Key Facts

Immunodeficiency disorders impair the body's ability to fight infections and, in some cases, malignancy. They are broadly classified as primary (inherited) or secondary (acquired). Understanding the immune system's components is essential for recognising patterns of susceptibility.

Epidemiology

Primary immunodeficiencies collectively affect approximately 1 in 2,000 live births. Antibody deficiencies account for approximately 65% of primary immunodeficiencies. Secondary immunodeficiency is far more common, with HIV infecting approximately 105,000 people in the UK and iatrogenic immunosuppression affecting hundreds of thousands.

Aetiology

Primary immunodeficiencies are classified by the component affected:

• B-cell/antibody defects (65%): CVID, X-linked agammaglobulinaemia, selective IgA deficiency
• T-cell defects (15%): DiGeorge syndrome, severe combined immunodeficiency (SCID)
• Combined B and T cell (10%): SCID variants, Wiskott-Aldrich syndrome
• Phagocyte defects (5%): Chronic granulomatous disease, leucocyte adhesion deficiency
• Complement defects (5%): C2 deficiency (most common), terminal complement deficiencies

Secondary causes: HIV, malnutrition, diabetes, uraemia, immunosuppressive drugs, splenectomy, haematological malignancy

Pathophysiology

Each component of the immune system provides distinct protective functions:

• Antibodies: Opsonisation, neutralisation, complement activation — deficiency leads to encapsulated bacterial infections
• T cells: Intracellular pathogen defence — deficiency leads to viral, fungal, and opportunistic infections
• Phagocytes: Bacterial and fungal killing — deficiency leads to skin abscesses, deep-seated infections
• Complement: Opsonisation, membrane attack complex — deficiency predisposes to Neisseria infections and SLE

Antibody Deficiency

• Recurrent sinopulmonary infections (Streptococcus pneumoniae, Haemophilus influenzae)
• Chronic diarrhoea (Giardia lamblia)
• Bronchiectasis from recurrent infections

T-Cell Deficiency

• Opportunistic infections: Pneumocystis jirovecii, CMV, Candida, Cryptosporidium
• Severe viral infections (measles, varicella)
• Failure to thrive in infancy

Phagocyte Defects

• Recurrent skin abscesses (Staphylococcus aureus, Aspergillus)
• Deep-seated infections: liver abscesses, lymphadenitis
• Delayed wound healing

Complement Deficiency

• Recurrent Neisseria meningitidis infections (terminal complement C5-C9)
• SLE-like illness (early classical pathway C1-C4)
• Hereditary angioedema (C1 esterase inhibitor deficiency)

Red Flags

• Failure to thrive with recurrent infections in infancy
• Two or more severe bacterial infections (meningitis, sepsis, osteomyelitis)
• Infections with unusual organisms or unusual severity
• Family history of early childhood death from infection
• Absent tonsils/lymph nodes on examination

Bedside

• Clinical assessment: Growth charts, lymph node palpation, tonsil inspection
• HIV point-of-care test: Rapid result in secondary immunodeficiency screening

Bloods

• FBC with differential: Lymphopenia (T-cell defects), neutropenia
• Serum immunoglobulins: IgG, IgA, IgM levels — low in antibody deficiencies
• Lymphocyte subsets: CD3 (T cells), CD4/CD8 ratio, CD19 (B cells), CD56 (NK cells)
• Complement levels: CH50/CH100 (total classical pathway), C3, C4, AP50 (alternative pathway)
• Vaccine antibody responses: Measure IgG to tetanus, pneumococcal serotypes pre/post vaccination
• HIV test: Fourth-generation combined antigen/antibody

Imaging

• CXR: Absent thymic shadow in SCID/DiGeorge, bronchiectasis
• CT thorax: Bronchiectasis, lymphadenopathy, granulomata

Special Tests

• NBT/DHR test: Chronic granulomatous disease — absent oxidative burst
• Genetic testing: Targeted or whole-exome sequencing for primary immunodeficiencies
• TREC assay: Newborn screening for SCID (measures T-cell receptor excision circles)

Non-pharmacological

• Patient education on infection avoidance and early treatment-seeking
• Avoidance of live vaccines in T-cell and severe combined deficiencies
• Genetic counselling for primary immunodeficiencies
• Spleen-related precautions if asplenic/hyposplenic

Pharmacological

• Immunoglobulin replacement therapy: IV (IVIg 0.4-0.6g/kg every 3-4 weeks) or subcutaneous (SCIg weekly) for antibody deficiencies
• Prophylactic antibiotics: Co-trimoxazole 960mg OD for Pneumocystis prophylaxis in T-cell defects
• Antifungal prophylaxis: Itraconazole in chronic granulomatous disease
• Antiretroviral therapy: For HIV — start regardless of CD4 count (NICE NG142)
• Interferon-gamma: In chronic granulomatous disease to enhance phagocyte function

Surgical

• Haematopoietic stem cell transplantation (HSCT): Curative for SCID, chronic granulomatous disease, Wiskott-Aldrich syndrome
• Gene therapy: Emerging treatment for ADA-SCID, X-linked SCID
• Thymic transplantation: For complete DiGeorge syndrome

Referral Criteria

• Any suspected primary immunodeficiency — refer to clinical immunology
• Recurrent infections requiring hospitalisation
• Family history of primary immunodeficiency
• Unexplained bronchiectasis

• SCID: Fatal within first year without HSCT; >90% survival with early matched sibling transplant
• CVID: Life expectancy reduced by 10-15 years; 20% develop autoimmune complications, 10% develop lymphoma
• X-linked agammaglobulinaemia: Good prognosis with adequate IgG replacement; chronic lung disease is main comorbidity
• Chronic granulomatous disease: Median survival now >40 years with prophylaxis; HSCT offers cure
• HIV: Near-normal life expectancy with early ART initiation; CD4 count <200 cells/µL defines AIDS

Classification of Primary Immunodeficiencies

Organisms by Immune Defect