Primary immunodeficiency comprises a group of inherited disorders, typically presenting in infancy or early childhood, in which one or more components of the immune system are absent or dysfunctional, leading to increased susceptibility to recurrent, severe, or unusual infections.

Exam domain	One-glance essentials
Definition / diagnosis	Inherited disorders causing quantitative or functional immune defects ^[1] Classify by antibody, combined, phagocyte, complement or immune-dysregulation phenotype ^[1]
Epidemiology / risks	Consanguinity, family history and male relatives suggest inherited disease ^[1] Certain syndromic features point to specific defects ^[1]
Core mechanism	The affected immune compartment predicts organism and infection pattern ^[1] Live organisms become dangerous in severe T-cell defects ^[1]
Clinical picture	Recurrent, severe, persistent or unusual infections ^[1] Poor growth, chronic diarrhoea, deep abscesses and absent tonsils are clues ^[1]
Investigations	Start with FBC/differential, immunoglobulins and HIV exclusion ^[2] Then lymphocyte subsets, vaccine responses, complement and functional/genetic tests ^[2]
Management	Treat infection early; immunoglobulin replacement for selected antibody defects ^[3] HSCT is curative for many severe combined disorders ^[3]
Complications	Bronchiectasis, chronic viral/fungal infection and failure to thrive ^[4] Autoimmunity, lymphoproliferation and malignancy may dominate ^[4]
Prevention / follow-up	Avoid live vaccines and non-irradiated blood when severe T-cell deficiency is possible ^[3] Prophylaxis and household vaccination reduce exposure ^[3]
Exam traps	*Repeated infection alone is common; pattern and severity matter* ^[2] A normal total white count does not exclude serious immunodeficiency ^[3]

References

^[1] Lecture slides: GC 096. Why do I always get sick.pdf (slide on PIDs vs SIDs definitions)

^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp. 406–411, Section 10.3.2 Primary Immunodeficiency)

^[3] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp. 406–411, Section 10.3.2 Primary Immunodeficiency)

^[4] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp. 406–411, Section 10.3.2 Primary Immunodeficiency)

Primary Immunodeficiency (PID) / Inborn Errors of Immunity (IEI) — Paediatrics

Primary immunodeficiency (PID) refers to a heterogeneous group of genetically determined defects in the immune system that predispose individuals to recurrent, severe, or unusual infections, as well as autoimmunity, auto-inflammation, allergy, malignancy, and hemophagocytosis ^[1]^[2]^[3].

"Diseases with a predisposition (mostly genetic) to recurrent infections, malignancy, autoimmune, auto-inflammatory and allergic diseases" — this is the working definition from the GC and investigations lectures ^[1]^[4].

The term has evolved:

Historically called Primary Immunodeficiency Diseases (PIDs)
Now referred to as Inborn Errors of Immunity (IEI) — this newer terminology (IUIS endorsed) better reflects the breadth of phenotypes beyond just "immunodeficiency" (i.e., includes immune dysregulation, auto-inflammation) ^[2]^[3]

Etymology:

"Primary" = the defect is intrinsic (originating in the immune system itself), as opposed to "secondary" immunodeficiency which is acquired from extrinsic causes (HIV, drugs, malnutrition, protein-losing states)
"Inborn" = present from birth (genetic), though clinical manifestation may not appear until later in life
"Errors" = specific molecular/genetic mistakes rather than a global "deficiency"

Key Distinction: Primary vs Secondary Immunodeficiency

Primary Immunodeficiencies (PIDs): Inherent dysfunctions of the immune system; generally genetic in aetiology; can be hereditary or arising from de novo mutations ^[1].

Secondary Immunodeficiencies (SIDs): Secondary to other conditions or pathologies; potential causes include lymphoproliferative diseases and malignancies, medications, infections (HIV), advanced age, malnutrition, protein-losing states ^[1].

This distinction is the first branch point in any child presenting with recurrent infections.

2. Epidemiology

PID occurs in approximately ~1 in 4,000 births ^[2]^[3] — though this is likely an underestimate due to underdiagnosis, particularly in resource-limited settings
> 440 different diseases were recognised (as per the older IUIS classification referenced in senior notes) ^[2]; the 2024 IUIS update now lists 559 entities across 10 categories, with 67 novel monogenic disorders added compared to the 2022 version ^[4]
First described in 1952 by Colonel Ogden Bruton — who identified X-linked agammaglobulinaemia (XLA) in a boy with recurrent bacterial infections and absent gamma globulins on serum protein electrophoresis ^[4]

From senior notes and lecture data ^[2]^[3]:

PID Category	Approximate Proportion
Humoral (antibody) deficiency	36.3% (most common category)
Combined immunodeficiency	19.8%
CID with syndromic features	15.2%
Phagocyte defects	14.9%
Complement deficiency	~2-5%
Immune dysregulation	Variable
Others (innate, auto-inflammatory, etc.)	Variable

Several PIDs are X-linked, accounting for male preponderance of some PID ^[4]
- XLA (Bruton's) — X-linked recessive (XLR)
- X-linked Hyper-IgM syndrome — XLR
- Wiskott-Aldrich syndrome — XLR
- X-linked SCID (IL-2Rγ chain deficiency) — XLR, the most common form of SCID
- X-linked CGD (~60% of CGD cases) — XLR
Other PIDs are autosomal recessive (e.g., some SCID forms, LAD) or autosomal dominant (e.g., hereditary angioedema types I/II)

Hong Kong has an active PID registry and newborn screening programme (NBS) for SCID using TREC (T-cell receptor excision circles) assays — increasingly adopted worldwide
Consanguinity rates are low in Hong Kong compared to Middle Eastern populations, but autosomal recessive PIDs still occur
Delayed treatment is associated with complications such as bronchiectasis ^[4] — hence early recognition and referral to paediatric immunologists is critical
The Queen Mary Hospital Paediatric Immunology service (Prof YL Lau's unit) is the major referral centre

This is a critical clinical pearl for paediatrics:

Age	Likely PID Category	Reason
Neonates (0–28 days)	SCID, LAD, complement deficiency	Severe early-onset; LAD → omphalitis/delayed cord separation
4–6 months	Humoral (antibody) deficiency (XLA)	Maternal IgG depletes by 4–6 months — so antibody deficiency manifests after this "grace period"
Infancy–early childhood	SCID, CGD, DiGeorge, WAS	T-cell and phagocyte defects present early with severe/unusual infections
Childhood–adolescence–early adulthood	CVID, selective IgA deficiency	CVID = late-onset hypogammaglobulinaemia ^[4]^[5]

Why do humoral deficiencies present after 4-6 months?

During pregnancy, maternal IgG crosses the placenta (active transport via FcRn receptors). This provides passive immunity to the newborn. IgG has a half-life of ~21 days. By 4–6 months, maternal IgG is depleted. In normal infants, the child's own B cells are now producing IgG. In XLA or other severe antibody deficiencies, the child cannot make their own IgG → infections begin. This is why "the honeymoon period" ends at 4–6 months.

3. Anatomy and Functional Immunology Review (Paediatric Focus)

Understanding PID requires understanding the normal immune system. Let's build from first principles.

Organ	Role	PID Relevance
Bone marrow	Haematopoiesis; B cell maturation	All PIDs with stem cell defects; BM failure syndromes
Thymus	T cell maturation and selection	DiGeorge syndrome → hypoplastic thymus → impaired T cell immunity ^[2]^[3]; absent thymus shadow on CXR in SCID ^[2]^[3]
Spleen	Filtering encapsulated bacteria; marginal zone B cells	Functional/anatomical asplenia (e.g., in sickle cell)
Lymph nodes	Antigen presentation; germinal centre reactions	Absent/hypoplastic in XLA (no germinal centres); lymphoproliferation in CVID
Tonsils	Mucosal-associated lymphoid tissue	Absent tonsils in XLA (no B cells to form lymphoid tissue) ^[2]
Gut-associated lymphoid tissue (GALT)	Mucosal immunity, IgA production	Relevant to GI infections in antibody deficiency

3.3 Key Cell Types and Their Functions

Origin: bone marrow stem cells → pro-B → pre-B → immature B → mature B → (antigen activation) → plasma cells
Function: produce immunoglobulins (antibodies)
Key step: Btk (Bruton tyrosine kinase) is essential for all stages of B cell development ^[2] — this is mutated in XLA
Class switching: B cells initially produce IgM, then switch to IgG, IgA, or IgE via CD40–CD40L interaction and AID (activation-induced cytidine deaminase)
- Hyper-IgM syndrome: failure of class switching (CD40L mutation in the most common X-linked form) → ↑IgM, ↓IgG/IgA/IgE ^[2]^[5]

Origin: bone marrow stem cells → migrate to thymus → undergo positive and negative selection → mature T cells
CD4+ (Helper T cells): orchestrate immune responses; activate B cells (via CD40L), macrophages (via IFN-γ); produce cytokines
CD8+ (Cytotoxic T cells): kill virus-infected cells, tumour cells
Defective T cells → susceptibility to viral, fungal, intracellular bacterial infections, and opportunistic organisms

Neutrophils: first responders; kill via oxidative burst (NADPH oxidase → superoxide → hypochlorous acid) and granule enzymes
- CGD: phagocytes fail to produce superoxide → inability to destroy microbes (especially catalase-positive organisms) ^[2]^[3]
- LAD: deficiency of neutrophil surface adhesion molecule (CD18) → inability to leave vasculature ^[2]^[3]
Macrophages/Monocytes: phagocytosis, antigen presentation, cytokine production

Three activation pathways: Classical (C1, C2, C4), Lectin, Alternative (C3)
Terminal pathway: C5–C9 → membrane attack complex (MAC)
Functions: opsonisation (C3b), chemotaxis (C3a, C5a), lysis (MAC)
Early component deficiency (C1, C2, C4) → predisposes to SLE ^[3]
C3 deficiency → predisposes to S. pneumoniae and H. influenzae ^[3]
C5–C9 deficiency → predisposes to Neisseria infections ^[3]

Innate lymphoid cells; kill virus-infected and tumour cells without prior sensitisation
Defects → susceptibility to herpesvirus infections

Ig Class	Key Properties	Clinical Relevance
IgG	Most abundant; crosses placenta; 4 subclasses	Pan-hypoglobulinaemia in XLA; ↓↓↓IgG in CVID
IgA	Mucosal immunity (secretory IgA); most produced daily	Selective IgA deficiency = most common PID ^[2]
IgM	First antibody produced; pentameric; complement fixation	↑ in Hyper-IgM syndrome
IgE	Allergic responses; anti-parasitic	Markedly elevated in Hyper-IgE syndrome ^[2]
IgD	B cell surface receptor; uncertain exact function	Less clinically relevant

This is crucial because paediatric normal ranges differ from adults:

Parameter	Neonate	6 months	1–5 years	> 5 years
Absolute lymphocyte count (ALC)	2,000–11,000	4,000–13,500	2,000–8,000	1,500–6,500
IgG (g/L)	5–17 (maternal)	1.0–4.0 (nadir)	5–13	6–16
IgM (g/L)	0.05–0.3	0.15–1.0	0.5–2.0	0.5–2.0
IgA (g/L)	0.01–0.05	0.03–0.8	0.2–1.0	0.7–4.0

Clinical Pearl: Lymphopenia in Infants

Lymphopenia in infants is defined by < 2,500 cells/μL ^[3] — do NOT use adult cut-offs (which are ~1,000–1,500). A "normal" adult lymphocyte count may actually represent severe lymphopenia in an infant, and SCID could be missed. Always use age-appropriate reference ranges.

Persistent lymphopenia < 1,500 cells/μL in children over 5 years is also a red flag ^[3].

3.6 Mechanism-First Framework: Predict Every Entity From the Broken Node [8]

The 500+ inborn errors of immunity look like a memorisation list. They are not. GC 144 deliberately teaches every entity in the same five-line format — immune pathway → gene → pathogens → tests → treatment ^[8] — because the first line predicts the other four. If you can say which node of the immune system is broken and what that node normally does, you can derive the pathogens, the blood-test signature, the age of onset and the treatment without memorising them.

Ask these four questions of any IEI and the whole entity falls out:

Question	What it predicts	Example
1. Which pathway is broken? (adaptive-humoral, adaptive-cellular, innate-cellular, innate-humoral, a single cytokine circuit, or a tolerance brake)	The category and the broad infection pattern	BTK → adaptive-humoral → sinopulmonary bacterial infections
2. What job did that pathway do? i.e. which pathogen class needs it to be cleared	The specific organisms	Terminal complement lyses Neisseria → C5–C9 deficiency = Neisseria only
3. Where in development is the block?	Which cell is missing on the CBC/lymphocyte subset, and the age of onset	IL2RG blocks IL-7/IL-15 signalling → T⁻ B⁺ NK⁻, presents in first months
4. Loss of a defence, or loss of a brake / gain of function?	Infection (deficiency) vs autoimmunity, autoinflammation, atopy or lymphoproliferation (dysregulation) — and therefore replace vs block as treatment	NLRP3 gain-of-function → IL-1 overproduction → fever + urticaria → IL-1 blockade

The one-line version

Deficiency of a defence → infection by whatever that defence normally kills. Gain of function or loss of a brake → inflammation, autoimmunity or atopy. Treatment mirrors the mechanism: replace what is missing, block what is overactive, cover the pathogen gap, and avoid the live organisms the gap lets in. ^[8]

GC 144 organises IEI on two axes — adaptive vs innate and humoral (soluble) vs cellular ^[8]. Every classical entity sits in one quadrant; the cytokine-circuit diseases (Category 6) and dysregulation diseases (Categories 4 and 7) are the wiring between quadrants.

Each pathogen class is cleared by one dominant mechanism. When a child's infections cluster around one class, that mechanism is what is broken ^[8].

