Primary immunodeficiencies (PIDs) encompass a vast array of over 450 identified types, with approximately 20 constituting over 90% of cases. Some conditions are so rare that they have fewer than ten documented cases.

Classifying PIDs

The classification of PIDs is a dynamic process that undergoes biennial revisions by an international committee of experts. This involves updating the grouping of PID conditions based on symptoms, introducing new conditions, and incorporating information on the underlying genetic causes.

Currently, PIDs are categorized into eight major subcategories, each organized according to the affected cells or components of the immune system. This comprehensive classification system enhances understanding and management strategies for the diverse spectrum of primary immunodeficiencies:

1. Combined Immunodeficiencies

This category encompasses severe combined immune deficiency (SCID) and combined immune deficiency (CID). Many disorders fall within this category, often necessitating a bone marrow transplant during early life.

2. Well-defined syndromes with Immunodeficiency

Conditions in this category often exhibit various non-immune system features. Examples include DiGeorge syndrome, Hyper IgE Syndrome, and Wiskott-Aldrich syndrome.

3. Predominantly Antibody Deficiencies

This extensive category includes severe and mild disorders characterized by low levels of antibodies or their ineffectiveness in guarding against significant infections. Examples include common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA).

4. Diseases of Immune Dysregulation

Disorders in this category involve the immune system’s struggle to control specific viruses or its failure to “switch off” activated ones. Examples include disorders leading to HLH (Haemophagocytic lymphohistiocytosis) and those involving autoimmunity, such as ALPS (autoimmune lymphoproliferative syndrome).

5. Congenital Defects of Phagocyte Number, Function, or Both

This category consists of neutrophil disorders, including chronic granulomatous disorder (CGD), leukocyte adhesion deficiency (LAD), and GATA2 deficiency.

6. Defects in Innate Immunity

Conditions in this category include chronic mucocutaneous candidiasis (CMC), such as STAT1 dysregulation, or those that make individuals prone to severe bacterial infections in early life, such as IRAK4 deficiency.

7. Autoinflammatory Disorders

This category comprises hereditary fever syndromes, including Muckle-Wells Syndrome and Familial Mediterranean Fever.

8. Complement Deficiencies

Complement disorders encompass conditions that make individuals prone to certain infections (like C8 deficiency) and those characterized by angioedema (such as C1 esterase deficiency and HAE).

This classification was reviewed by the Chair of the Medical Advisory Panel in January 2019.