ImmunologyTier 1Medical Sciences concept

Primary immunodeficiency syndromes - key syndromes and defects (XLA, CVID, DiGeorge, CGD)

Core concept

Classify by the arm that has failed - the infection pattern names the defect

Arm	Typical organisms	Onset
Antibody (B cell)	Encapsulated bacteria - pneumococcus, H. influenzae, Neisseria; enterovirus, Giardia, Campylobacter, mycoplasma	After 6 months, when maternal IgG wanes
T cell / combined	Opportunists - PJP, CMV, EBV, candida, Cryptosporidium, disseminated BCG/live vaccines, mycobacteria	First months of life
Phagocyte	Catalase-positive organisms - S. aureus, Serratia, Burkholderia, Nocardia, Aspergillus	Early, with abscesses and poor wound healing
Complement	Neisseria (terminal), encapsulated (early classical); SLE-like autoimmunity	Any age

Warning signs: >=2 pneumonias or >=8 otitis in a year, failure to thrive, deep abscess, persistent thrush after 1 y, need for IV antibiotics to clear infection, family history, unexplained bronchiectasis in an adult
Most adult-diagnosed primary immunodeficiency is CVID - and the first presentation is often bronchiectasis, autoimmune cytopenia or granulomatous disease, not infection

Key detail

Syndrome	Gene/defect	Inheritance	Immunology	Clinical signature
X-linked agammaglobulinaemia (Bruton)	BTK - transmits the pre-BCR signal for B-cell maturation	XL	B cells ABSENT (<1-2%), all Ig low, T cells normal	Boy, absent tonsils and lymph nodes, sinopulmonary infection from 6 mo, enteroviral meningoencephalitis
CVID	Heterogeneous (TACI, BAFF-R, ICOS, NFKB1, CTLA-4, LRBA); mostly unknown	Sporadic/AD	Low IgG (obligatory) + low IgA and/or IgM; B cells normal or low but non-functional; poor vaccine response; T cells normal with reversed CD4:CD8	Adult onset, bronchiectasis, autoimmune cytopenias, granulomatous-lymphocytic ILD, enteropathy, splenomegaly, lymphoma and gastric cancer risk
Selective IgA deficiency	-	-	IgA <0.07 g/L, other Ig normal	Commonest PID (~1:600), usually asymptomatic; *anaphylaxis to blood products containing IgA; coeliac (false-negative tTG IgA*)
Hyper-IgM	CD40L (CD154) on activated T cells - commonest form	XL	Normal/high IgM, low IgG/IgA/IgE; no class-switch recombination, no germinal centres	PJP and Cryptosporidium (it is really a T-cell defect), neutropenia, sclerosing cholangitis
DiGeorge (22q11.2 deletion)	TBX1; 3rd/4th pharyngeal pouch	de novo mostly	Thymic hypoplasia -> low T cells (variable, often mild); Ig usually normal	CATCH-22 - conotruncal cardiac defects (TOF, interrupted arch, truncus), hypocalcaemia from parathyroid hypoplasia, cleft palate, facies, learning and psychiatric disease
SCID	RAG1/RAG2 (no V(D)J recombination), IL2RG (common gamma chain, XL - commonest), ADA, JAK3, IL7R	Varies	T- (B+/-, NK+/-)	Paediatric emergency: FTT, thrush, PJP, chronic diarrhoea, absent thymic shadow; never give live vaccines; irradiated CMV-negative blood only
Wiskott-Aldrich	WAS - actin cytoskeleton	XL	Low IgM, high IgA/IgE, poor polysaccharide response, progressive T-cell loss	Eczema + thrombocytopenia with SMALL platelets + immunodeficiency; autoimmunity, lymphoma
Chronic granulomatous disease	NADPH oxidase - CYBB (gp91phox) X-linked ~65%, or autosomal (p47, p22, p67)	XL/AR	No respiratory burst - abnormal DHR/nitroblue tetrazolium	Catalase-positive organisms, granulomas causing obstruction (gastric outlet, bladder), IBD-like colitis, poor wound healing
Hyper-IgE (Job)	STAT3 (AD); DOCK8 (AR)	AD/AR	IgE >2,000 IU/mL, eosinophilia, dec Th17	Staph abscesses ("cold"), pneumonia with PNEUMATOCELES, chronic candidiasis, coarse facies, retained primary teeth, hyperextensibility, scoliosis, fractures; DOCK8 adds viral warts, molluscum, severe atopy, malignancy
Ataxia-telangiectasia	ATM - DNA repair	AR	Low IgA/IgG2, low T cells, high AFP	Ataxia -> telangiectasia -> sinopulmonary infection, lymphoma, radiosensitivity
Leukocyte adhesion deficiency	CD18 (ITGB2)	AR	Neutrophilia with no pus	Delayed cord separation, omphalitis, no abscess formation
Complement terminal (C5-C9), properdin	-	AR / XL (properdin)	Low CH50, normal AH50 pattern varies	Recurrent Neisseria meningitidis, often unusual serogroups

Clinical relevance

Screening tier

FBC with film and differential (lymphopenia, neutropenia, small platelets, Howell-Jolly bodies)
IgG, IgA, IgM (+ IgE if Job suspected), IgG subclasses
Specific antibody responses to tetanus, diphtheria and pneumococcal polysaccharide, with test immunisation and re-measurement at 4 weeks - function matters more than level
Lymphocyte subsets - CD3/CD4/CD8/CD19/CD56
CH50 (classical) and AH50 (alternative)
DHR-123 flow cytometry (has replaced NBT) for CGD
HIV serology first in every case - the commonest secondary immunodeficiency
Newborn screening by TRECs detects SCID before infection

Management principles

Immunoglobulin replacement (IVIg or SCIg) for XLA, CVID, hyper-IgM - target trough and clinical response, not a number alone
Antimicrobial prophylaxis - cotrimoxazole (PJP, and in CGD), itraconazole (CGD), penicillin (asplenia/complement)
Vaccination - inactivated vaccines; live vaccines contraindicated in T-cell and severe combined defects; meningococcal ACWY + B in complement deficiency and asplenia
HSCT is curative for SCID, WAS, CGD, hyper-IgM; gene therapy established for ADA-SCID and X-SCID
Irradiated, CMV-negative, leucodepleted blood products in T-cell defects (transfusion-associated GVHD risk)
Avoid live rotavirus vaccine and BCG until SCID is excluded in a family with a known case

Correlations

Screening tests for primary immunodeficiency
Infection patterns by immunodeficiency type
TRECs and SCID newborn screening
Complement deficiencies and infection risk
Asplenia and encapsulated organisms
Bronchiectasis in adults; granulomatous-lymphocytic ILD
Autoimmune polyendocrine syndromes; CTLA-4 and LRBA deficiency
Leukocyte adhesion deficiency

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