Infection pattern in the history	What normally clears it	So the defect is in…	Entities
Encapsulated bacteria (pneumococcus, Hib, Moraxella) → sinusitis, otitis, pneumonia, bronchiectasis	Opsonisation: IgG + C3b coat the polysaccharide capsule so phagocytes can grip it	Antibody production or C3 or the spleen	XLA, CVID, Hyper-IgM, C3 deficiency, asplenia
Neisseria meningitis/sepsis, often recurrent, otherwise well	Membrane-attack-complex lysis (C5–C9) — Neisseria is thin-walled and killed by lysis, not phagocytosis	Terminal complement	C5–C9 deficiency (also properdin)
Catalase-positive bacteria (Staph aureus, Serratia, Burkholderia, Nocardia) and Aspergillus → deep abscesses, liver/lung/bone, granulomas	Respiratory burst (NADPH oxidase → superoxide → hypochlorite) inside the phagosome	Phagocyte killing	CGD (CYBB X-linked; NCF1 AR)
Staphylococcal/Gram-negative skin and mucosal infections without pus, delayed cord separation, neutrophilia	Neutrophil adhesion and migration out of vessels (CD18 integrins)	Phagocyte trafficking	LAD
Recurrent bacterial infections, gingivitis, ANC < 0.5	Neutrophil production	Phagocyte number	Severe congenital neutropenia (ELANE, HAX1), cyclic neutropenia
Everything at once in an infant: CMV, RSV, VZV (incl. vaccine strain), PJP, Candida, BCG, + failure to thrive + chronic diarrhoea	T cells — cytotoxic clearance of intracellular organisms and help for B cells, so antibody fails too ("combined")	T-cell development	SCID (IL2RG, ADA, RAG1/2), Omenn, complete DiGeorge
Mycobacteria only (BCG-osis, NTM osteomyelitis) ± Salmonella	IFN-γ / IL-12 macrophage loop — macrophage presents mycobacteria and releases IL-12; T/NK cell answers with IFN-γ; macrophage's STAT1 receives it and activates killing	One node of that loop	MSMD: IFNGR1/2, IL12B/IL12RB1, STAT1 loss-of-function ^[8]
One severe viral illness — HSV encephalitis, life-threatening influenza or COVID-19 — or recalcitrant HPV warts ("tree-man")	Type I interferon (IFN-α/β): TLR3/TLR7 sense viral RNA → IRF7 → IFN-α/β → IFNAR → antiviral state in every cell	Sensor, interferon, or receptor	"Mendelian viral infections": TLR3/UNC93B1 (HSV encephalitis), IRF7/IFNAR/TLR7 (influenza, COVID-19), EVER1/2 and DOCK8 (HPV) ^[8]
Chronic mucocutaneous Candida (mouth, nails, skin) ± staphylococcal skin abscesses, nothing invasive	IL-17/IL-22 (Th17) axis — recruits neutrophils and antimicrobial peptides to epithelium	Th17 differentiation or IL-17 signalling	CMC (IL17RA, IL17F, STAT1 gain-of-function), AD-HIES (STAT3 loss-of-function → no Th17)
Enteroviruses (chronic meningoencephalitis, vaccine-strain polio), Giardia	Neutralising IgG and secretory IgA at mucosa	Antibody	XLA especially (no B cells at all)
Recurrent fever + urticaria, no organism ever found	Not an infection — the NLRP3 inflammasome is firing without a trigger	A gain-of-function "alarm"	CAPS (FCAS → Muckle-Wells → CINCA/NOMID)
Neonatal-onset Crohn's-like colitis, perianal fistulae, pyoderma	IL-10 brake on gut macrophages	Loss of an anti-inflammatory brake	IL-10 / IL-10R deficiency ^[8]
Early severe eczema, food allergy, eosinophilic GI disease, IgE > 20,000	Th2 restraint	Gain-of-function in the IL-4/STAT6 axis	Primary atopic disorders (STAT6 GOF, also JAK1 GOF, DOCK8, WAS, STAT3-HIES overlap) ^[8]

Why 'combined' is the worst quadrant

B cells cannot class-switch or make high-affinity IgG without CD40L and cytokines from CD4 T cells. So a pure T-cell block (IL2RG, DiGeorge) still produces functional antibody failure even when B cells are numerically present — hence "combined". This is also why Hyper-IgM from CD40L deficiency behaves partly like a T-cell defect (PJP, Cryptosporidium) while Hyper-IgM from AID deficiency (B-cell-intrinsic) does not.

Each gene sits at a step in lymphocyte development. The step tells you which cell is absent (lymphocyte subset), which product is absent (IgGAME) and which newborn-screen marker is low (TREC = new T cells leaving the thymus; KREC = new B cells leaving the marrow) ^[8].

Block	Gene(s)	Lymphocyte subset	Ig / other clue	Onset
pre-B → B	BTK (X-linked)	B⁻ T⁺ NK⁺	All Ig ↓↓, KREC ↓, no tonsils/nodes	After 4–6 months when maternal IgG is gone
Class switch	CD40L (X-linked), CD40, AID	B⁺	IgM ↑ or normal, IgG/IgA/IgE ↓	Infancy (CD40L)
Terminal B differentiation	Polygenic; TACI, ICOS, NFKB1	B⁺ but switched-memory B ↓	IgG ↓ + IgA ↓; poor vaccine response	Usually after age 4, often adult
Common γ-chain cytokine signalling (IL-7 for T, IL-15 for NK)	IL2RG (X-linked), JAK3	T⁻ B⁺ NK⁻	Ig ↓ (B cells useless without T help); TREC ↓; ALC < 2,500	Birth–6 months
Lymphocyte purine metabolism (toxic dATP kills every lymphocyte)	ADA (AR)	T⁻ B⁻ NK⁻	+ absent thymus and cupped/flared costochondral junctions ("rib notching") on CXR ^[8]	Birth–6 months
V(D)J recombination	RAG1/RAG2 (AR)	T⁻ B⁻ NK⁺	Hypomorphic ("leaky") RAG → Omenn syndrome: oligoclonal maternal/autologous T cells, erythroderma, eosinophilia, IgE ↑ — T count can look normal ^[8]	Infancy
No thymus	22q11.2 deletion	T ↓ (partial) or T⁻ (complete)	Hypocalcaemia, conotruncal heart disease, cleft palate	Neonatal (cardiac, calcium)
Cytoskeleton	WASP (X-linked)	T ↓ with age	Small platelets ↓, IgM ↓, IgE ↑, eczema	Infancy (bleeding)
Th17 differentiation	STAT3 dominant-negative (AD)	Normal counts; Th17 ↓	IgE ↑↑, eosinophilia	Childhood

This is the single best argument against rote learning. Several transcription factors appear twice on the IUIS list with opposite phenotypes ^[8]:

Gene	Loss of function	Gain of function
STAT1	MSMD — macrophage cannot answer IFN-γ → BCG-osis, NTM, Salmonella ^[8]	Chronic mucocutaneous candidiasis — excess IFN signalling suppresses Th17 → Candida, plus autoimmunity (thyroid, diabetes)
STAT3	AD-HIES (Job syndrome) — no Th17 → Candida + Staph abscesses; no STAT3 in connective tissue → retained teeth, fractures, scoliosis, pneumatoceles; IgE ↑ ^[8]	Early-onset autoimmunity, lymphoproliferation, short stature
STAT6	(No human disease of note)	Primary atopic disorder — severe early eczema, food allergy, eosinophilic GI disease ^[8]
NLRP3	(Loss is silent)	CAPS — IL-1β overproduction → fever, urticaria, deafness, CNS inflammation ^[8]
PIK3CD	Antibody deficiency	APDS — lymphoproliferation, EBV, bronchiectasis
CARD11	Combined immunodeficiency	B-cell lymphoproliferation (BENTA)

Reading rule: loss of a defence pathway → infections by that pathway's pathogens; loss of a brake or gain of a signal → inflammation, autoimmunity, atopy or lymphoproliferation. Both live in the same 10-category IUIS list, which is why GC 144 draws the "immune deficiency vs immune dysregulation" see-saw: complement, innate, antibody and combined defects load the deficiency side; autoinflammation and autoimmunity load the dysregulation side; many entities (CVID, WAS, IPEX, APDS) sit on both ^[8].

Antibody deficiency presents after 4–6 months because transplacental maternal IgG peaks at birth (≈ adult level), falls to its nadir at 3–6 months, and the infant's own IgG only reaches ~60% of adult level by 1 year (IgM ~75%, IgA ~20%) ^[8]. A 3-year-old boy with pneumococcal pneumonia since 6 months of age, panhypogammaglobulinaemia and absent B cells is the classic XLA vignette ^[8].
T-cell defects present from birth — there is no maternal substitute for cellular immunity. SCID almost always declares itself within the first year ^[8], often with a live vaccine (BCG at birth in Hong Kong; rotavirus; varicella vaccine strain) or PJP.
Phagocyte and complement defects are variable — LAD in the neonatal period (cord), CGD in infancy to adolescence, terminal complement often in teenage years with a first Neisseria episode.
Cytokine-circuit and dysregulation diseases can present at any age, and autosomal dominant forms often have incomplete penetrance — an affected parent may be asymptomatic, so a "negative" family history does not exclude them ^[8].
Inheritance short-cut: the X-linked entities cluster — XLA, X-SCID, X-CGD, WAS, X-linked Hyper-IgM, XLP, IPEX — so a boy with affected maternal uncles points here; consanguinity points to the AR entities (ADA, RAG, AR-CGD, MSMD, IL-10R) ^[8].

Mechanism	Therapeutic logic	Examples
Missing product	Replace the product	IVIG/SCIG for XLA, CVID, Hyper-IgM; C1-INH concentrate for HAE
Missing cell lineage	Replace the factory	HSCT for SCID, WAS, CGD, LAD, IL-10R deficiency; gene therapy for ADA-SCID/X-SCID; G-CSF to push neutrophil production in SCN
Overactive cytokine	Block the cytokine	IL-1 blockade (anakinra, canakinumab) for CAPS; dupilumab (anti-IL-4Rα) for STAT6 atopic disease; secukinumab (anti-IL-17A) paradoxically not for HIES infections but for its inflammation; anti-TNF/IL-6/IL-23 for IL-10R colitis; JAK inhibitors for STAT1/STAT3 gain-of-function; emapalumab (anti-IFN-γ) for HLH/MAS ^[8]
Predictable pathogen gap	Cover the gap	Co-trimoxazole for PJP (T-cell), Staph/Nocardia (CGD); itraconazole for Aspergillus (CGD); anti-mycobacterials for MSMD; antivirals + vaccination for type I IFN defects
Live organisms the gap lets in	Avoid	No BCG/rotavirus/MMR/varicella in T-cell defects and CGD; irradiated blood in cellular defects

Pathway: innate-cellular; the gene (CYBB, X-linked) encodes gp91-phox, a subunit of NADPH oxidase → the respiratory burst is absent ^[8].
Job of that pathway: killing engulfed organisms with superoxide/hypochlorite. Organisms that make their own catalase (Staph, Serratia, Burkholderia, Nocardia, Aspergillus) destroy the small amount of hydrogen peroxide they leak, so the phagocyte has nothing left to kill them with → catalase-positive bacteria, mycobacteria (including BCG) and fungi ^[8].
Development: neutrophils are present in normal numbers (ANC normal), so the CBC is unhelpful; the DHR test measures the burst directly ^[8]. Ingested but unkilled organisms → chronic macrophage activation → granulomas (lung, gut, bladder) and high IgGAM from chronic stimulation.
Loss of defence, so the phenotype is infection: deep abscesses, BCG lymphadenitis with calcified nodes, aspergillus pneumonia eroding a rib, brain abscesses. Treatment = cover the gap (co-trimoxazole + itraconazole) and, definitively, replace the factory (HSCT) ^[8].

Every other entity in section 4 can be rebuilt the same way.

4. Aetiology (Focus on Hong Kong Relevance) and Pathophysiology

"Molecular basis of many has been worked out. Mostly single gene disorders." ^[4]

The vast majority of PIDs are monogenic (single-gene) disorders. Understanding the affected gene tells you exactly which component of the immune system is broken and predicts the clinical phenotype.

Before diagnosing PID, one must exclude much more common causes of recurrent infections in childhood ^[2]:

A. Normal healthy children

Majority (50%) of children with recurrent infections are normal and healthy ^[2]
Features: short duration, self-limiting, uncomplicated, healthy between episodes ^[2]
Risk factors: start of school, siblings ^[2]
Normal children can have up to 8–10 URTIs per year ^[2]

B. Non-immunologic defects

Category	Example	Mechanism
Obstruction to flow	Bronchial obstruction → recurrent pneumonia of same lobe	Stasis allows bacterial growth
	Eustachian tube dysfunction → recurrent otitis media	Poor drainage of middle ear
	Urinary tract obstruction → recurrent UTI	Urinary stasis
Damaged barrier	Burns, sinus tract, open fracture → pyogenic infection	Loss of skin/mucosal barrier
	Midline/middle ear defect → recurrent meningitis	CSF leak provides direct route for bacteria
Inadequate clearance	Primary ciliary dyskinesia (PCD) → bronchiectasis	Immotile cilia cannot clear mucus
	Abnormal mucus (e.g., cystic fibrosis)	Thick mucus traps bacteria
	CNS abnormalities → recurrent aspiration	Swallowing dysfunction
Foreign body	VP shunt, prosthetic valve, central line, indwelling catheter	Biofilm formation

C. Secondary immunodeficiency

Iatrogenic: steroids, immunosuppressants, splenectomy ^[2]
Neoplasms: leukaemia, lymphoma
Antibody loss: nephrotic syndrome, protein-losing enteropathy
Malnutrition: most common cause of secondary immunodeficiency worldwide
Infections: HIV (very important in Hong Kong differential)

D. Primary immunodeficiency — our focus

The International Union of Immunological Societies (IUIS) classifies PID into 10 categories ^[4]:

Combined immunodeficiency (CID)
CID with associated/syndromic features
Predominantly antibody (humoral) deficiency
Immune dysregulation
Phagocyte defect (congenital defects of phagocyte number/function)
Defects of intrinsic and innate immunity
Autoinflammatory disorders
Complement deficiency
Bone marrow failure
Phenocopies of PID

Table 10 "Phenocopies of PID": Conditions that present as inherited immunodeficiencies, but which are not due to germline mutations and instead arise from acquired mechanisms. Two categories: (1) somatic mutations in specific immune cell populations (e.g., autoimmune lymphoproliferative syndrome / ALPS), and (2) autoantibodies against specific cytokines or immunological factors (e.g., IFN-γ), with depletion of these factors leading to immunodeficiency ^[4].

4.4 Detailed Aetiology and Pathophysiology by Category

CATEGORY 1: PREDOMINANTLY ANTIBODY (HUMORAL) DEFICIENCY (36.3% — most common category)

General Principles:

Commonly cause sinopulmonary and GI infections ^[2]
- Why these sites? → (1) These are sites where most immunoglobulin is deposited (IgA in mucosa, IgG in serum bathing respiratory/GI surfaces), and (2) they are open to the external environment ^[2]
Common complications: bronchiectasis, granulomatous-lymphocytic ILD (GLILD), IBD ^[2]
Timing: present after 4–6 months due to maternal IgG depletion ^[2]
Common pathogens: encapsulated bacteria (S. pneumoniae, H. influenzae), Giardia lamblia, enteroviruses ^[2]

Why encapsulated bacteria? Encapsulated organisms have polysaccharide capsules that resist phagocytosis. The primary defence against them is opsonisation — coating with antibodies (especially IgG2) and complement (C3b) so phagocytes can recognise and engulf them. Without antibodies, opsonisation fails → encapsulated bacteria proliferate unchecked.

"A-gamma-globulinaemia" = absence (a-) of gamma (γ) globulins (= antibodies)
Inheritance: X-linked recessive (XLR) → affects boys ^[2]
Pathophysiology: abnormal Bruton tyrosine kinase (Btk) gene ^[2]^[3]
- Btk is a cytoplasmic tyrosine kinase that transduces signals from the pre-B cell receptor
- Essential for ALL stages of B cell development ^[2]
- Mutation → B cell maturation arrest at the pro-B to pre-B stage → virtually no mature B cells in the periphery
- No B cells → no plasma cells → no immunoglobulin production of any class
Investigations: ↓B cells (< 1% CD19+), pan-hypogammaglobulinaemia (all Ig classes decreased) ^[2]^[4]
- Hence absent tonsils (tonsils are B cell-rich lymphoid tissue) ^[2]
- Immunisation is useless (no B cells to respond to vaccines) ^[2]
Clinical features: recurrent sinopulmonary and GI infections ^[2]^[3]
- Usually presents with pneumonia, sinusitis, otitis media ^[2]
- Occurs between 6–18 months of age (after maternal IgG wanes) ^[3]
- Enteroviral meningoencephalitis is a dreaded complication
Treatment: IV immunoglobulin (IVIG) replacement ^[4]
Note: look at functional IgG (because absolute IgG can be falsely high — e.g., from maternal IgG in young infants or from non-functional IgG) ^[2]

Exam Tip: XLA

The classic exam vignette: A 9-month-old boy with recurrent pneumonia, sinusitis, otitis media. On examination, tonsils are absent. Serum immunoglobulins are undetectable. B cell count is < 1%. Family history reveals a maternal uncle who died young from infections. → XLA (Bruton's).

