammaglobulinemia]] |
|[[X-linked agammaglobulinemia]] |
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|Humoural |
|Humoural |
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+ | | |
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|- |
|- |
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|[[Chronic granulomatous disease]] |
|[[Chronic granulomatous disease]] |
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|Phagocytic |
|Phagocytic |
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+ | | |
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|- |
|- |
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− | ! colspan=" |
+ | ! colspan="3" |Childhood Onset with Survival to Adulthood |
|- |
|- |
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|[[Common variable immunodeficiency]] |
|[[Common variable immunodeficiency]] |
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|Humoural |
|Humoural |
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+ | | |
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|- |
|- |
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|[[IgA deficiency]] |
|[[IgA deficiency]] |
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|Humoural |
|Humoural |
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+ | | |
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|- |
|- |
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|[[IgG subclass deficiency]] |
|[[IgG subclass deficiency]] |
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|Humoural |
|Humoural |
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+ | | |
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|- |
|- |
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|[[Complement deficiencies]] |
|[[Complement deficiencies]] |
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|Complement |
|Complement |
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+ | | |
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|- |
|- |
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|[[X-linked agammaglobulinemia]] |
|[[X-linked agammaglobulinemia]] |
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|Humoural |
|Humoural |
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+ | | |
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|- |
|- |
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|[[X-linked hyper-IgM syndrome]] |
|[[X-linked hyper-IgM syndrome]] |
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|Humoural |
|Humoural |
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+ | | |
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|- |
|- |
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|[[Chronic granulomatous disease]] |
|[[Chronic granulomatous disease]] |
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|Phagocytic |
|Phagocytic |
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+ | | |
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|- |
|- |
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|[[Severe combined immunodeficiency]] |
|[[Severe combined immunodeficiency]] |
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|Combined |
|Combined |
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+ | | |
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|- |
|- |
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|[[Wiskott-Aldrich syndrome]] |
|[[Wiskott-Aldrich syndrome]] |
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|Combined |
|Combined |
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+ | | |
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|- |
|- |
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|[[Ataxia-telangiectasia]] |
|[[Ataxia-telangiectasia]] |
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|Combined |
|Combined |
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+ | | |
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|- |
|- |
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|[[Leukocyte adhesion deficiency]] |
|[[Leukocyte adhesion deficiency]] |
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|Phagocytic |
|Phagocytic |
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+ | | |
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|} |
|} |
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− | |||
− | ==Red Flags for Immunodeficiency== |
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− | ===Children=== |
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− | |||
− | *≥4 new ear infections in 1 year |
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− | *≥2 serious sinus infections in 1 year |
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− | *≥2 months on antibiotics with little effect |
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− | *≥2 pneumonias in 1 year |
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− | *Failure to gain weight or grow normally |
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− | *Recurrent deep skin or organ abscesses |
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− | *Persistent thrush in mouth or fungal skin infection |
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− | *Need for IV antibiotics to treat infections |
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− | *≥2 deep-seated infections including bacteremia |
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− | *A family history of primary immunodeficiency |
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− | |||
− | ===Adults=== |
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− | |||
− | *≥2 new ear infections in 1 year |
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− | *≥2 new sinus infections in 1 year (in the absence of allergy) |
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− | *≥2 new pneumonias in 2 years |
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− | *Chronic diarrhea with weight loss |
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− | *Recurrent viral infections, such as colds, herpes, warts, or condylomata |
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− | *Recurrent need for IV antibiotics to treat infections |
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− | *Recurrent, deep abscesses of skin or internal organs |
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− | *Persistent thrush or fungal infections |
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− | *Infection with non-tuberculous mycobacteria |
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− | *A family history of primary immunodeficiency |
