ImmunologyTier 1Medical Sciences concept

Screening tests for primary immunodeficiency

Core concept

Clinical pattern	First-line tests
Recurrent sinopulmonary infection, bronchiectasis	Quantitative IgG, IgA, IgM + specific antibody responses
Opportunistic infection, FTT in infancy, thrush	Lymphocyte subsets (CD3/4/8/19/56), HIV, TRECs in a neonate
Recurrent abscess, poor wound healing, catalase-positive organisms	FBC/differential, DHR-123 (respiratory burst)
Recurrent Neisseria, or second episode of meningococcal disease	CH50 and AH50
Recurrent angioedema	C4 (then C1-INH level and function)

*Send HIV serology in every case* - the commonest cause of acquired immunodeficiency, and it must be excluded before a primary diagnosis is made
Exclude secondary causes first: HIV, protein loss (nephrotic, protein-losing enteropathy), malignancy (CLL, myeloma, lymphoma), drugs (rituximab, steroids, anticonvulsants, chemotherapy), malnutrition, splenectomy, chronic renal or liver disease

Antibody (B-cell) screen - the commonest need in adults

1. Quantitative immunoglobulins - IgG, IgA, IgM (add IgE if hyper-IgE suspected)
- Low IgG is required for a diagnosis of CVID; check with serum electrophoresis to exclude a paraprotein or hypogammaglobulinaemia of myeloma
2. IgG subclasses - IgG1-4; isolated subclass deficiency with a normal specific response is often clinically insignificant
3. Specific antibody responses - the FUNCTIONAL test, and the one that matters
- Protein (T-dependent) antigens: tetanus, diphtheria, Hib conjugate
- Polysaccharide (T-independent) antigen: 23-valent pneumococcal (Pneumovax) - this is the response selectively lost in specific antibody deficiency, and it cannot be assessed in children under 2
- Test-immunise and remeasure at 4 weeks - a >=4-fold rise, or protective titres to >=70% of serotypes, is a normal response
4. Isoagglutinins (anti-A / anti-B) - naturally occurring, mostly IgM against polysaccharide blood group antigens; a cheap functional screen of IgM antibody production
- Uninterpretable in blood group AB, and low under 6 months of age
5. Anti-streptolysin O - evidence of past natural antibody responses
6. B-cell number by flow (CD19/CD20) - absent in XLA, normal or low in CVID; memory B-cell subsets (switched CD27+IgD-) refine CVID prognosis

The other arms

T cell / combined - lymphocyte subsets (absolute counts, not just percentages), lymphocyte proliferation to mitogens (PHA) and antigens, HIV, thymic shadow on CXR in an infant, 22q11 FISH/array
- Newborn screening by TRECs detects T-cell lymphopenia (SCID) before any infection
Phagocyte - FBC and differential with film (neutropenia, giant granules of Chediak-Higashi), DHR-123 flow cytometry (has replaced NBT for CGD; also identifies X-linked carriers), CD18/CD11b flow for leukocyte adhesion deficiency
Complement - CH50 (classical + terminal), AH50 (alternative + terminal), then individual components; C4 and C1-INH level and function for angioedema
NK cells - CD16/CD56 number and cytotoxicity; perforin expression in suspected HLH

A normal immunoglobulin level does not exclude antibody deficiency - specific antibody deficiency has normal IgG with an absent polysaccharide response
Do not start immunoglobulin replacement before taking the diagnostic samples - once IVIg is given, endogenous production and specific antibody responses cannot be assessed for months
Do not give live vaccines (MMR, varicella, yellow fever, BCG, oral polio, live rotavirus) until a T-cell defect is excluded; use irradiated, CMV-negative, leucodepleted cellular blood products
Timing clues
- Onset after 6 months -> antibody deficiency (maternal IgG waned)
- Onset in the first weeks -> combined/T-cell defect or phagocyte defect
- Adult onset -> CVID, or a secondary cause
Bronchiectasis in a non-smoker without CF should always prompt immunoglobulins - CVID is commonly diagnosed a decade late, by which time lung damage is fixed
Autoimmunity, granulomatous disease, enteropathy and lymphoma may be the presenting features of CVID rather than infection
Genetic testing (targeted panel or exome) where the phenotype is suggestive - increasingly first-line in children and changes management (HSCT, gene therapy, targeted agents such as abatacept for CTLA-4 haploinsufficiency)

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