"Common" = most frequent form of severe antibody deficiency ^[2]^[4]^[5]
"Variable" = heterogeneous clinical manifestation ^[2]^[3]
"Immunodeficiency" = impaired immunity
Epidemiology: the most frequent primary immunodeficiency (overall, counting all severity levels) ^[4]^[5]
- Note: Selective IgA deficiency is the most common PID overall, but CVID is the most common severe PID requiring treatment
Pathophysiology: impaired B cell differentiation → defective immunoglobulin production ^[2]^[3]
- Unlike XLA, B cells are present (CD19+ > 1%) but fail to differentiate into effective plasma cells
- The exact mechanism is heterogeneous; only 10–15% have identified genetic mutations
- Mutations described in four genes: ICOS, CD19, BAFF-R and TNFRSF13B (also known as TACI — transmembrane activator and CAML interactor) ^[4]^[5]
  - TACI (TNFRSF13B) is the most commonly implicated gene (10–15% of patients) → required for final maturation of B lymphocytes ^[5]
- Many cases have no identified genetic defect → likely polygenic or epigenetic
Ix: ↓↓↓IgG, ↓IgA and/or IgE ^[2]; IgM may be low or normal
Clinical features — a late-onset hypogammaglobulinaemia that presents often in childhood/adolescence/early adulthood ^[4]^[5]:
- Recurrent infections: sinopulmonary and GI infections ^[2]^[4]
  - Recurrent respiratory tract infections with the development of bronchiectasis ^[4]
  - Intermittent or chronic diarrhoea ^[4]
- Polyclonal lymphoproliferation with splenomegaly, lymphadenopathy or nodular lymphoid hyperplasia of the small bowel occurs in approximately 1/3 of patients ^[4]^[5]
- Autoimmune phenomena: autoimmune haemolytic anaemia (AIHA), idiopathic thrombocytopenic purpura (ITP) in up to 25% ^[4]^[5]
- Granulomatous disease in 8–22% ^[4]^[5]
- An increased risk of gastrointestinal and lymphoid malignancies ^[2]^[4]^[5]

CVID: Why So Variable?

CVID is a "wastebasket" diagnosis — it captures patients with low IgG, impaired vaccine responses, and recurrent infections who don't fit a more specific diagnosis (like XLA). The heterogeneity comes from the fact that many different molecular defects can produce this phenotype. As genetic testing improves, more and more "CVID" patients are being reclassified into specific monogenic entities (e.g., APDS — activated PI3Kδ syndrome).

Pathophysiology: failure to switch IgM to IgG/IgA ^[2]
- Most common form: X-linked (CD40 ligand / CD154 deficiency)
  - CD40L on T helper cells interacts with CD40 on B cells to trigger class switch recombination
  - Mutation in Exon 5 of CD40L (e.g., c.761C>T, p.T254M) ^[5]
  - Without this signal, B cells can only produce IgM
- Autosomal recessive forms: AID (activation-induced cytidine deaminase) deficiency, UNG deficiency
Ix: ↑IgM, ↓IgG/IgA/IgE ^[2]
Clinical features:
- Recurrent sinopulmonary infections (similar to other antibody deficiencies)
- Opportunistic infections (especially Pneumocystis jirovecii, Cryptosporidium) — because CD40L deficiency also impairs T cell–macrophage interaction → partial T cell defect
- Cryptosporidium → sclerosing cholangitis (biliary tree infection → chronic inflammation)
- Neutropenia (cyclic or chronic) → oral ulcers
- Autoimmune cytopenias

Why is X-linked Hyper-IgM a 'combined' deficiency in disguise?

Although classified under "antibody deficiency" in some older textbooks, X-linked HIGM (CD40L deficiency) actually impairs T cell–B cell cooperation AND T cell–macrophage cooperation. The CD40L on T cells is needed to activate macrophages to kill intracellular organisms. Hence, patients get opportunistic infections (PCP, Cryptosporidium) that you'd usually associate with T cell defects. The IUIS now classifies X-linked HIGM under "Combined Immunodeficiency" for this reason.

Epidemiology: most common PID overall (prevalence ~1/500 in Caucasians, lower in Asian populations) ^[2]
Pathophysiology: selective failure of IgA production; exact mechanism poorly understood; likely multifactorial (genetic + environmental)
Clinical features: usually asymptomatic ^[2]
- May occasionally present with recurrent sinopulmonary or GI infections ^[2]
- Associated with coeliac disease, autoimmune conditions
- Important: some patients have anti-IgA antibodies → risk of anaphylaxis with blood products containing IgA (must use IgA-depleted products or washed red cells)
- Can evolve to CVID in a minority

General Principles:

Commonly cause severe ± unusual viral and fungal infections ^[2]
Examples: severe bronchiolitis, oral thrush, PJP (Pneumocystis jirovecii pneumonia), disseminated CMV infection ^[2]
T cells are essential for orchestrating both cellular and humoral immunity → T cell defects almost always have a humoral component too (B cells need T cell help)

A. Severe Combined Immunodeficiency (SCID)

"Severe" = fatal without treatment; "Combined" = both B and T cell arms affected
Pathophysiology: heterogeneous group of disorders with impaired B and T cell development ^[2]^[3]
- Most common form: X-linked SCID (IL-2Rγ chain / common gamma chain deficiency)
  - IL-2Rγ is shared by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, IL-21
  - Absence → no signalling for T cell and NK cell development (IL-7 and IL-15 dependent)
  - Phenotype: T⁻ B⁺ NK⁻ SCID
- Other forms:
  - JAK3 deficiency (AR) — JAK3 signals downstream of IL-2Rγ → same phenotype (T⁻ B⁺ NK⁻)
  - RAG1/RAG2 deficiency (AR) — RAG genes required for V(D)J recombination → T⁻ B⁻ NK⁺
  - Adenosine deaminase (ADA) deficiency (AR) — toxic metabolite accumulation kills all lymphocyte precursors → T⁻ B⁻ NK⁻
  - IL-7Rα deficiency (AR) — T⁻ B⁺ NK⁺

SCID Subtype	Gene	T	B	NK
X-linked (most common)	IL2RG	⁻	⁺	⁻
JAK3 deficiency	JAK3	⁻	⁺	⁻
RAG1/RAG2 deficiency	RAG1/RAG2	⁻	⁻	⁺
ADA deficiency	ADA	⁻	⁻	⁻
IL-7Rα deficiency	IL7R	⁻	⁺	⁺

Investigations: ↓ absolute lymphocyte count (ALC), absent thymus shadow on CXR ^[2]^[3]
- TREC assay (T-cell receptor excision circles) — used in newborn screening; SCID infants have very low/absent TRECs
Clinical features: fatal without treatment ^[2]^[3]
- Usually present with failure to thrive (FTT), recurrent severe infections, chronic diarrhoea ^[2]^[3]
- Infections: PCP, severe RSV/parainfluenza, disseminated BCG (after vaccination), persistent oral candidiasis, CMV
- Chronic diarrhoea → malabsorption → FTT
- Skin: generalised erythroderma (from maternal T cell engraftment causing graft-versus-host disease)
- Complications from live vaccines (BCG, rotavirus, oral polio) — disseminated infection
Treatment: HSC (haematopoietic stem cell) transplantation ^[4] — this is curative. Gene therapy is available for ADA-SCID and X-linked SCID.

SCID is a Paediatric Emergency

SCID is fatal without treatment — most untreated infants die within the first 1–2 years of life from overwhelming infection. Newborn screening (NBS) using TREC assays allows pre-symptomatic detection and early HSCT, which dramatically improves survival (> 90% if transplanted before 3.5 months without active infection). This is why SCID NBS is being implemented globally. If you see a lymphopenic neonate, think SCID until proven otherwise.

CATEGORY 3: CID WITH ASSOCIATED/SYNDROMIC FEATURES (15.2%)

These PIDs have immunodeficiency PLUS other recognisable syndromic features.

Pathophysiology: 22q11.2 deletion → defective development of pharyngeal pouch system ^[2]^[3]
- The 3rd and 4th pharyngeal pouches give rise to the thymus and parathyroid glands
- Heterozygous deletion (usually de novo, occasionally inherited AD)
Classical triad ^[2]^[3]:
1. Conotruncal cardiac anomalies (e.g., tetralogy of Fallot, interrupted aortic arch, truncus arteriosus, VSD)
2. Hypoplastic thymus → impaired T cell immunity
3. Hypoplastic parathyroid → hypocalcaemia
Other features: palatal abnormalities (cleft palate, velopharyngeal insufficiency), developmental delay, characteristic facies (long face, small ears, hooded eyelids), learning difficulties, psychiatric problems (↑ risk of schizophrenia in adolescence)
Immunological spectrum: varies from mild T cell deficiency (most patients — "partial DiGeorge") to complete absence of T cells ("complete DiGeorge" — rare, presents like SCID)
Mnemonic: CATCH-22
- Cardiac anomaly
- Abnormal facies
- Thymic aplasia/hypoplasia
- Cleft palate
- Hypocalcaemia
- Chromosome 22q11.2 deletion

Inheritance: X-linked recessive
Pathophysiology: mutation in WAS protein (WASP) gene → WASP is involved in actin cytoskeletal reorganisation in haematopoietic cells → affects T cells, B cells, platelets, and monocytes
Clinical features: triad of immunodeficiency + thrombocytopenia + eczema ^[2]
- Small platelets (micro-thrombocytopenia) — distinguishing feature (mean platelet volume is LOW, unlike ITP where it's normal/high)
- Eczema (can be severe, mimics atopic dermatitis)
- Recurrent infections (initially sinopulmonary; later opportunistic)
- Increased risk of autoimmunity and lymphoma

Inheritance: autosomal recessive
Pathophysiology: mutation in ATM gene (ataxia-telangiectasia mutated) → ATM is a kinase involved in DNA double-strand break repair
- Defective DNA repair → chromosomal instability, impaired V(D)J recombination (→ immunodeficiency), impaired cell cycle checkpoints (→ cancer predisposition), progressive neurodegeneration
Clinical features: cerebellar ataxia, developmental delay, ↑ risk of lymphoma ^[2]
- Oculocutaneous telangiectasia (small dilated blood vessels on conjunctiva, ears, face — appear around age 3–6 years)
- Progressive cerebellar ataxia (begins in toddlerhood)
- Variable immunodeficiency (IgA deficiency, IgG subclass deficiency, T cell defects)
- Elevated serum alpha-fetoprotein (AFP)
- Radiosensitivity — avoid unnecessary radiation exposure

Pathophysiology: most commonly due to STAT3 dominant-negative mutations (AD-HIES) or DOCK8 deficiency (AR-HIES)
Clinical features ^[2]:
- Pneumatocele (lung cysts from recurrent staphylococcal pneumonia)
- Mucocutaneous candidiasis
- Retained primary teeth (failure of primary tooth exfoliation)
- Minimal trauma fractures and scoliosis (connective tissue abnormality)
- Less allergy/anaphylaxis than expected for IgE level — paradoxically, despite markedly elevated IgE (often > 2000 IU/mL), these patients do NOT have severe allergic disease
- Coarse facies, wide nasal bridge
- "Cold" staphylococcal abscesses (lack of inflammation → do not become warm/red)

Clinical features: abnormal response to EBV ^[2]
- Either succumb to initial EBV infection (fulminant infectious mononucleosis) or develop secondary lymphoma ^[2]
- Hemophagocytic lymphohistiocytosis (HLH) triggered by EBV
Two forms: XLP1 (SH2D1A/SAP deficiency), XLP2 (XIAP deficiency)

CATEGORY 4: PHAGOCYTE DEFECTS (14.9%)

General Principles:

Commonly cause recurrent bacterial infections ^[2]
Common pathogens: skin commensals (Staphylococcus), fungi (Aspergillus, Candida) ^[2]

Inheritance: majority (60%) X-linked, some autosomal recessive ^[2]^[3]
Pathophysiology: phagocytes (especially neutrophils) fail to produce superoxide → inability to destroy microbes (especially catalase-positive organisms) ^[2]^[3]^[5]
- NADPH oxidase complex (gp91phox, p22phox, p47phox, p67phox) is the enzyme that generates the respiratory burst → producing superoxide (O₂⁻) → hydrogen peroxide (H₂O₂)
- CGD = phagocyte don't have NADPH, can't produce ROS, can't kill pathogens ^[5]
- Why catalase-positive organisms? Most bacteria produce H₂O₂ as a metabolic byproduct. In CGD, even though the phagocyte can't make its own H₂O₂, it can still use the bacterium's H₂O₂ to kill catalase-NEGATIVE organisms (the bacterial H₂O₂ effectively helps kill itself). But catalase-positive organisms (Staphylococcus, Aspergillus, Burkholderia, Serratia, Nocardia) destroy their own H₂O₂ with catalase → the phagocyte has no oxidative killing mechanism at all
- Mnemonic for catalase-positive organisms: "PLACESS" — Pseudomonas, Listeria, Aspergillus, Candida, E. coli, Staphylococcus, Serratia (though the most important for CGD are Staph aureus, Aspergillus, Burkholderia, Serratia, Nocardia)
- Granuloma formation results from chronic inflammation — macrophages that engulf but cannot kill organisms aggregate into granulomas ^[2]^[3]
Clinical features: recurrent pyogenic infection with granuloma formation ^[2]^[3]
- Common sites: lung, skin, lymph nodes, liver ^[2]^[3]
- Usually presents with lymphadenitis, hepatosplenomegaly, skin/perianal abscess, TB/BCG dissemination ^[2]^[3]
- BCG dissemination is particularly important in Hong Kong/Asian context where BCG vaccination is given at birth
Diagnosis: Dihydrorhodamine (DHR) flow cytometry test or Nitroblue tetrazolium (NBT) test
- NBT: neutrophils incubated with NBT dye → normal neutrophils produce superoxide which reduces yellow NBT to blue formazan. In CGD, no colour change (no superoxide produced)
- DHR: more sensitive; normal neutrophils oxidise DHR to fluorescent rhodamine-123; CGD neutrophils do not fluoresce

Pathophysiology: deficiency of neutrophil surface adhesion molecule (CD18 / β2-integrin) ^[2]^[3]
- CD18 pairs with CD11a/b/c to form β2-integrins (LFA-1, Mac-1, p150,95)
- These are essential for firm adhesion of neutrophils to activated endothelium and subsequent transmigration (diapedesis) into tissues
- Without CD18 → neutrophils cannot leave the vasculature and migrate to the site of infection/inflammation ^[2]^[3]
Ix: ↑ neutrophil count (persistent neutrophilia, because neutrophils are trapped inside the vessel) ^[2]
Clinical features: poor wound healing with absent pus formation ^[2]^[3]
- Hallmark: absent pus formation — there is infection but no pus, because neutrophils cannot get out of the blood vessels
- Classical presentation: omphalitis with delayed separation of the umbilical cord ^[2]^[3]
  - Normal cord separation occurs by 1–3 weeks; in LAD, separation is delayed beyond 30 days
  - Why? The umbilical cord separates via a process of dry gangrene and neutrophil-mediated tissue remodelling. Without neutrophil migration, this process is severely delayed

Cyclic neutropenia: AD mutation in ELANE gene → neutrophil counts oscillate with ~21-day periodicity; febrile episodes and oral ulcers during nadirs
Kostmann syndrome: AR or AD mutation → severe persistent neutropenia from birth → recurrent life-threatening bacterial infections

General Principles:

Commonly cause recurrent bacterial infections and SLE-like illness ^[2]
Common pathogens: encapsulated bacteria ^[2]

Complement Component	Clinical Association	Mechanism
C1, C2, C4 (early classical pathway)	Predisposes to SLE ^[3]	Classical pathway is essential for clearance of immune complexes and apoptotic cells. Without it, these accumulate → autoimmune inflammation
C3 (central component)	Predisposes to S. pneumoniae and H. influenzae infection ^[3]	C3 is the convergence point of all complement pathways; C3b is the main opsonin
C5–C9 (terminal / MAC pathway)	Predisposes to Neisseria gonorrhoeae/meningitidis infection ^[3]	MAC is needed to lyse Neisseria spp. (gram-negative diplococci with thin cell walls vulnerable to lysis)
C1-esterase inhibitor	Hereditary angioedema (HAE) ^[5]	C1-INH normally inhibits kallikrein; deficiency → excess bradykinin → bradykinin-mediated angioedema (NON-histaminergic → does NOT respond to antihistamines/adrenaline)

Hereditary Angioedema (HAE):

Autosomal dominant ^[5]
Type I (85%): low C1-INH level — SERPING1 gene mutation → reduced production ^[5]
Type II (15%): normal C1-INH level but low function — SERPING1 gene mutation → dysfunctional protein ^[5]
Type III (rare): gene encoding coagulation factor XII ^[5]
All types → inability to inhibit kallikrein → excess bradykinin activation and bradykininergic angioedema ^[5]
Clinically: episodic swelling of subcutaneous/submucosal tissues (face, extremities, GI tract, larynx — potentially fatal); no urticaria (distinguishes from allergic angioedema)

The immune system attacks self or fails to switch off. Classic members: ALPS (FAS-pathway apoptosis defect → lymphadenopathy, splenomegaly, autoimmune cytopenias, double-negative T cells), IPEX (FOXP3 → no regulatory T cells → neonatal enteropathy, type 1 diabetes, eczema), familial HLH (perforin/granule-release defects → uncontrolled macrophage activation), and the IL-10 pathway defect below.

