The overall prevalence of IEI is estimated to be approximately 1 in 1,000 to 1 in 5,000. Common variable immunodeficiency (CVID), the most frequently diagnosed IEI, has a prevalence of 1 in 25,000 to 1 in 50,000. Certain IEIs are more common in populations with high consanguinity or founder mutations.

IEIs arise from single-gene mutations that impair the development, differentiation, or function of immune cells or molecules. These mutations can be inherited in autosomal recessive, autosomal dominant, or X-linked patterns (see RareShare Guide on Genetic Inheritance). The underlying defects can affect:

• Innate immunity: including phagocyte (cells capable of engulfing particles) function (e.g., Chronic Granulomatous Disease), complement pathways, and pattern recognition receptors (e.g., TLR signaling defects).

• Adaptive immunity: affecting B-cell development (e.g., agammaglobulinemia), T-cell signaling (e.g., Severe Combined Immunodeficiency or SCID), or antibody production (e.g., CVID).

• Immune regulation: causing autoimmunity or hyperinflammatory syndromes (e.g., IPEX, ALPS, CTLA4 deficiency).

A mechanism-based approach referencing the major defective immunological pathway is used to classify IEIs. The major categories of IEI include:

• Predominantly Antibody Deficiencies: This is the largest single group, accounting for approximately 50% of all diagnosed PIDs. These disorders are characterized by absent, low, or faulty antibodies, leading to increased susceptibility to infections. Examples include Common Variable Immune Deficiency (CVID) and X-linked agammaglobulinemia (XLA).

• Combined Immunodeficiencies (CIDs) and Predominantly T-cell Deficiencies: These affect cellular immunity and are often severe, encompassing conditions like Severe Combined Immunodeficiency (SCID).

• Phagocytic Disorders: These involve defects in innate cellular function, such as Chronic Granulomatous Disease (CGD).

• Complement Deficiencies: Accounting for a small percentage of PIDs (less than 2%), these defects impair functions like opsonization and lysis that target the destruction of microorganisms. Deficiencies in complement components are associated with autoimmune diseases such as Systemic Lupus Erythematosus (SLE).  

While IEIs typically result from a mutation in a single gene, a combination of genetic vulnerability and environmental factors may also contribute to manifestation of the disease.

Symptoms of IEIs are highly variable depending on the specific genetic defect and family history. Common features may include:

• Recurrent or severe infections involving the respiratory tract, skin, gastrointestinal system or bloodstream.

• Failure to thrive in infants or children, such as poor growth and weight loss.

• Chronic diarrhea or malabsorption.

• Autoimmune problems such as lupus, type 1 diabetes or thyroiditis.

• Allergic manifestations including eczema or food allergies.

• Enlarged lymph nodes, spleen or liver.

• Inflammation of internal organs.

• Blood disorders such as cytopenias or low numbers of mature blood cells.

IEI diagnosis requires a combination of clinical evaluation, laboratory testing, and genetic analysis including:

1. Clinical suspicion: based on recurrent, severe, or unusual infections; poor growth; or family history.

2. Basic laboratory tests:

   • Complete blood count with differential (for lymphopenia or neutropenia)

   • Quantitative immunoglobulin levels (IgG, IgA, IgM, IgE)

   • Vaccine response testing (to evaluate antibody function)

3. Advanced immunologic testing:

   • Flow cytometry for lymphocyte subsets (T, B, NK cells)

   • Neutrophil oxidative burst testing (for phagocyte defects)

   • Complement activity assays

4. Genetic testing:

   • Targeted gene panels, whole-exome sequencing (WES), or whole-genome sequencing (WGS) for molecular confirmation.

5. Functional assays:

   • Cytokine release, proliferation, or signaling studies to assess immune function.

Management depends on the type and severity of the immune defect, and aims to prevent infection, correct immune dysfunction and manage complications.

• Infection prevention and control:

  • Prophylactic antibiotics, antifungals, or antivirals.

  • Immunoglobulin replacement therapy (IVIG or SCIG) for antibody deficiencies.

  • Aggressive treatment of infections.

• Immune restoration or modulation:

  • Hematopoietic stem cell transplantation (HSCT) is curative for several severe forms such as SCID, Wiskott–Aldrich syndrome, and chronic granulomatous disease.

  • Gene therapy has shown success in specific IEIs like ADA-SCID and X-linked SCID.

  • Immunosuppressive or biologic therapies (e.g., corticosteroids, rituximab, abatacept, or JAK inhibitors) for autoimmune or hyperinflammatory complications.

• Supportive care:

  • Nutritional support, infection surveillance, vaccination with inactivated vaccines, and avoidance of live vaccines in most cases.

The prognosis for IEI varies widely depending on the genetic subtype, severity, and timing of diagnosis and treatment. Early diagnosis and appropriate management have significantly improved survival and quality of life. Severe combined immunodeficiencies are fatal within the first year of life if untreated, but with HSCT or gene therapy, survival rates now can exceed 90% for some types. Individuals with milder IEIs, such as CVID, may live into adulthood but are at risk for chronic lung disease, autoimmunity, and malignancy.

For patients successfully managed with immunoglobulin replacement therapy or who have survived curative HSCT, the focus shifts from immediate life extension to the management of chronic morbidity. Patients may face ongoing risks from severe chronic infections or progressive organ damage.

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2. Tangye SG, Nguyen T, Deenick EK, Bryant VL, Ma CS. 2023. “Inborn errors of human B cell development, differentiation, and function.” J Exp Med. 220(7):e20221105. doi: 10.1084/jem.20221105. Epub 2023 Jun 5. PMID: 37273190; PMCID: PMC10242086.

3. The Binding Site:  Primary Immunodeficiency (PID).

4. Centers for Disease Control and Prevention:  About Primary Immunodeficiency (PI).

5. Immune Deficiency Foundation:  What is PI?.