Immunology and AllergyTier 1Disease (DEADMAN)

Immunodeficiency syndromes - primary defects of cellular immunity

Description

Arm	Organisms	Typical syndromes
T cell (cellular)	Intracellular: CMV, EBV, disseminated VZV, PJP, atypical mycobacteria, chronic mucocutaneous candidiasis	DiGeorge, SCID, MHC class II deficiency, IL-12/IFN-gamma axis defects
B cell (antibody)	Encapsulated bacteria - S. pneumoniae, H. influenzae; Giardia; enterovirus	XLA, CVID, IgA deficiency
Complement	Neisseria (terminal C5-C9), encapsulated (early classical)	Terminal pathway deficiency
Phagocyte	Catalase-positive - S. aureus, Serratia, Burkholderia, Nocardia, Aspergillus	CGD, LAD, Chediak-Higashi

Key T-cell syndromes

22q11.2 deletion (DiGeorge) - thymic hypoplasia, hypoparathyroidism/hypocalcaemia, conotruncal cardiac defects, cleft palate, dysmorphism
- Most are partial with adequate T-cell function; complete athymia is rare
SCID - see combined B- and T-cell note
Mendelian susceptibility to mycobacterial disease - IL-12/IL-12R, IFN-gammaR, STAT1 defects
Chronic mucocutaneous candidiasis - IL-17 axis, AIRE (APECED), STAT1 gain-of-function
Hyper-IgE (Job) syndrome - STAT3: eczema, cold staphylococcal abscesses, pneumatocoeles, retained primary teeth, hyperextensibility

Primary T-cell defects are rare - combined ~1:50,000-100,000
22q11.2 deletion ~1:4,000 live births (commonest microdeletion syndrome)
Secondary cellular immunodeficiency vastly outnumbers primary: HIV, malignancy, transplantation, corticosteroids, calcineurin inhibitors, anti-CD52/CD20, malnutrition
Adult presentation of a primary T-cell defect is uncommon - exclude HIV first

Thymic development failure -> absent or non-functional T cells (22q11.2, FOXN1)
TCR signalling defects (ZAP-70, CD3 chains)
MHC expression defects
- Class II (bare lymphocyte syndrome) -> dec CD4
- Class I -> dec CD8
Cytokine axis defects
- IL-12/IFN-gamma -> disseminated BCG and non-tuberculous mycobacteria
- IL-17/Th17 -> chronic mucocutaneous candidiasis
Loss of T-cell help -> secondary antibody failure -> combined phenotype
Impaired thymic negative selection and Treg failure -> autoimmunity alongside infection

When to suspect

Recurrent or severe infection with intracellular organisms - opportunistic and viral (CMV, EBV, disseminated varicella), chronic mucocutaneous candidiasis, PJP, atypical mycobacteria
Disseminated disease after a live vaccine (BCG, rotavirus, MMR, VZV)
Failure to thrive, chronic diarrhoea, persistent lymphopenia
Autoimmunity + infection + granuloma in the same patient
Contrast: recurrent sinopulmonary bacterial infection in a young adult points to a humoral defect - CVID - with low IgG the key screening abnormality, not a cellular defect

First-line

FBE with differential - absolute lymphocyte count (persistent lymphopenia is the cheapest clue and is routinely ignored)
HIV serology + RNA - always, first
Lymphocyte subsets: CD3, CD4, CD8, CD19, CD16/56
Immunoglobulins + vaccine responses (T-cell help failure)
CXR - absent thymic shadow in infancy

Second-line

Lymphocyte proliferation to mitogen (PHA) and antigen (candida, tetanus)
Naive (CD45RA+) vs memory (CD45RO+) T cells - naive depletion indicates thymic output failure
TRECs - newborn screening for SCID
FISH/microarray for 22q11.2; targeted gene panel or WES
Flow for MHC class II expression, DHR for CGD (excludes phagocyte defect)

Traps

A. Infection - prevention

PJP prophylaxis: trimethoprim-sulfamethoxazole - for any significant CD4 depletion or defined T-cell defect
Antifungal (fluconazole/itraconazole) and antiviral (valaciclovir) prophylaxis by phenotype
Azithromycin for MAC where indicated
Aggressive early empirical treatment of febrile episodes with broad cover including atypicals

B. Vaccination

All live vaccines contraindicated - BCG, MMR, VZV, rotavirus, oral polio, yellow fever
- Live-vaccine dissemination is a classic presenting event
Inactivated vaccines given but responses may be poor
Vaccinate household contacts (cocooning)
Irradiated, CMV-negative, leucodepleted blood products - prevent transfusion-associated GVHD

C. Immunoglobulin replacement

D. Definitive

Allogeneic HSCT - curative for SCID and severe combined defects
- Outcome best if performed before 3.5 months and before infection is established -> the rationale for newborn TREC screening
Thymus transplantation for complete DiGeorge athymia
Gene therapy for defined monogenic disease (ADA-SCID, X-SCID)

E. Syndrome-specific

22q11.2: calcium and PTH management, cardiac surgery, speech/palate, developmental and psychiatric follow-up (schizophrenia risk ~25%)
IFN-gamma for CGD and some mycobacterial susceptibility defects

22q11.2: congenital heart disease, hypoparathyroidism, palatal anomalies, learning difficulty, psychiatric illness
Autoimmune cytopenias, thyroiditis, enteropathy
APECED/AIRE: hypoparathyroidism + adrenal insufficiency + mucocutaneous candidiasis
EBV-driven lymphoproliferative disease and lymphoma
Malignancy - virally driven (EBV, HPV)
Graft-versus-host disease from non-irradiated blood products

Untreated SCID is fatal in the first 1-2 years
Partial defects survive to adulthood with recurrent opportunistic infection and organ damage (bronchiectasis)
Post-HSCT survival for SCID >90% if transplanted early and infection-free, falling substantially once infection is established

Monitor

Lymphocyte subsets and immunoglobulins
Growth and development
HRCT for chronic lung damage
Malignancy and autoimmunity surveillance
Late immune reconstitution failure after HSCT - B-cell function may need ongoing Ig replacement

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