IL-10 / IL-10 Receptor Deficiency (Very-Early-Onset IBD) [8]

Immune pathway: IL-10 is the master anti-inflammatory brake on gut macrophages; IL10RA/IL10RB (AR, loss of function) removes the brake ^[8]
Presentation: neonatal-onset (first month of life) Crohn's-like colitis — chronic diarrhoea, perianal sepsis and fistulae, pyoderma/folliculitis, oral ulcers, failure to thrive ^[8]
Hong Kong data: exome sequencing identified compound heterozygous IL-10 receptor 1 mutations in a neonate with Crohn's disease presenting in the first month (Mao, Lau et al., Genes & Immunity 2012) ^[8]
Tests: genetics (conventional immunology screens are normal) ^[8]
Treatment: HSCT is curative; bridging with steroids and biologics blocking TNF-α, IL-6 or IL-23 ^[8]
Teaching point: any IBD before age 2 (and certainly in the first months) should be sequenced — it is an IEI until proven otherwise

CATEGORY 6: DEFECTS OF INTRINSIC AND INNATE IMMUNITY — "MENDELIAN / MONOGENIC INFECTIONS" [8]

"Some IEIs are sensitive to one particular type of pathogen only" ^[8] — unlike the traditional deficiencies (no B cells → all bacteria; no T cells → everything), these are single-cytokine-circuit defects. The child is otherwise healthy and gets only the one class of organism that the circuit handles. Autosomal dominant forms frequently show incomplete penetrance ^[8].

Immune pathway: IFN-γ / IL-12 loop — macrophage/dendritic cell ingests mycobacteria and secretes IL-12 (p35/p40) and IL-23; T and NK cells answer via IL-12Rβ1/β2 with IFN-γ; the macrophage receives IFN-γ through IFNGR1/2 → JAK1/JAK2 → STAT1 → transcription of killing programmes ^[8]
Gene (lecture example): STAT1, AD or AR, loss of function ^[8]; other nodes: IFNGR1, IFNGR2, IL12B, IL12RB1, TYK2, IRF8, NEMO (syndromic)
Pathogens: mycobacteria (BCG, NTM, TB) and Salmonella — these are the intracellular organisms whose killing depends entirely on IFN-γ-primed macrophages ^[8]
Hong Kong vignette: two siblings heterozygous for STAT1 c.2129C>T (p.Ser710Phe) with disseminated BCG infection — multifocal osteomyelitis of the radius, skull and ribs on bone scan, healing over 2 years of anti-mycobacterial therapy ^[8]
Tests: advanced functional assays (IFN-γ/IL-12 production and STAT1 phosphorylation on stimulation) + genetics ^[8]
Treatment: anti-mycobacterials (prolonged), IFN-γ supplementation for receptor-partial/IL-12 axis defects, HSCT for complete IFNGR deficiency; never give BCG to a sibling at risk ^[8]

Immune pathway: type I interferon (IFN-α/β). Viral nucleic acid is sensed by TLR3 (endosomal dsRNA, in CNS cells) or TLR7 (ssRNA, in plasmacytoid DC) → IRF3/IRF7 → IFN-α/β secreted → binds IFNAR1/2 on every cell → STAT1/STAT2 → antiviral state
Phenotype: a single life-threatening viral illness in an otherwise healthy child ^[8]:
- HSV-1 encephalitis — TLR3, UNC93B1, TRIF (CNS-restricted defect)
- Severe influenza or COVID-19 pneumonitis — IRF7, IFNAR1/2, TLR7 (X-linked, young men) ^[8]
- Recalcitrant HPV warts / "tree-man" syndrome (epidermodysplasia verruciformis) — EVER1/EVER2, and the NK/T-cell defects DOCK8, GATA2, WHIM (CXCR4) ^[8]
Tests: genetics ± functional interferon assays ^[8]
Treatment: antivirals (aciclovir, oseltamivir), vaccination, early treatment of viral illness ^[8]
Contrast with type II interferon (IFN-γ) defects above: type I IFN → viruses; type II IFN → intracellular bacteria (mycobacteria, Salmonella) ^[8]

Immune pathway: IL-17/IL-22 (Th17) axis — Th17 cells and innate lymphoid cells secrete IL-17A/F and IL-22, which drive neutrophil recruitment and antimicrobial peptides at skin and mucosa; this is the specific anti-Candida (and anti-Staph) defence of epithelium
Genes: IL17RA, IL17F, ACT1 (pure CMC); STAT1 gain-of-function (the commonest cause — excess type I/II interferon signalling suppresses Th17 development; adds autoimmune thyroiditis, diabetes, aneurysms); STAT3 loss-of-function (AD-HIES — CMC is one component); CARD9 (invasive Candida/dermatophyte CNS disease)
Phenotype: persistent oral thrush after age 1 (a Jeffrey Modell warning sign), nail dystrophy and paronychia, oesophageal candidiasis; no invasive candidiasis (that needs neutrophils/T cells, which are intact) ^[8]
Phenocopy: neutralising autoantibodies against IL-17 and IL-22 in APECED (AIRE deficiency) produce identical CMC ^[8]
Treatment: long-term azoles; JAK inhibitors for STAT1 gain-of-function

Recurrent fever and systemic inflammation without autoantibodies, autoreactive T cells or infection — the innate immune system fires spontaneously. Members: FMF (pyrin), TRAPS, mevalonate kinase deficiency, PFAPA (polygenic) and the lecture example below.

Cryopyrin-Associated Periodic Syndrome (CAPS) [8]

Immune pathway: the NLRP3 inflammasome and IL-1 — NLRP3 (cryopyrin) normally assembles with ASC and caspase-1 only when it senses danger; caspase-1 cleaves pro-IL-1β to active IL-1β ^[8]
Gene: NLRP3, autosomal dominant, GAIN of function → inflammasome assembles without a trigger → continuous IL-1β ^[8]
Features: recurrent fever and urticaria-like (neutrophilic) rash ^[8], often cold-triggered in the mild form. Spectrum of severity:
- FCAS (familial cold autoinflammatory syndrome) — cold-induced rash, fever, arthralgia
- Muckle-Wells — plus sensorineural deafness and AA amyloidosis
- CINCA/NOMID (chronic infantile neurological, cutaneous and articular syndrome / neonatal-onset multisystem inflammatory disease) — urticaria from birth, chronic aseptic meningitis with papilloedema and headache, cerebral vasculitis, deforming arthropathy with epiphyseal overgrowth, deafness, developmental delay ^[8]
Somatic (mosaic) NLRP3 mutation gives milder disease than a germline mutation, and may be missed by PCR-Sanger and only found on whole-exome sequencing — a Hong Kong CINCA child (urticaria since birth, papilloedema, cerebral vasculitis; Lee, Lau et al. HKJP 2006) was later shown to be a somatic mosaic ^[8]
Tests: genetics (inflammatory markers are persistently high; no autoantibodies) ^[8]
Treatment: IL-1 blockade — anakinra (IL-1 receptor antagonist) or canakinumab (anti-IL-1β) ^[8]; the HK adult with CINCA carrying both NLRP3 and NLRP12 variants had resolution of rash and mucosal ulceration after 3 years of canakinumab ^[8]
Exam link: CAPS/CINCA is on the differential of systemic JIA (fever + rash + arthritis + serositis/lymphadenopathy), alongside Kawasaki disease, IBD, SLE, MCTD, PAN, JDM, Behçet, leukaemia/lymphoma and malaria ^[8]; sJIA is itself treated as an autoinflammatory disease with IL-1 and IL-6 blockade

Immune pathway: Th2 signalling — IL-4/IL-13 → IL-4Rα → JAK1 → STAT6 ^[8]
Gene (lecture example): STAT6, AD, GAIN of function ^[8] (JEM 2023 cohort of 16 patients including a Hong Kong child); related monogenic atopy: JAK1 gain-of-function, CARD11 dominant-negative, DOCK8, WAS, STAT3-HIES, IPEX, Netherton (SPINK5)
Features: early-onset (infancy), widespread treatment-resistant eczema, multiple food allergies with anaphylaxis, asthma, eosinophilic gastro-oesophageal disease, recurrent skin infections (Staph, Candida, molluscum), short stature, osteoporosis, vascular anomalies, B-cell lymphoma in a minority ^[8]
Tests: IgE very high and absolute eosinophil count > 500/μL in every patient ^[8]; genetics
Treatment: biologics — dupilumab (anti-IL-4Rα) produced falling eosinophils and IgE, eczema scores dropping over 10 doses, and catch-up growth in the Hong Kong patient ^[8]; JAK inhibitors are the alternative
Teaching point: "any rare immunological phenomenon can have a monogenic basis" ^[8] — severe atopy that fails standard therapy, starts in infancy and comes with infections or growth failure deserves sequencing

Fanconi anaemia, dyskeratosis congenita, Shwachman-Diamond syndrome and GATA2 deficiency (monocytopenia on the CBC, NK-cell deficiency, HPV warts, NTM infection, MDS/AML) — overlap with haematology ^[8].

Conditions that present as inherited immunodeficiencies but are not due to germline mutations ^[4]. Two mechanisms: neutralising autoantibodies against a cytokine (the phenotype equals loss of that cytokine's gene) and somatic mutations in an immune-cell population (e.g., somatic NLRP3 in CINCA, somatic FAS in ALPS) ^[8].

Autoantibody against	Phenocopies which gene defect	Clinical picture	Notes
Type I interferon (anti-IFN-α/ω)	IFNAR / IRF7 deficiency	Severe COVID-19 pneumonitis, severe influenza, West Nile encephalitis, disseminated VZV ^[8]	Found in ~10–20% of life-threatening COVID-19 and rises with age; also in APECED and thymoma. Tests: serum autoantibody. Treatment: vaccination, early antivirals, plasma exchange/replacement therapy ^[8]
IFN-γ	MSMD	Disseminated NTM and Salmonella in previously healthy adults ^[8]	Strongly associated with HLA-DRB116:02 / DQB105:02 — South-East and East Asian adults (including Hong Kong); treat with anti-mycobacterials ± rituximab
IL-17A/F and IL-22	IL-17 pathway	Chronic mucocutaneous candidiasis ^[8]	Hallmark of APECED (AIRE deficiency)
GM-CSF	CSF2RA/B	Pulmonary alveolar proteinosis; cryptococcal/Nocardia infection	—
IL-6	IL-6 signalling	Staphylococcal abscesses with low CRP	—

GC 144 Hong Kong cases — link each to its mechanism

Entity (gene)	Case as taught	Mechanism it illustrates
Leaky RAG1 SCID	13-month girl: severe RSV pneumonia → ARDS on ECMO; cutaneous reactivation of varicella vaccine strain; failure to thrive; persistent lymphopenia, T-low B-low NK+, impaired proliferation; compound heterozygous RAG1 → BMT at 20 months, 100% donor chimerism, CD3 T cells rising on engraftment ^[8]	Hypomorphic RAG allows a few T cells so it is missed on counts alone; live vaccine reactivation + one severe virus in an infant = think SCID; HSCT rebuilds the T-cell factory
ADA-SCID	Baby boy with Klebsiella and carbapenem-resistant pneumonia; CXR absent thymic shadow and rib "notching" (cupped costochondral junctions) ^[8]	ADA is a house-keeping enzyme, so a metabolic (T⁻B⁻NK⁻) SCID also has skeletal signs; absent thymus = no T-cell factory
X-linked SCID (IL2RG)	David Vetter, 12 years in a sterile bubble (1972–84) ^[8]	γc failure = no T/NK; without HSCT the only defence is isolation
AD-HIES (STAT3)	Young man with cold staphylococcal abscesses, pinna abscess, coarse facies; CXR pneumatoceles after staphylococcal pneumonia; retained primary teeth, scoliosis on radiographs ^[8]	STAT3 loss removes Th17 (Candida/Staph) and connective-tissue STAT3 signalling (teeth, bone, lung cysts)
XLA (BTK)	3-year-old boy, sinopulmonary infections since 6 months, pneumococcal pneumonia, panhypogammaglobulinaemia + absent B cells; CT sinusitis and bronchiectasis; urticaria after first IVIG; growth percentiles rose after IVIG; a 30-year-old XLA man with bronchiectasis on HRCT ^[8]	Onset when maternal IgG is gone; replacement of the product restores growth; delayed diagnosis → irreversible bronchiectasis
X-CGD (CYBB)	Presented in infancy with buttock abscess; pulmonary aspergillosis and TB; BCG lymphadenitis with calcified axillary node; two failed HSCT; at 17 years multiple brain abscesses and disseminated aspergillosis on PET-CT (iliopsoas, gluteal, abdominal wall, lungs) → third HSCT at 18 ^[8]	No respiratory burst = catalase-positive bacteria and Aspergillus everywhere; only replacing the phagocyte factory cures it
AR-CGD (NCF1)	3-month girl with granulomatous lung inflammation, PET-avid mediastinal mass; histology granuloma with central necrosis and epithelioid rim ^[8]	Unkilled organisms → chronic macrophage activation → granuloma; also the enthesitis-related JIA/iritis seen in CGD boys reflects the same inflammatory drive
MSMD (STAT1 LOF)	Two siblings heterozygous p.Ser710Phe with disseminated BCG osteomyelitis (radius, skull, ribs), healed after prolonged anti-mycobacterial treatment ^[8]	Macrophage cannot receive IFN-γ; only mycobacteria/Salmonella affected; BCG at birth in HK unmasks it
IL-10R1 deficiency	Neonate with diarrhoea, perianal sepsis and pyoderma in the first month; colonoscopy with deep ulceration and cobblestoning → HSCT ^[8]	Loss of the IL-10 brake on gut macrophages; treated by blocking downstream cytokines then replacing the marrow
CINCA/NOMID (NLRP3)	Infant with urticaria since birth, papilloedema, headache and cerebral vasculitis; somatic NLRP3 mosaic missed by Sanger, found on WES; a 48-year-old with NLRP3 + NLRP12 variants, rash and tongue ulceration cleared after 3 years of canakinumab ^[8]	Gain-of-function alarm → IL-1β; block the cytokine
Primary atopic disorder (STAT6 GOF)	Hong Kong boy with severe eczema, eosinophilia and IgE ~20,000; growth hormone at 16 then dupilumab at 19 → eczema scores fell and height/weight caught up ^[8]	Gain-of-function Th2 signal; block IL-4Rα

6. Clinical Features

Features suggestive of primary immunodeficiency (PID) ^[3]:

Patient Factors:

Family history of immunodeficiency or unexplained early death (before age 30) ^[3]
Failure to gain weight or grow normally (failure to thrive) ^[3]
Persistent lymphopenia ^[3]:
- Count < 1,500 cells/μL in patients over 5 years ^[3]
- Count < 2,500 cells/μL in younger children ^[3]

Factors Related to Infections:

≥ 6 new infections within 1 year ^[3]
≥ 2 serious sinus infections or pneumonias within 1 year ^[3]
≥ 4 new ear infections within 1 year ^[3]
≥ 2 episodes of sepsis or meningitis in a lifetime ^[3]
Recurrent or resistant candidiasis ^[3]
Recurrent tissue or organ abscesses ^[3]
Infection with an opportunistic organism ^[3]
Unexplained autoimmunity or fever ^[3]
Chronic diarrhoea ^[3]
Granuloma ^[3]
Non-healing wounds ^[3]
Extensive skin lesions ^[3]

Factors Related to Treatment:

≥ 2 months of antibiotics with little effect ^[3]
Need for IV antibiotics or hospitalisation to clear infections ^[3]
Complications from a live vaccine ^[3]

Mnemonic: SPUR for Infections Suggesting PID

Severe — requiring IV antibiotics or hospitalisation Persistent — not resolving with standard treatment Unusual — opportunistic organisms, unusual sites Recurrent — repeated episodes at the same or different sites

If a child's infections are SPUR, think PID.