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==Investigations== |
==Investigations== |
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*CBC and peripheral blood film, for lymphopenia, abnormal or unusual lymphocytes or phagocytes, and any other notable abnormalities |
*CBC and peripheral blood film, for lymphopenia, abnormal or unusual lymphocytes or phagocytes, and any other notable abnormalities |
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**Lymphopenia may suggest T-cell immunodeficiency |
**Lymphopenia may suggest T-cell immunodeficiency |
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+ | *Other general screening tests for immunodeficiency: immunoglobulin levels (IgG, IgM, IgA), lymphocyte subpopulations, vaccine titres, and complement assessment (e.g. CH50, AH50) |
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*For suspected defect in '''humoural immunity''' |
*For suspected defect in '''humoural immunity''' |
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**Serum immunoglobulin levels (IgG, IgM, IgA, and IgE) |
**Serum immunoglobulin levels (IgG, IgM, IgA, and IgE) |
Latest revision as of 11:21, 25 October 2023
- See also immunodeficiency and acquired immunodeficiency
Clinical Manifestations
Red Flags for Immunodeficiency
Children | Adults | |
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New ear infections | ≥4 in 1 year | ≥2 in 1 year |
Serious sinus infections | ≥2 in 1 year | ≥2 in 1 year, in the absence of allergy |
Pneumonias | ≥2 in 1 year | ≥2 in 1 year |
Deep skin or organ abscesses | Recurrent | Recurrent |
Oral thrush or fungal skin infections | Persistent | Persistent |
Family history of primary immunodeficiency | Any | Any |
Other |
|
|
Differential Diagnosis
Children
Disease | Defect | Age at Diagnosis | Notes |
---|---|---|---|
Humoural (65%) | |||
X-linked agammaglobulinemia | BTK mutation | X-linked, very low antibody levels | |
Common variable immunodeficiency (CVID) | multiple | 20-40 years | low IgG with poor antibody response |
Transient hypogammaglobulinemia of infancy | |||
Hyper-IgM syndrome | multiple | X-linked or autosomal recessive, high IgM with poor T-cell function | |
IgA deficiency | decreased IgA | low IgA, often associated with other immunodeficiencies | |
Cell-Mediated (5%) | |||
DiGeorge syndrome | thymus aplasia | ||
Chronic mucocutaneous candidiasis | |||
Combined (15%) | |||
Severe combined immunodeficiency disease (SCID) | near-absolute T cell deficiency | lymphopenia with hypogammaglobulinemia | |
Wiskott-Aldrich syndrome | WASP mutation | X-linked, eczema, thrombocytopenia, low IgM with high IgA | |
Ataxia-telangiectasia | ATM mutation | autosomal recessive, with low IgA, CD3, and CD4, and malignancies | |
X-linked lymphoproliferative disease | SAP mutation | X-linked, low EBNA antibodies | |
CD40 ligand deficiency | |||
Hyper-IgE syndrome (Job syndrome) | STAT3 mutation | eczema, pneumatoceles, mucocutaneous candidiasis, recurrent cutaneous and respiratory infections, and elevated IgE | |
Phagocytic (10%) | |||
Chronic granulomatous disease (CGD) | NADPH oxidase | GI and GU granulomas, infections with Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, and Aspergillus | |
Leukocyte adhesion deficiency | multiple types | autosomal recessive | |
TLR3 deficiency | recurrent HSV encephalitis | ||
Complement (5%) | |||
C2 deficiency and other classical complement deficiencies | classical complement pathway | low CH50, autoimmune disease in C1-C4, bacteremia and meningitis | |
Properdin deficiency | alternative complement pathway | more severe than classical complement deficiencies | |
Immune Dysregulation | |||
Hemophagocytic lymphohistiocytosis | |||
Autoimmune lymphoproliferative disorder (ALPS) | |||
Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) | |||
Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) |
Adults
Disease | Arm of Immune System | Notes |
---|---|---|
Adult-Onset Common | ||
IgA deficiency | Humoural | |
Common variable immunodeficiency | Humoural | |
IgG subclass deficiency | Humoural | |
Complement deficiencies | Complement | |
Good syndrome | Combined humoural and cell-mediated | Very rare. Associated with thymoma and autoimmune diseases |
Delayed Presentation Possible | ||
Adenosine deaminase deficiency | Combined | |
Wiskott-Aldrich syndrome | Combined | |
X-linked agammaglobulinemia | Humoural | |
Chronic granulomatous disease | Phagocytic | |
Childhood Onset with Survival to Adulthood | ||
Common variable immunodeficiency | Humoural | |
IgA deficiency | Humoural | |
IgG subclass deficiency | Humoural | |
Complement deficiencies | Complement | |
X-linked agammaglobulinemia | Humoural | |
X-linked hyper-IgM syndrome | Humoural | |
Chronic granulomatous disease | Phagocytic | |
Severe combined immunodeficiency | Combined | |
Wiskott-Aldrich syndrome | Combined | |
Ataxia-telangiectasia | Combined | |
Leukocyte adhesion deficiency | Phagocytic |
Investigations
- CBC and peripheral blood film, for lymphopenia, abnormal or unusual lymphocytes or phagocytes, and any other notable abnormalities
- Lymphopenia may suggest T-cell immunodeficiency
- Other general screening tests for immunodeficiency: immunoglobulin levels (IgG, IgM, IgA), lymphocyte subpopulations, vaccine titres, and complement assessment (e.g. CH50, AH50)
- For suspected defect in humoural immunity
- Serum immunoglobulin levels (IgG, IgM, IgA, and IgE)
- Specific antibody titres
- Pre- and post-vaccination IgG titres
- Flow cytometry to count B cells
- For suspected defect in cellular immunity
- TREC newborn screen
- Flow cytometry to count CD4 and CD8 T-cells and NK cells
- Flow cytometry is almost always abnormal in SCID
- Cutaneous delayed hypersensitivity
- Spontaneous NK cytotoxicity
- For suspected deficiencies in phagocytes
- CBC and differential
- Neutrophil staining for morphology on a peripheral blood film
- Dihydrorhodamine 1,2,3 response (DHR) for neutrophil function
- Flow cytometry for adhesion molecules
- For suspected complement deficiencies
- CH50 assay (for total complement activity)
- AH50 assay (for alternative pathway activity)
- Lectin pathway function
- Level and/or function of specific complement factors
Further Reading
- Primary immunodeficiency. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):61. doi: 10.1186/s13223-018-0290-5
- Attending to Warning Signs of Primary Immunodeficiency Diseases Across the Range of Clinical Practice. J Clin Immunol. 2014;34(1):10-22. doi: 10.1007/s10875-013-9954-6
- Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015;35(8):696-726. doi: 10.1007/s10875-015-0201-1