Primary immunodeficiency
From IDWiki
- See also immunodeficiency and acquired immunodeficiency
Clinical Manifestations
Red Flags for Immunodeficiency
| Children | Adults | |
|---|---|---|
| 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