The type of infection gives you the biggest clue to which arm of the immune system is defective:

Feature	Antibody (B cell) Deficiency	T cell / Combined Deficiency	Phagocyte Defect	Complement Deficiency
Age of onset	> 4–6 months	Early infancy (< 6 months)	Variable (can be neonatal)	Variable
Typical organisms	Encapsulated bacteria, Giardia, enteroviruses	Viruses (CMV, EBV, HSV), fungi (PCP, Candida), mycobacteria	Catalase-positive bacteria, fungi	Encapsulated bacteria, Neisseria
Infection sites	Sinopulmonary, GI	Disseminated; oral thrush; GI	Skin, LN, liver, lung	Meningitis, sepsis
FTT	Less prominent	Prominent	Variable	Less prominent
Autoimmunity	CVID → AIHA, ITP	IPEX, ALPS	Rare	SLE (early complement def)
Special features	Absent tonsils (XLA), bronchiectasis (CVID)	Absent thymus shadow (SCID), oral thrush	Absent pus (LAD), granulomas (CGD), delayed cord separation (LAD)	Recurrent Neisseria

Recurrent infections (the hallmark symptom)

Why? The immune system cannot adequately detect, opsonise, or kill specific pathogens depending on the defect

Failure to thrive (FTT)

Why? Chronic infection → increased metabolic demand + chronic diarrhoea → malabsorption + anorexia from chronic inflammation → caloric deficit → poor growth
Particularly prominent in SCID and combined deficiencies

Chronic diarrhoea

Why? (1) GI infections (Giardia, Cryptosporidium, rotavirus) due to impaired mucosal immunity; (2) autoimmune enteropathy (especially in IPEX); (3) nodular lymphoid hyperplasia (CVID)

Oral thrush / persistent candidiasis

Why? T cells and neutrophils are the primary defence against Candida. Persistent oral thrush beyond infancy (after 12 months) is a red flag for T cell or combined deficiency

Skin abscesses (recurrent, deep)

Why? Phagocyte defects → inability to contain and kill skin flora (especially Staphylococcus aureus) → deep-seated abscesses
In CGD: "cold" abscesses due to impaired inflammatory response

Eczema

Why? Immune dysregulation; seen in WAS (WASP dysfunction disrupts regulatory T cell function → autoimmune-like skin inflammation) and Hyper-IgE syndrome

Absent or hypoplastic tonsils and lymph nodes

Why? In XLA, there are virtually no B cells → no germinal centres can form in lymphoid tissue → tonsils and lymph nodes are absent/tiny
In SCID, both B and T cell compartments are depleted → lymphoid hypoplasia

Hepatosplenomegaly

Why? (1) Chronic infection → reactive expansion of the reticuloendothelial system; (2) Granuloma formation (CGD); (3) Lymphoproliferation (CVID, ALPS)

Absent thymic shadow on CXR (neonates/infants)

Why? In SCID and complete DiGeorge, the thymus is absent or hypoplastic → no thymic shadow visible on AP chest X-ray. The thymus is normally prominent in infants.

Delayed umbilical cord separation (LAD)

Why? Normal cord separation requires neutrophil infiltration to remodel the necrotic tissue. In LAD, neutrophils cannot migrate → cord remains attached for weeks

Absent pus (LAD)

Why? Pus is composed of dead neutrophils and debris. If neutrophils cannot reach the infection site, no pus forms — even though there is active infection and tissue destruction

Lymphadenopathy and splenomegaly (CVID, CGD)

Why? In CVID: polyclonal lymphoproliferation from chronic antigenic stimulation without effective clearance. In CGD: granulomatous inflammation

Petechiae / purpura / bleeding (WAS)

Why? Micro-thrombocytopenia → bleeding tendency; small platelets have shorter lifespan and are cleared more rapidly by the spleen

Telangiectasia (Ataxia-Telangiectasia)

Why? ATM deficiency affects vascular development/maintenance → dilated small blood vessels (telangiectasia), particularly on the bulbar conjunctiva and ears

Coarse facies, retained primary teeth (Hyper-IgE)

Why? STAT3 is involved in connective tissue development; STAT3 dysfunction → skeletal abnormalities (scoliosis, fractures, retained teeth, coarse facies)

Clinical presentation of PID includes: infection, auto-immunity, auto-inflammation, malignancy (e.g., lymphoid cancer), hemophagocytosis, and allergy ^[2]

Manifestation	Examples	Mechanism
Autoimmunity	AIHA, ITP (CVID); SLE-like illness (complement def); autoimmune cytopenias (WAS)	Loss of immune regulation / tolerance; failure to clear self-antigens (complement def)
Malignancy	Non-Hodgkin lymphoma (CVID, AT, WAS); EBV-driven lymphoma (XLP)	Defective immune surveillance; impaired DNA repair (AT); uncontrolled viral oncogenesis (XLP)
Lymphoproliferation	Splenomegaly, lymphadenopathy, GLILD (CVID); massive lymphoproliferation (ALPS)	Defective apoptosis (ALPS); chronic antigenic stimulation without effective clearance
Granulomatous disease	Non-caseating granulomas (CVID, CGD)	Chronic inflammation from persistent antigenic stimulation (CVID) or inability to kill organisms (CGD)
Allergic/inflammatory	Eczema (WAS, Hyper-IgE); food allergy (various)	Immune dysregulation

High Yield Summary

PID = genetically determined defects in immunity; now called Inborn Errors of Immunity (IEI) ^[2]^[4]
559 entities, 10 IUIS categories (2024 update) ^[4]
Most common PID overall = Selective IgA deficiency; most common severe PID = CVID ^[2]^[4]
Antibody deficiency is the most common category (36.3%) — presents after 4–6 months with sinopulmonary/GI infections by encapsulated bacteria ^[2]
XLA: Btk mutation → no B cells → pan-hypogammaglobulinaemia → absent tonsils → IVIG treatment ^[2]^[3]
CVID: most common severe PID; heterogeneous; late-onset hypogammaglobulinaemia; infections + autoimmunity + lymphoproliferation + malignancy ^[4]^[5]
SCID: T⁻ ± B⁻ ± NK⁻; fatal without HSCT; present with FTT + severe infections + absent thymus; lymphopenia in infants = < 2,500/μL ^[2]^[3]
DiGeorge: 22q11.2 deletion → CATCH-22 (Cardiac, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcaemia) ^[2]^[3]
CGD: NADPH oxidase defect → can't kill catalase-positive organisms → granulomas; BCG dissemination important in HK ^[2]^[3]^[5]
LAD: CD18 deficiency → neutrophils can't leave vessels → absent pus, delayed cord separation, neutrophilia ^[2]^[3]
Complement: early (C1,2,4) → SLE; C3 → encapsulated bacteria; C5-9 → Neisseria; C1-INH → hereditary angioedema ^[3]^[5]
Warning signs: SPUR infections, FTT, FHx of unexplained early death, persistent lymphopenia, complications from live vaccines ^[3]
Many are treatable: IVIG for antibody deficiency, HSCT for SCID, gene therapy for ADA-SCID; delayed treatment → bronchiectasis ^[4]

Active Recall - Primary Immunodeficiency

^[1] Lecture slides: GC 096. Why do I always get sick.pdf (slide on PIDs vs SIDs definitions) ^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp. 406–411, Section 10.3.2 Primary Immunodeficiency) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 637–638, PID etiology and clinical manifestation) ^[4] Lecture slides: Investigations of Imm Disorders 2025.pdf (pp. 4, 8, 9, 15, 21 — IUIS classification, molecular diagnostics, CVID) ^[5] Senior notes: Jerry's immunodeficiencies.pdf (CVID, Hyper-IgM, HAE, CGD gene details) ^[6] Senior notes: Maksim Medicine Notes.pdf (p. 303, Bronchiectasis aetiology including PID) ^[7] Senior notes: Ryan Ho Haemtology.pdf (p. 117, ITP secondary causes including CVID) ^[8] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (2024 update; pp. 7–10 deficiency vs dysregulation, four-quadrant map, pathogens by defence system, entity list; pp. 17–48 SCID, HIES, XLA, CGD, MSMD, complement, IL-10R, CAPS/CINCA, STAT6 primary atopic disorder, anti-IFN-I phenocopies; pp. 12–15 history; pp. 49–50 investigations)

Differential Diagnosis of Primary Immunodeficiency in Children

The clinical challenge in paediatrics is not merely "does this child have PID?" but rather "why does this child keep getting infections?" — and that differential is much broader than PID alone. This section systematically works through the differential diagnosis at two levels:

Level 1: What is causing recurrent infections in this child? (PID vs. non-PID causes)
Level 2: If PID is suspected, which category/specific PID is it?

1. Level 1: Differential Diagnosis of Recurrent Infections in Childhood

"Not as rare as previously thought — ever-expanding list! Many patients remain undiagnosed or present later in life. High index of suspicion for early diagnosis and intervention. Vigilance — warning signs of primary immunodeficiencies. Differentials: exclude anatomical and functional disorders. May also present with non-infectious symptoms." ^[1]

This GC lecture slide neatly frames the approach: think broadly, exclude common mimics, maintain a high index of suspicion.

Recurrent infections are common in childhood — some children can have up to 8–10 URTIs per year! ^[2]

The majority (50%) of children with recurrent infections are normal and healthy ^[2]. Features that reassure you: short duration, self-limiting, uncomplicated, healthy between episodes ^[2]. Risk factors include start of school and siblings ^[2] — these are simply increased antigen exposure, not immunodeficiency.

So before invoking PID, systematically consider three broad non-PID categories:

These cause site-specific recurrent infections — the same anatomical site keeps getting infected, which is the clue.

Category	Example	Resulting Infection Pattern	Why It Mimics PID
Obstruction to flow	Bronchial obstruction (e.g., foreign body, tumour, malacia)	Recurrent pneumonia of the same lobe	Repeated infection, but always same location — PID causes infections at varying sites
	Eustachian tube obstruction (e.g., adenoid hypertrophy)	Recurrent otitis media	Very common in young children; anatomically short horizontal Eustachian tube
	Urinary tract obstruction (e.g., PUJ obstruction, VUR)	Recurrent UTI	Urinary stasis promotes bacterial colonisation
Damaged barrier	Burns, sinus tracts, open fracture	Pyogenic infection	Breached skin/mucosal barrier allows direct bacterial entry
	Midline / middle ear defect (e.g., dermal sinus, CSF leak)	Recurrent meningitis	CSF rhinorrhoea/otorrhoea provides direct route for bacteria (typically S. pneumoniae)
Inadequate clearance	Primary ciliary dyskinesia (PCD)	Bronchiectasis, sinusitis, otitis media	Immotile cilia cannot clear mucus → stagnation → infection. Associated with situs inversus (Kartagener's) ^[6]
	Cystic fibrosis (CF)	Recurrent pneumonia, bronchiectasis	Abnormally thick mucus traps bacteria. Sweat chloride test is diagnostic ^[8]
	CNS abnormalities	Recurrent aspiration pneumonia	Bulbar dysfunction → chronic aspiration
Foreign body	VP shunt, prosthetic valve, central line, indwelling catheter	Biofilm-associated infections	Foreign material provides nidus for bacterial adherence

Key Clinical Pearl: Site-Specific = Think Structural

If a child has recurrent infections at the same anatomical site (e.g., always the right lower lobe pneumonia, always left-sided otitis media), think structural/anatomical cause first, NOT immunodeficiency. PID tends to cause infections at multiple and varying sites because the immune defect is systemic.

These are acquired causes of immune compromise that must be excluded before labelling a child with PID:

Cause	Mechanism	Key History Points
Iatrogenic: steroids, immunosuppressants, splenectomy ^[2]	Drug-induced immune suppression or loss of splenic filtration	Drug history is critical; post-splenectomy → encapsulated organisms
Neoplasms (leukaemia, lymphoma)	Marrow infiltration → cytopenias; tumour-related immune dysregulation	Pallor, bruising, hepatosplenomegaly, bone pain, weight loss
Antibody / protein loss: nephrotic syndrome ^[2]	Urinary loss of IgG (and other proteins) → hypogammaglobulinaemia	Oedema, proteinuria, hypoalbuminaemia
Malnutrition	Most common cause of secondary immunodeficiency worldwide; impairs all arms of immunity	Dietary history, growth faltering, micronutrient deficiency
HIV infection ^[2]^[7]	CD4+ T cell depletion → progressive cellular immunodeficiency	Maternal HIV status, vertical transmission risk, travel/exposure history
Protein-losing enteropathy	GI loss of immunoglobulins	Chronic diarrhoea, hypoalbuminaemia, oedema

Secondary causes of hypogammaglobulinaemia must be excluded — this is an explicit requirement in ESID diagnostic criteria for CVID: "Exclude drugs [Hx], myeloma [bone marrow], lymphoma. Ig loss (not hypo-IgM) in urine, gastro-intestinal or skin." ^[4]

The most common "diagnosis"! Reassurance is appropriate when:

Infections are self-limiting URTIs
Growth and development are normal
The child is well between episodes
No unusual organisms, no hospitalisations needed
Family history is unremarkable

2. Level 2: Differential Diagnosis Within PID — Which Arm Is Affected?

Once you suspect PID (infections are Severe, Persistent, Unusual, Recurrent — "SPUR"), the next step is to determine which component of the immune system is defective. The pattern of infections is your strongest clinical clue.

