Immunology and AllergyTier 1Disease (DEADMAN)

Immunodeficiency syndromes - agammaglobulinaemia and hypogammaglobulinaemia

Description

Failure of antibody production -> recurrent encapsulated bacterial sinopulmonary and GI infection

The three that matter

	Defect	B cells	Ig	Onset
XLA (Bruton)	BTK, X-linked recessive	Absent (<2%)	All classes absent	6-9 months (after maternal IgG wanes)
CVID	Heterogeneous; TACI, ICOS, BAFF-R, NFKB1	Present but do not differentiate	dec IgG + (IgA or IgM)	Bimodal, peak 20-40
Selective IgA deficiency	Unknown; commonest PID	Present	IgA <0.07 g/L, IgG/IgM normal	Often asymptomatic

Discriminator: absent circulating B cells = XLA. Normal B-cell number with low Ig = CVID
Secondary hypogammaglobulinaemia is far commoner than primary
- Rituximab and other anti-CD20, myeloma, CLL, nephrotic syndrome, protein-losing enteropathy, corticosteroids, antiepileptics

XLA

BTK mutation -> pre-B-cell receptor signalling fails
- -> maturation arrest beyond the pre-B-cell stage
- -> near-complete absence of circulating B lymphocytes
- -> absent immunoglobulin of all classes
T-cell number and function normal

CVID

Defective B-cell terminal differentiation to plasma cells
- Class-switch and memory B-cell (CD27+IgD-) generation impaired
Monogenic cause identified in only ~10-20%
Coexisting T-cell dysregulation explains the autoimmune and granulomatous phenotype

Selective IgA deficiency

Clinical pattern - infection phenotype localises the defect

Antibody deficiency: recurrent sinopulmonary infection (S. pneumoniae, H. influenzae), otitis, bronchiectasis, GI infection (Giardia, Campylobacter), malabsorption, polyarthropathy
Contrast T-cell defect: opportunistic, viral and fungal infection (PJP, CMV, disseminated VZV, chronic mucocutaneous candidiasis, atypical mycobacteria)
Recurrent sinopulmonary bacterial infection in a young adult = humoral, not cellular, defect
Enteroviral meningoencephalitis - characteristic of XLA

First-line testing

Serum IgG, IgA, IgM - low IgG is the key screening abnormality
Lymphocyte subsets - CD19/CD20 count
- Absent mature B cells = XLA (Bruton, BTK mutation)
- Normal B cells + low Ig = CVID
Vaccine response: pre/post pneumococcal polysaccharide and tetanus/Hib titres
- Cannot interpret once Ig replacement has started - test first
SPEP, HIV, renal and GI protein loss, drug history - exclude secondary causes before labelling primary
BTK sequencing / flow for BTK protein confirms XLA
Baseline HRCT chest for bronchiectasis

A. Immunoglobulin replacement - the mainstay

Monthly IVIg, or weekly/fortnightly SCIg
- Typical 0.4-0.6 g/kg/month IV; titrate to trough IgG and, more importantly, to infection frequency
- SCIg: steadier levels, home administration, no systemic reaction, local site reactions instead
Same approach in XLA and CVID
Australia: supplied under the National Blood Authority Criteria for the Clinical Use of Immunoglobulin

B. Infection management

Prompt, longer-course antibiotics for any bacterial infection - low threshold
Prophylactic antibiotics (e.g. azithromycin) if breakthrough infection despite adequate trough
Airway clearance and physiotherapy once bronchiectasis established

C. Vaccination

Live vaccines contraindicated - MMR, VZV, yellow fever, oral polio, BCG
Inactivated vaccines safe but likely ineffective - give to household contacts instead
After significant varicella exposure: passive immunisation with VZIG (not active/live vaccination) - they cannot mount an antibody response
- Consider aciclovir prophylaxis

D. CVID-specific complications

Granulomatous-lymphocytic interstitial lung disease - steroids, rituximab
Autoimmune cytopenias - steroids, rituximab; Ig replacement alone insufficient
Enteropathy - exclude Giardia and coeliac-like villous atrophy

Traps

Selective IgA deficiency: risk of anaphylaxis to blood products containing IgA - use washed cells
Do not give Ig replacement for isolated IgA deficiency

Prognosis transformed by Ig replacement - now normal or near-normal lifespan in XLA
Bronchiectasis is the main preventable morbidity - driven by delay to diagnosis, not by trough level alone
CVID mortality driven by lung disease, lymphoma and enteropathy, not by acute infection
- Non-infectious complications predict death far more strongly than infection burden

Monitor

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