Feature	Antibody (B cell) Deficiency	T cell / Combined Deficiency	Phagocyte Defect	Complement Deficiency
Proportion	36.3% ^[2]	19.8% (CID) + 15.2% (syndromic) ^[2]	14.9% ^[2]	~2–5%
Age of onset	After 4–6 months (maternal IgG wanes) ^[2]	Early infancy (< 6 months); neonatal in SCID	Variable; neonatal in LAD	Variable
Typical organisms	Encapsulated bacteria (S. pneumoniae, H. influenzae), Giardia, enterovirus ^[2]^[3]	Viruses (CMV, VZV, HSV), fungi (PCP, Candida), mycobacteria (BCG) ^[3]	Catalase-positive bacteria (Staph, Serratia, Burkholderia), fungi (Aspergillus) ^[2]^[5]	Encapsulated bacteria (early components: SLE); Neisseria (terminal components) ^[3]
Infection sites	Sinopulmonary and GI ^[2]^[3]	Disseminated; oral cavity; lungs; GI	Skin, lymph nodes, liver, lung ^[2]	Meningitis, sepsis
Key clinical features	Bronchiectasis, arthritis, chronic enteroviral meningoencephalitis ^[3]; absent tonsils (XLA)	FTT, chronic diarrhoea, PCP, GVHD ^[3]; absent thymus (SCID)	Lymphadenitis, hepatosplenomegaly, impaired wound healing, soft tissue abscesses, gingivitis/oral ulcers ^[3]; absent pus (LAD); granulomas (CGD)	Angioedema (C1-INH def); SLE-like autoimmune disease (early complement def) ^[3]
FTT	Less prominent	Prominent ^[3]	Variable	Uncommon
Autoimmunity	CVID → AIHA, ITP ^[2]	IPEX → enteropathy, DM1	Rare	SLE (C1, C2, C4 def) ^[3]
Ig pattern	↓↓IgG ± ↓IgA/IgM (XLA, CVID); ↑IgM + ↓IgG/A (HIGM)	Variable; may have normal Ig if B cells present but non-functional	Usually normal Ig	Usually normal Ig
Lymphocyte count	Normal T cells; ↓/absent B cells (XLA)	Low ALC (SCID); variable	Normal	Normal
Neutrophil count	Normal	Normal	↓ (congenital neutropenia) or ↑ (LAD — trapped in vessels) ^[2]	Normal

This table is extremely high-yield for exams — it tells you exactly what to look for:

Phagocytic defect features ^[3]:

Lymphadenitis
Hepatosplenomegaly
Impaired wound healing
Soft tissue abscesses
Gingivitis / periodontal disease / oral mucosal ulcerations
Infection with catalase-positive bacteria and fungi

B-cell defect features ^[3]:

Failure to thrive
Arthritis
Bronchiectasis
Recurrent bacterial sinopulmonary infections (S. pneumoniae, H. influenzae)
Chronic diarrhoea (Giardia, enterovirus)
Chronic enteroviral meningoencephalitis
Infection with encapsulated bacteria

T-cell defect features ^[3]:

Failure to thrive
Recurrent viral infections (VZV, CMV, HSV)
Chronic diarrhoea
Pneumocystis jirovecii (PCP)
GVHD (from maternally-engrafted T cells in SCID, or from non-irradiated blood products)

Complement defect features ^[3]:

Angioedema
Autoimmune disease (SLE)
Infection with encapsulated bacteria

3. Specific PID Entities — Key Differentiating Features

When you've narrowed down the arm of the immune system, the next step is identifying the specific entity. Below is the differential within each category, focusing on the distinguishing features:

Entity	Distinguishing Feature	Ig Pattern	B Cells
XLA (Bruton's)	Boy; absent tonsils; onset 6–18 months; XLR ^[2]^[3]	Pan-hypogammaglobulinaemia	< 1% CD19+ ^[2]^[4]
CVID	Late-onset; variable manifestations; infections + autoimmunity + lymphoproliferation + malignancy ^[4]; absent switched memory B cells ^[4]	↓↓↓IgG, ↓IgA ± ↓IgM ^[2]	Present (> 1%) but dysfunctional
Hyper-IgM syndrome	Opportunistic infections (PCP, Cryptosporidium) despite being "antibody deficiency"; neutropenia ^[2]	↑IgM, ↓IgG/IgA/IgE ^[2]	Present
Selective IgA deficiency	Most common PID; usually asymptomatic ^[2]; risk of anaphylaxis with IgA-containing blood products	↓IgA only; other Ig normal	Normal
Specific antibody deficiency	Normal total Ig levels but poor antibody response to vaccines (absent protective levels despite vaccination) ^[4]	Normal quantitative Ig; abnormal functional response	Normal
Transient hypogammaglobulinaemia of infancy	Prolonged physiological nadir of IgG beyond 6 months; self-resolving by age 2–4 years	Low IgG (matures with age)	Normal

XLA vs CVID — How to Tell Apart

Both present with recurrent sinopulmonary infections and hypogammaglobulinaemia, but:

XLA: male, early onset (6–18 months), absent B cells (< 1%), absent tonsils/lymphoid tissue, pan-hypo Ig
CVID: either sex, later onset (childhood/adolescence/adulthood), B cells present but dysfunctional, autoimmunity and lymphoproliferation are common (not seen in XLA)
The lab investigation case in the Investigations lecture highlights the CVID work-up: HIV negative, tetanus/HAV/HBV antibodies negative despite vaccination, isohaemagglutinin positive, switched memory B cells absent ^[4]

Entity	Distinguishing Feature	Inheritance
SCID (various subtypes)	Most severe; FTT, absent thymus on CXR, low ALC < 2500 in infants ^[2]^[3]; fatal without treatment ^[2]; multiple genetic subtypes (T⁻B⁺NK⁻ in X-linked IL2RG; T⁻B⁻NK⁺ in RAG) ^[4]	X-linked (most common) or AR
DiGeorge syndrome	CATCH-22: Cardiac, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcaemia; 22q11.2 deletion ^[2]^[3]	AD (usually de novo)
Wiskott-Aldrich syndrome	Triad: immunodeficiency + thrombocytopenia + eczema ^[2]; microthrombocytopenia (small platelets); bloody diarrhoea (secondary to thrombocytopenia) ^[5]	XLR
Ataxia-Telangiectasia	Cerebellar ataxia, developmental delay, ↑ risk of lymphoma ^[2]; oculocutaneous telangiectasia; elevated AFP; radiosensitivity	AR
Hyper-IgE syndrome	Pneumatocele, mucocutaneous candidiasis, retained primary teeth, minimal trauma fractures and scoliosis, less allergy/anaphylaxis than expected for IgE level ^[2]; massive cold Staph abscesses ^[5]; STAT3 (AD, loss of function) ^[5]	AD (STAT3) or AR (DOCK8)
XLP (Duncan disease)	Abnormal response to EBV → either succumb to initial infection or develop secondary lymphoma ^[2]	XLR

Entity	Distinguishing Feature	Key Investigation
CGD	Catalase-positive organism infections; granuloma formation; BCG dissemination ^[2]^[5]; X-linked (CYBB) in 60% ^[2]^[5]	Low DHR (dihydrorhodamine) reduction ^[5]; NBT test
LAD	Omphalitis + delayed cord separation; absent pus; persistent neutrophilia ^[2]^[3]	Flow cytometry for CD18 expression
Severe congenital neutropenia (Kostmann)	Severe persistent neutropenia from birth; recurrent life-threatening bacterial infections	ANC < 200/μL; bone marrow shows maturation arrest
Cyclic neutropenia	Regular ~21-day cycling of neutrophil count; oral ulcers and febrile episodes during nadirs	Serial CBCs showing cyclical pattern

Entity	Distinguishing Feature
C1, C2, C4 deficiency	SLE-like autoimmune disease (failure to clear immune complexes) ^[3]
C3 deficiency	Recurrent S. pneumoniae and H. influenzae (C3b is the major opsonin) ^[3]
C5–C9 deficiency	Recurrent Neisseria meningitidis/gonorrhoeae (MAC needed to lyse Neisseria) ^[3]
C1-esterase inhibitor deficiency (HAE)	Bradykinin-mediated angioedema (no urticaria); does NOT respond to antihistamines/adrenaline ^[5]
MBL deficiency	Usually clinically silent; may contribute to recurrent infections in children, especially when combined with other risk factors

The four-column table above covers the broad-spectrum deficiencies. A separate group of IEIs makes an otherwise healthy child susceptible to a single class of organism because one cytokine circuit is broken ^[10]. Recognising the pattern tells you which circuit to test.

Pattern	Circuit	Entity	Test / treatment
Mycobacteria only (disseminated BCG, NTM osteomyelitis) ± Salmonella; normal Ig, normal lymphocyte counts	IFN-γ / IL-12 loop	MSMD — STAT1 LOF, IFNGR1/2, IL12RB1 ^[10]; phenocopy = anti-IFN-γ autoantibody in adults	Functional IFN-γ/IL-12 assays, genetics; prolonged anti-mycobacterials
One catastrophic viral illness — HSV encephalitis, ICU influenza/COVID-19 in a child, or recalcitrant HPV warts	Type I interferon	Mendelian viral infections — TLR3, IRF7, IFNAR, TLR7, EVER1/2 ^[10]; phenocopy = anti-IFN-I autoantibody (severe COVID-19)	Genetics, serum autoantibody; antivirals + vaccination
Mucocutaneous Candida only (thrush after age 1, nail dystrophy) ± Staph skin infection, never invasive	IL-17 / Th17	CMC — STAT1 GOF, IL17RA/F; AD-HIES (STAT3 LOF) if with IgE ↑, cold abscesses, pneumatoceles, retained teeth; phenocopy = anti-IL-17/22 in APECED	IgE, Th17 count, genetics; azoles; JAK inhibitor for STAT1 GOF
Recurrent fever + urticarial rash, cultures always negative, ± deafness, papilloedema, arthropathy	NLRP3 inflammasome / IL-1	CAPS (FCAS, Muckle-Wells, CINCA/NOMID) — NLRP3 GOF, germline or somatic mosaic ^[10]; differential of systemic JIA	Genetics (WES if Sanger negative); anakinra/canakinumab
Colitis with perianal fistulae in the first months of life	IL-10 brake	IL-10R deficiency ^[10]	Genetics; anti-TNF/IL-6/IL-23 bridging → HSCT
Infantile eczema resistant to everything + food anaphylaxis + eosinophilic oesophagitis, IgE > 20,000, eosinophils > 500	IL-4 / STAT6 (Th2)	Primary atopic disorder — STAT6 GOF ^[10]; also DOCK8, WAS, STAT3-HIES, IPEX	IgE, AEC, genetics; dupilumab

Deficiency vs dysregulation on the same list

GC 144 draws IEI as a see-saw: complement, innate, antibody and combined defects load the "immune deficiency" side; autoinflammation and autoimmunity load the "immune dysregulation" side ^[10]. Impaired tolerance mechanisms push a deficient patient toward autoimmunity, and autoantibodies against cytokines push a dysregulated patient toward deficiency (phenocopies). So a child referred for "recurrent infections" may actually present with IBD, cytopenias, arthritis, atopy or lymphoma — any rare immunological phenomenon can have a monogenic basis ^[10].

PID may also present with non-infectious symptoms ^[1]. This is a critical point because many PIDs are missed when clinicians only think about infections.

Non-Infectious Presentation	PID Entities to Consider	Why
Autoimmune cytopenias (AIHA, ITP)	CVID, ALPS, WAS, HIGM	Immune dysregulation → loss of self-tolerance; CVID: autoimmune phenomena in up to 25% ^[4]
SLE-like illness	Early complement deficiency (C1, C2, C4)	Failed immune complex clearance → deposition → inflammation
Lymphoproliferation (unexplained LAD, HSM)	CVID, ALPS, XLP	Chronic antigenic stimulation or defective apoptosis (ALPS: FAS mutation)
Eczema	WAS, Hyper-IgE, SCID (Omenn), IPEX, DiGeorge	Immune dysregulation → skin inflammation ^[7]
Inflammatory bowel disease (early-onset)	IL-10 receptor deficiency, CVID, CGD, IPEX	IL-10R deficiency: early-onset IBD (diarrhoea, perianal sepsis, pyoderma gangrenosum) ^[5]
Malignancy (especially lymphoma)	CVID, AT, WAS, XLP	Defective immune surveillance + DNA repair defects (AT)
Granulomatous disease	CVID, CGD	CVID: granulomatous disease in 8–22% ^[4]; CGD: frustrated phagocytosis → granuloma

Genetic/Metabolic/Immunodeficiency syndromes featuring eczema and ↑ IgE level: Wiskott-Aldrich syndrome, Hyper-IgE syndrome, DiGeorge syndrome, Ataxia-Telangiectasia, SCID ^[7]

Common Exam Pitfalls

Transient hypogammaglobulinaemia of infancy vs true antibody deficiency: Physiological nadir of maternal IgG occurs around 3–6 months. Some infants have a prolonged nadir (up to age 2–4). They may have mild infections but eventually normalise. Do NOT diagnose XLA or CVID too early — repeat Ig levels at follow-up.
Physiological lymphocytosis in infants vs leukaemia: Infants normally have lymphocyte-predominant differential counts (unlike adults who are neutrophil-predominant). A high lymphocyte count in an infant is NOT necessarily abnormal. Conversely, lymphopenia < 2,500/μL in infants is a red flag for SCID ^[3] — do not dismiss it as "normal."
Atypical lymphocytes on blood film can be mistaken for blasts in acute lymphoblastic leukaemia (ALL) ^[9] — always consider the clinical context and get haematology review.
Recurrent meningitis: Think structural (midline/middle ear defect) ^[2] before PID. A CSF leak from a cribriform plate fracture or dermal sinus is a more common cause than complement deficiency.
BCG dissemination in Hong Kong: Since BCG is given at birth in HK, disseminated BCG infection may be the first presentation of SCID, CGD, or MSMD (Mendelian susceptibility to mycobacterial diseases). BCG vaccine will disseminate in SCID, CGD, and MSMD (STAT1 loss-of-function, IFN-γ pathway defects) ^[5].

7. Approach to History and Physical Examination in Suspected PID [3]

This is really about "what to ask and look for" to narrow the differential:

Domain	What to Ask	Why
HPI	Poor weight gain/weight loss; recurrent infections; oral mucosal ulcers/oral candidiasis; chronic diarrhoea; chronic lung/heart/GI diseases	Defines the severity and pattern
Drug history	Immunosuppressants; IVIG use	Rules out secondary causes; prior IVIG suggests known PID
Family history	Consanguinity (for AR PID); inheritance pattern; FHx of recurrent infection, unexplained death, or autoimmune disease; FHx of HIV/HBV/HSV	Consanguinity → AR PID; X-linked → affected males on maternal side
Growth and development	Weight, height, head circumference	FTT suggests combined/T cell deficiency
Birth history	Maternal illness (HIV, CMV); delayed separation of umbilical cord (persistent attachment beyond 30 days)	Delayed cord separation → LAD
Neonatal factors	Neonatal hypocalcaemia	Hypocalcaemia → DiGeorge syndrome
Feeding history	Food intolerance; duration of breastfeeding	Chronic diarrhoea; breast milk provides some passive immunity
Immunisation history	Complications from live vaccines: CNS complication following polio vaccine; diarrhoea following rotavirus vaccine; disseminated BCG following BCG vaccine	Live vaccine complications → SCID, CGD, MSMD

System	What to Look For	Differential
General	Dysmorphic features; short stature; muscle wasting/atrophy of buttock fat (FTT)	DiGeorge (facial dysmorphism); HIES (coarse facies)
Lymphoid tissue	Overabundance or paucity of tonsils/LN/spleen	Adenopathy and hepatosplenomegaly: CGD; Absence of lymphoid tissues: XLA/CVID ^[3]
ENT	Hearing loss/ear discharge; postnasal drip/purulent nasal discharge; mouth ulcers/gingivitis/mucosal candidiasis/poor dentition/diminished or absent tonsils	Chronic sinopulmonary → antibody def; absent tonsils → XLA
Respiratory	Crackles, wheeze, clubbing	Bronchiectasis → CVID, CGD
Cardiovascular	Murmur, cyanosis	Conotruncal anomaly → DiGeorge
Skin	Eczema, abscesses, petechiae, telangiectasia, non-healing wounds	WAS (eczema + petechiae), CGD (abscesses), LAD (non-healing), AT (telangiectasia)
Neurological	Ataxia, developmental delay	AT (cerebellar ataxia), DiGeorge (developmental delay)
Skeletal	Scoliosis, fractures, retained primary teeth	Hyper-IgE syndrome

High Yield Summary — Differential Diagnosis

50% of children with recurrent infections are normal and healthy ^[2] — always start by asking: are the infections truly SPUR (Severe, Persistent, Unusual, Recurrent)?
Exclude structural/anatomical causes (site-specific infections: same lobe pneumonia → bronchial obstruction; recurrent meningitis → midline defect) and secondary immunodeficiency (HIV, drugs, nephrotic syndrome, malnutrition, malignancy) before diagnosing PID ^[2]
Pattern of infections narrows the PID category: sinopulmonary with encapsulated bacteria → antibody; viral/fungal/opportunistic → T cell/combined; skin abscesses with catalase-positive organisms → phagocyte; Neisseria → complement ^[2]^[3]
CVID is the most common severe PID but must exclude secondary causes of hypogammaglobulinaemia ^[4]
XLA: absent B cells + absent tonsils + pan-hypogammaglobulinaemia; CVID: B cells present but dysfunctional + late onset + autoimmunity/lymphoproliferation ^[2]^[4]
PID can present with non-infectious manifestations: autoimmunity, malignancy, lymphoproliferation, eczema, granulomatous disease, early-onset IBD ^[1]^[2]^[3]
In Hong Kong, BCG dissemination may be the first presentation of SCID, CGD, or MSMD ^[5]
Immunisation history is critical: complications from live vaccines (BCG, rotavirus, oral polio) are red flags for PID ^[3]

Active Recall - Differential Diagnosis of PID

References

^[1] Lecture slides: GC 096. Why do I always get sick.pdf (slide: "General principles — warning signs, differentials") ^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp. 406–411, Section 10.3.2 Primary Immunodeficiency) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 638–640, Clinical manifestation, warning signs, history and PE) ^[4] Lecture slides: Investigations of Imm Disorders 2025.pdf (pp. 4, 6, 7, 14, 16 — IUIS classification, CVID case, ESID criteria) ^[5] Senior notes: Jerry's immunodeficiencies.pdf (PID classification table with genes, pathogens, treatments) ^[6] Senior notes: Maksim Medicine Notes.pdf (p. 303, Bronchiectasis aetiology including PCD, CF, PID) ^[7] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1787, Immunodeficiency syndromes featuring eczema) ^[8] Lecture slides: Evaluation of wheezing in infants and children - UpToDate.pdf (immunologic evaluation, sweat chloride, PCD workup) ^[9] Senior notes: Ryan Ho Haemtology.pdf (p. 47, atypical lymphocytes vs blasts differential) ^[10] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (pp. 7–13 deficiency vs dysregulation, pathogens by defence system, past medical/infection history; pp. 38–48 MSMD, complement, IL-10R, CAPS/CINCA, STAT6 primary atopic disorder, anti-IFN-I phenocopies; p. 56 differential of systemic JIA)

Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities for Primary Immunodeficiency in Children

There is no single "diagnostic criterion" that encompasses all 559 IEI entities. The diagnosis of PID in paediatrics is a layered process: clinical suspicion → screening investigations → targeted phenotypic investigations → genetic confirmation. Each specific PID entity has its own diagnostic criteria (the best formalised being CVID via ESID), but the overarching approach is the same.

Approach to diagnosis of PID: Clinical history → Physical examination → Phenotypic investigations (IgG, IgA, IgM levels; vaccine responses; T, B, NK cell enumerations; lymphocyte subsets; cell function tests) → Genetic testing ^[4]

Many IEIs require tailored investigations, and cannot be picked up by initial screening tests. Always consult immunology when clinically suspicious. ^[10]

This is a critical teaching point: the screening CBC + immunoglobulins will catch many common PIDs (XLA, CVID, SCID, severe congenital neutropenia) but will miss entities where cell counts and Ig levels are normal but cell function is defective (e.g., CGD, some CIDs, MSMD). Clinical suspicion should drive the investigation, not a single normal screening test.

CVID is the most common severe PID requiring treatment, and the only PID with widely-used formal diagnostic criteria (from ESID — European Society for Immunodeficiencies). This is very high-yield for exams.

ESID Diagnostic Criteria for CVID ^[4]:

ALL of the following must be met:

At least one of the following clinical features:
- Increased susceptibility to infection
- Autoimmune manifestations
- Granulomatous disease
- Unexplained polyclonal lymphoproliferation
- Affected family member with antibody deficiency
AND marked decrease of IgG AND marked decrease of IgA, with or without low IgM levels (measured at least twice; < 2 SD of the normal levels for their age)
AND at least one of the following:
- Poor antibody response to vaccines (and/or absent isohaemagglutinins); i.e., absence of protective levels despite vaccination where defined
- Low switched memory B cells (< 70% of age-related normal value)
AND secondary causes of hypogammaglobulinaemia have been excluded
AND diagnosis is established after the 4th year of life (but symptoms may be present before)
AND no evidence of profound T-cell deficiency, defined as 2 out of the following:
- CD4 numbers/μL: 2–6y < 300; 6–12y < 250; > 12y < 200
- % naive CD4: 2–6y < 25%; 6–16y < 20%; > 16y < 10%
- T cell proliferation absent

Understanding Every ESID Criterion — Why Each Matters

Clinical features: CVID is not just infections — autoimmunity, granulomas, and lymphoproliferation are all recognised manifestations. This criterion ensures you're not diagnosing CVID in someone with incidental low Ig.
IgG + IgA low, measured twice: Confirms persistent hypogammaglobulinaemia (not a transient dip from acute illness). You need IgG low because that's the main protective isotype, and IgA low because isolated IgG deficiency with normal IgA is more likely to be IgG subclass deficiency.
Impaired vaccine response or low switched memory B cells: This demonstrates functional B cell impairment, not just low immunoglobulin numbers. The CVID case in the Investigations lecture showed: tetanus, HAV, HBV antibodies negative despite vaccination; switched memory B cells absent ^[4] — this is the classic phenotypic finding.
Exclude secondary causes: You MUST rule out drugs (rituximab, anti-epileptics), protein-losing states (nephrotic syndrome), malignancy (CLL, lymphoma), HIV — these all cause secondary hypogammaglobulinaemia.
After age 4: Before age 4, transient hypogammaglobulinaemia of infancy is still in the differential, and immune maturation is incomplete. CVID diagnosis is reserved for > 4 years (though symptoms may start earlier).
No profound T-cell deficiency: If T cells are severely depleted, you're dealing with a combined immunodeficiency (SCID, CID), not CVID. The age-specific CD4 thresholds reflect paediatric physiology — younger children normally have higher CD4 counts.

While formal diagnostic criteria exist for only a few PIDs, most rely on a combination of clinical phenotype + laboratory phenotype + genetic confirmation:

PID	Key Diagnostic Criteria / Findings
XLA	Male; low/zero B-cell count (CD19+ < 1%); pan-hypogammaglobulinaemia (low IgG, IgA, IgM) ^[2]^[5]; low KREC on newborn screening ^[5]; confirmed by BTK gene mutation
SCID	Low TREC on newborn screening ^[5]; Low ALC (< 2,500/μL in infants) ^[3]; low/zero T-cell count; low naïve T cells ^[5]; absent thymus shadow on CXR ^[2]; confirmed by genetic testing (IL2RG, JAK3, RAG1/2, ADA, etc.)
CGD	Low dihydrorhodamine (DHR) reduction on flow cytometry ^[5]; or abnormal NBT test; confirmed by genetic testing (CYBB, CYBA, NCF1, NCF2, NCF4) ^[5]
LAD	Flow cytometry showing absence/reduction of CD18 (β2-integrin) on neutrophils; persistent neutrophilia ^[2]; delayed cord separation + absent pus clinically
DiGeorge	FISH or microarray showing 22q11.2 deletion; ± low T cells; ± hypocalcaemia; ± conotruncal cardiac anomaly on echocardiography
WAS	Low platelets (micro-thrombocytopenia — low MPV) ^[5]; low IgM ^[5]; confirmed by WAS gene mutation
Hyper-IgE	High IgE; high absolute eosinophil count ^[5]; CXR showing massive pneumatoceles ^[5]; clinical features (cold abscesses, retained teeth, fractures); confirmed by STAT3 or DOCK8 mutation
Complement deficiency	Low CH50 (total classical pathway); low AH50 (alternative pathway); individual complement component levels; confirmed genetically
HAE	Low C4 (screening); C1-INH level (Type I) and function (Type II); C1-INH deficiency with bradykininergic angioedema ^[5]

The diagnostic algorithm for PID in children proceeds in a stepwise fashion: clinical suspicion → first-line screening tests → second-line targeted tests → definitive genetic testing.

5. Investigation Modalities — Detailed Guide

5.1 FIRST-LINE (SCREENING) INVESTIGATIONS

These are available in any general paediatric setting and should be ordered when PID is suspected.

The single most important and accessible initial test. The GC 144 lecture slide provides a masterful summary of CBC interpretation in IEI ^[10]:

Complete blood count findings in IEI ^[10]:

ALC low < 3,000 (< 1 year) or < 1,000 (> 1 year) → severe combined immunodeficiencies

AEC high → primary atopic disorders

ANC < 1 [×10⁹/L] → severe congenital neutropenia

ANC high → leukocyte adhesion deficiency

AMC low → GATA2 deficiency

PLT low → Wiskott-Aldrich syndrome

Parameter	Normal Paediatric Range	Abnormal Finding	Suggests
ALC (Absolute Lymphocyte Count)	< 1y: > 3,000/μL; > 1y: > 1,000/μL ^[10]	Low	SCID, other CID — T cells make up the bulk of circulating lymphocytes in infancy
			Lymphopenia in infants < 2,500/μL is a red flag ^[3]
ANC (Absolute Neutrophil Count)	Age-dependent; typically > 1.5 × 10⁹/L beyond neonatal period	Low (< 1.0)	Severe congenital neutropenia (Kostmann) ^[10]; cyclic neutropenia; autoimmune neutropenia
		Persistently high	LAD — neutrophils trapped in vessels because they cannot adhere and transmigrate ^[2]^[10]
AEC (Absolute Eosinophil Count)	< 0.5 × 10⁹/L	High	Primary atopic disorders, Hyper-IgE syndrome ^[10]; also consider parasites, allergic disease
AMC (Absolute Monocyte Count)	0.2–0.8 × 10⁹/L	Low	GATA2 deficiency (myelodysplasia + immunodeficiency) ^[10] — rare but important
Platelet count	150–400 × 10⁹/L	Low	Wiskott-Aldrich syndrome (micro-thrombocytopenia — check MPV is LOW) ^[5]^[10]
Hb	Age-dependent	Low	Chronic disease; autoimmune haemolytic anaemia (CVID, ALPS); BM failure

Why is ALC so critical in infants? Infants normally have a lymphocyte-predominant differential (lymphocytes are the majority cell type, unlike adults who are neutrophil-predominant). The normal infant lymphocyte count is high (4,000–13,500/μL at 6 months). An ALC that appears "low-normal" by adult standards (e.g., 2,000/μL) is actually severely lymphopenic in an infant and may indicate SCID. Always use age-appropriate reference ranges.

Exam Trap: Neutrophilia in LAD

A child with recurrent skin infections, absent pus, delayed cord separation, and a markedly elevated neutrophil count (e.g., WBC 50 × 10⁹/L with 80% neutrophils). Students often think "infection" or "leukaemia" when they see a very high WBC. But in LAD, the neutrophilia is persistent even between infections because neutrophils cannot leave the bloodstream. The combination of neutrophilia + absent pus + delayed cord separation = LAD until proven otherwise.

IgGAME findings in IEI ^[10]:

Low IgGAM → agammaglobulinaemia, e.g., XLA

High IgE → Hyper-IgE, primary atopic disorder

High IgM → Hyper-IgM syndrome

High IgGAM → chronic granulomatous disease (persistent antigenic stimulation from chronic infections drives polyclonal hypergammaglobulinaemia)

Low IgM → DOCK8 deficiency, Wiskott-Aldrich syndrome, Ataxia-Telangiectasia

Pattern	Interpretation	Entities
Pan-hypogammaglobulinaemia (↓ IgG, IgA, IgM)	No antibody production at all	XLA ^[2]; some forms of SCID
↓↓↓ IgG + ↓ IgA ± ↓ IgM	Impaired but not absent B cell function	CVID ^[2]^[4]
↑ IgM + ↓ IgG, IgA, IgE	Class-switch failure	Hyper-IgM syndrome ^[2]
Isolated ↓ IgA	Selective IgA deficiency	Most common PID; usually asymptomatic ^[2]
Markedly ↑ IgE (> 2,000 IU/mL)	Immune dysregulation	Hyper-IgE syndrome ^[5]^[10]; also consider atopic disease, parasites, ABPA
↑ IgG, IgA, IgM (polyclonal)	Chronic infection/inflammation driving B cell activation	CGD (paradoxically, phagocyte defect causes chronic infection → polyclonal Ig rise) ^[10]; chronic infections in general
Normal	Does NOT exclude PID	Complement deficiency, CGD, LAD, MSMD, some CID — always correlate clinically

Important caveats in paediatrics:

IgG is normally high at birth (maternal IgG) → nadir at 3–6 months → gradually rises. Low IgG at 3–6 months may be physiological (transient hypogammaglobulinaemia of infancy) — repeat testing at 12 months.
IgA is normally very low in infancy (barely detectable at birth) and rises slowly through childhood. Do not diagnose selective IgA deficiency before age 4 ^[4].
Ig levels must be measured at least twice and compared to age-appropriate reference ranges (< 2 SD) ^[4].

Why CXR? Three key findings:

Thymus shadow — normally visible in infants on AP CXR as a sail-shaped shadow in the anterior mediastinum
- Absent thymus shadow → SCID, complete DiGeorge ^[2]^[3]
- Why? The thymus is where T cells mature. In SCID, there are no T cell precursors to populate the thymus → thymic atrophy. In DiGeorge, the thymus fails to develop due to pharyngeal pouch defect.
Bronchiectasis — tram-track opacities, ring shadows, signet-ring sign
- CXR may show bronchiectasis in XLA, CVID ^[5]^[6]
- Represents end-organ damage from recurrent sinopulmonary infections. Delayed treatment is associated with complications such as bronchiectasis ^[4].
Pneumatoceles — thin-walled air-filled cysts
- CXR showing massive pneumatoceles → Hyper-IgE syndrome ^[5]
- Result from necrotising staphylococcal pneumonia with destruction of lung parenchyma

Always test for HIV when investigating possible immunodeficiency — HIV is the most important secondary cause to exclude
In infants < 18 months: HIV PCR (DNA or RNA) because maternal HIV antibodies persist → serological tests unreliable
In children > 18 months: HIV antibody test (4th generation Ag/Ab combo test)

5.2 SECOND-LINE (TARGETED) INVESTIGATIONS

Ordered based on the clinical pattern and first-line results, ideally in consultation with a paediatric immunologist.

This is the cornerstone of phenotypic immune assessment. Uses fluorescently-labelled monoclonal antibodies against cell surface markers (CD antigens) to count specific lymphocyte populations.

Lymphocyte subset findings in IEI ^[10]:

Low T cells (with or without low B and/or NK) → combined immunodeficiencies

Low B cells only → agammaglobulinaemia

In some forms of CID, T cell count may be normal but function is impaired, or they may be maternally grafted memory T cells in Omenn syndrome, a form of SCID ^[10]

Marker	Cell Type	Interpretation When Low	Interpretation When Normal/High
CD3+	Total T cells	SCID, CID, DiGeorge	Does not exclude functional T cell defect
CD4+	Helper T cells	HIV, SCID, DiGeorge	—
CD8+	Cytotoxic T cells	Some CID	—
CD19+ (or CD20+)	B cells	XLA (< 1%); some SCID subtypes	Does not exclude CVID (B cells present but dysfunctional)
CD16+/CD56+	NK cells	X-linked SCID (T⁻B⁺NK⁻)	—
CD4⁻CD8⁻ TCRα/β+	Double-negative T cells	—	Elevated → ALPS (autoimmune lymphoproliferative syndrome) ^[4]

Special subset: Switched Memory B Cells (CD19+CD27+IgD⁻)

These are B cells that have undergone class-switch recombination in germinal centres
Low switched memory B cells (< 70% of age-related normal value) → key finding in CVID ^[4]
Also low in asplenia/hyposplenia (marginal zone B cells depend on splenic architecture)

Omenn Syndrome — The SCID Trap

In Omenn syndrome (a form of SCID caused by hypomorphic RAG mutations), T cells may be normal or even elevated in count ^[10]. However, these T cells are oligoclonal, activated, and autoreactive — they cause an erythrodermic rash, eosinophilia, elevated IgE, and hepatosplenomegaly. The T cells may also include maternally grafted memory T cells ^[10] that crossed the placenta. Do not be reassured by a "normal" T cell count in a sick infant — always check T cell function (proliferation assays) and naïve T cell markers.

Even if total Ig levels are borderline, you need to assess whether the B cells can mount a functional response to antigens.

Vaccine Type	What It Tests	Expected Response	In PID
Protein antigens (tetanus, diphtheria, hepatitis B)	T-dependent B cell response (requires T cell help)	Protective antibody titre post-vaccination	Absent in XLA, CVID; absent in Hyper-IgM (for IgG response)
Polysaccharide antigens (Pneumovax-23, unconjugated)	T-independent B cell response (marginal zone B cells)	Rise in specific anti-pneumococcal antibodies	Absent in CVID, specific antibody deficiency

The CVID case showed: tetanus, HAV, HBV antibodies negative despite vaccination ^[4] — this is a classic functional antibody deficiency finding.
Isohaemagglutinins (anti-A, anti-B blood group antibodies): naturally occurring IgM antibodies. Absent isohaemagglutinins = impaired antibody production ^[4]. Note: not applicable in blood group AB individuals (who naturally lack isohaemagglutinins) or in infants < 6 months (not yet produced).

Test	What It Measures	Normal Result	Abnormal in
Dihydrorhodamine (DHR) flow cytometry	NADPH oxidase-dependent oxidative burst	DHR is oxidised to fluorescent rhodamine-123 → bright fluorescence	CGD → low/absent fluorescence ^[5]
Nitroblue tetrazolium (NBT) test	Same pathway (older, less sensitive)	Yellow NBT reduced to blue-purple formazan by superoxide	CGD → no colour change
CD18/CD11b expression (flow cytometry)	Surface adhesion molecule expression	Present on > 95% neutrophils	LAD → absent or severely reduced CD18

Why DHR over NBT? DHR flow cytometry is more sensitive and quantitative — it can detect carrier states (X-linked CGD carriers show a bimodal fluorescence pattern: some neutrophils fluoresce normally, others do not, reflecting random X-inactivation). NBT is a qualitative slide-based test — less reliable for subtle defects.

Test	What It Measures	Interpretation
CH50 (Total Haemolytic Complement — classical pathway)	Functional integrity of the entire classical pathway (C1 → C9)	Low → deficiency of any classical pathway component. If CH50 is zero → likely a complement component is completely absent
AH50 (Alternative Pathway)	Functional integrity of the alternative pathway	Low → Factor B, Factor D, or properdin deficiency
Individual complement levels	Specific component (C3, C4, etc.)	Targeted based on CH50/AH50 results
C4 level	Screening for HAE	Low C4 even between attacks in HAE (C4 is consumed by uninhibited C1)
C1-INH level and function	Diagnose HAE Type I (low level) and Type II (low function, normal level)	Type I: 85%, low level; Type II: 15%, normal level but low function ^[5]

Interpretation logic:

CH50 low + AH50 normal → classical pathway defect (C1, C2, or C4)
CH50 low + AH50 low → common pathway defect (C3, or terminal C5–C9)
CH50 normal + AH50 low → alternative pathway defect (Factor B, D, properdin)

Peripheral blood mononuclear cells stimulated with mitogens (PHA, ConA, anti-CD3) or specific antigens (Candida, tetanus toxoid)
Measured by ³H-thymidine incorporation or CFSE dilution
Normal response = T cells proliferate vigorously
Absent/reduced response = T cell functional defect (even if T cell count is normal)
T cell proliferation absent → used as part of ESID criteria to define "profound T-cell deficiency" excluding CVID ^[4]

Cell function tests include: expression of CD40-ligand on activated T cells for Hyper-IgM syndrome ^[4]

Test	Application
Induced CD40L (CD154) expression on activated T cells	Hyper-IgM syndrome (X-linked) — CD40L is not expressed after T cell activation ^[4]^[5]
Perforin/granzyme expression	Familial HLH — perforin-deficient NK cells
NK cell cytotoxicity assay	NK cell deficiency
Cytokine production assays (IFN-γ, IL-12, IL-17)	MSMD (IFN-γ pathway); chronic mucocutaneous candidiasis (IL-17 pathway) ^[5]
Toll-like receptor (TLR) signalling	Innate immunity defects

Genetic testing has an important role in: Diagnosis (all cases), Family studies (HIGM, HAE cases), Prognostication, Prenatal diagnosis, Defining new diseases ^[4]

Molecular basis of many has been worked out. Mostly single gene disorders. Several are X-linked, accounting for male preponderance of some PID. ^[4]

Modality	When to Use	Examples
Targeted single-gene sequencing (Sanger)	Known phenotype strongly suggests a specific gene	BTK for XLA; WAS for Wiskott-Aldrich; CYBB for X-linked CGD
Next-generation sequencing (NGS) gene panels	PID panel covering 300+ known IEI genes	First-line genetic test at most centres now; rapid turnaround
Whole exome sequencing (WES)	Undiagnosed PID after panel testing; atypical phenotype	Identifies novel variants; requires bioinformatic expertise
Whole genome sequencing (WGS)	Research; very atypical cases	Detects non-coding variants, structural variants
Chromosomal microarray / FISH	DiGeorge (22q11.2 deletion); other syndromic PID	22q11.2 microdeletion detection
Chromosomal breakage analysis	Suspected Fanconi anaemia or other DNA repair defects	Diepoxybutane (DEB) or mitomycin C (MMC) induced chromosomal breakage

This is increasingly relevant and a growing area in paediatric practice:

Test	What It Detects	Mechanism	PID Screened
TREC assay (T-cell Receptor Excision Circles)	By-products of TCR gene rearrangement during T cell development in the thymus	Low/absent TRECs = insufficient T cell production = possible SCID	SCID and other severe T cell lymphopenias ^[5]
KREC assay (Kappa-deleting Recombination Excision Circles)	By-products of Ig light chain gene rearrangement during B cell development	Low/absent KRECs = insufficient B cell production	XLA and other agammaglobulinaemias ^[5]

TREC — "T-cell Receptor Excision Circles" — are small circular DNA fragments excised during V(D)J recombination of the T cell receptor in the thymus. Every newly-produced T cell (a "recent thymic emigrant") contains TRECs. In SCID, the thymus produces no/few T cells → no TRECs are generated → low TREC on newborn screening blood spot ^[5].

KREC — "Kappa-deleting Recombination Excision Circles" — are the B cell equivalent, generated during Ig kappa light chain gene rearrangement. In XLA, B cell development is arrested → no KRECs ^[5].

Modality	Finding	Significance
CXR (AP + lateral)	Absent thymic shadow	SCID, complete DiGeorge ^[2]
	Pneumatoceles	Hyper-IgE syndrome ^[5]
	Bronchiectasis	CVID, XLA, CGD (end-organ damage from chronic infections) ^[5]^[6]
	Diffuse bilateral infiltrates	PCP (in SCID, HIV)
HRCT thorax	Bronchiectasis (signet ring sign, tram-tracking), GLILD	Better sensitivity than CXR for bronchiectasis; essential for monitoring CVID lung disease
Echocardiography	Conotruncal cardiac anomalies	DiGeorge syndrome ^[2]
Abdominal ultrasound	Hepatosplenomegaly, abscesses	CGD (liver abscesses); ALPS/CVID (splenomegaly)

Test	Purpose
Serum alpha-fetoprotein (AFP)	Elevated in Ataxia-Telangiectasia (mechanism unclear; possibly related to aberrant transcription from chromosomal instability)
Sweat chloride test	Exclude cystic fibrosis as a cause of recurrent sinopulmonary infections and bronchiectasis ^[8]
Nasal nitric oxide + ciliary studies	Exclude primary ciliary dyskinesia ^[8]
Serum protein electrophoresis (SPE)	Pan-immunoparesis pattern → think inherited or acquired immunodeficiencies ^[11]; exclude myeloma/lymphoma in older adolescents
Bone marrow examination	If BM failure suspected (Fanconi, dyskeratosis congenita); also to exclude malignancy as secondary cause

Suspected Category	First-Line	Second-Line	Definitive
Antibody deficiency	Serum IgG/A/M/E; CBC	B cell count (CD19); vaccine responses; isohaemagglutinins; switched memory B cells	BTK gene (XLA); TACI, ICOS, BAFF-R (CVID); CD40L gene (HIGM)
Combined / T cell	CBC (ALC); CXR (thymus)	T cell subsets (CD3/4/8); lymphocyte proliferation; NK cells (CD16/56); naïve T cell markers	IL2RG, JAK3, RAG1/2, ADA; FISH for 22q11.2 (DiGeorge)
Phagocyte	CBC (ANC)	DHR flow cytometry; CD18 expression	CYBB, CYBA, NCF1/2/4 (CGD); ITGB2 (LAD); ELANE (cyclic/SCN)
Complement	CH50, AH50; C3, C4	Individual complement components; C1-INH level + function	SERPING1 (HAE); specific complement gene sequencing
Innate / MSMD	May be normal screening	IFN-γ / IL-12 axis functional tests; TLR signalling assays	STAT1, IFNGR1/2, IL12B, IL12RB1

High Yield Summary — Diagnosis of PID

Diagnostic approach: Clinical history → Physical examination → Phenotypic investigations → Genetic testing ^[4]. No single screening test catches all PIDs.
First-line: CBC with differential + Serum Ig (IgG/A/M/E) + CXR + HIV test.
CBC interpretation in IEI (GC 144): ALC low → SCID; ANC low → SCN; ANC high → LAD; PLT low → WAS; AEC high → primary atopic/HIES. ^[10]
IgGAME interpretation: low IgGAM → XLA; high IgE → HIES; high IgM → HIGM; high IgGAM → CGD; low IgM → WAS/DOCK8/AT. ^[10]
ESID criteria for CVID: clinical features + ↓IgG + ↓IgA (×2) + impaired vaccine response or ↓switched memory B cells + exclude secondary causes + Dx after age 4 + no profound T cell deficiency. ^[4]
DHR flow cytometry is the gold standard for CGD diagnosis (low/absent fluorescence). ^[5]
Newborn screening: TREC for SCID, KREC for XLA ^[5] — enables pre-symptomatic detection and early HSCT.
Genetic testing is important for all cases: diagnosis, family studies, prognostication, prenatal diagnosis, defining new diseases. ^[4]
Absent thymus on CXR → SCID or complete DiGeorge; pneumatoceles → HIES; bronchiectasis → CVID/XLA (delayed treatment). ^[2]^[5]
Always use age-appropriate reference ranges — lymphopenia < 2,500/μL in infants is a red flag for SCID. ^[3]

Active Recall - Diagnosis of Primary Immunodeficiency

References

^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp. 406–411, Section 10.3.2 Primary Immunodeficiency) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 638–640, Clinical manifestation, diagnosis, warning signs) ^[4] Lecture slides: Investigations of Imm Disorders 2025.pdf (pp. 4, 10, 14, 16 — Approach to PID diagnosis, ESID criteria, CVID case, genetic testing) ^[5] Senior notes: Jerry's immunodeficiencies.pdf (PID classification table with tests, genes, pathogens, treatments) ^[6] Senior notes: Maksim Medicine Notes.pdf (p. 303, Bronchiectasis aetiology including PID) ^[8] Lecture slides: Evaluation of wheezing in infants and children - UpToDate.pdf (immunologic evaluation, sweat chloride, PCD workup) ^[10] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (p. 50, CBC/IgGAME/lymphocyte subset interpretation in IEI) ^[11] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p. 27, SPE interpretation — pan-immunoparesis)

Management and Treatment Modalities for Primary Immunodeficiency in Children

Managing PID in paediatrics is fundamentally different from managing an acquired immunodeficiency. The defect is intrinsic and lifelong — you cannot "cure" the gene defect with antibiotics alone. Management therefore rests on four pillars:

Definitive/curative therapy — correct the underlying immune defect (HSCT, gene therapy)
Replacement therapy — supply the missing immune component (IVIG/SCIG for antibody deficiency)
Antimicrobial prophylaxis — prevent infections that the defective immune system cannot handle
Supportive and preventive care — infection avoidance, vaccination guidance, family counselling, monitoring for non-infectious complications

Many are treatable: HSC transplantation for Severe Combined Immunodeficiency; IV immunoglobulin for X-linked agammaglobulinemia. Delayed treatment associated with complications such as bronchiectasis. ^[4]

This slide message is the exam-relevant take-home: early diagnosis and treatment prevents irreversible end-organ damage (especially bronchiectasis, which once established is permanent).

3. Treatment Modalities — Detailed Guide

3.1 IMMUNOGLOBULIN REPLACEMENT THERAPY

This is the mainstay of treatment for antibody deficiency — the single most commonly used PID treatment.

XLA — IVIG / SCIG replacement ^[5]
CVID with recurrent infections and confirmed hypogammaglobulinaemia ^[4]^[5]
Hyper-IgM syndrome (IgG is low despite elevated IgM)
SCID and other CID (as a bridge while awaiting HSCT, or if HSCT not feasible)
Hyper-IgE syndrome — IVIG as part of combined management ^[5]
Any PID with demonstrated antibody deficiency and recurrent infections

Route	Abbreviation	How It Works	Advantages	Disadvantages
Intravenous immunoglobulin	IVIG	Pooled IgG from > 1,000 donors; infused IV over 2–4 hours	Rapid ↑ in serum IgG; given every 3–4 weeks	Requires IV access; infusion reactions (headache, fever, chills); hospital visits; risk of anaphylaxis in IgA-deficient patients with anti-IgA antibodies
Subcutaneous immunoglobulin	SCIG	Same product injected subcutaneously via pump or manual push	Home-based; more stable serum IgG levels (smaller doses more frequently); fewer systemic side effects	Local site reactions (swelling, redness); patient/parent must be trained for home administration; weekly or biweekly dosing

Paediatric considerations:

SCIG is increasingly preferred in children because it can be given at home → less school disruption, less hospital anxiety, promotes independence in older children/adolescents
Parents are trained to administer SCIG; older adolescents can self-administer → promotes autonomy (important for developmental stage)
For infants and small children, IVIG may be initially preferred for dose accuracy and monitoring, then transitioned to SCIG when family is confident

Typical IVIG dose: 400–600 mg/kg every 3–4 weeks
Target: maintain trough IgG level > 5–8 g/L (some centres aim for > 8 g/L to reduce infection frequency, particularly in patients with bronchiectasis)
Dose adjusted based on trough levels, clinical response (frequency/severity of infections), and presence of end-organ damage

Reaction	Mechanism	Management
Infusion-related (headache, fever, chills, myalgia)	Rate-dependent; complement activation by Ig aggregates	Slow the infusion rate; pre-medicate with paracetamol ± antihistamine
Anaphylaxis	Anti-IgA antibodies in IgA-deficient patients → reacts to IgA in the IVIG preparation	Use IgA-depleted IVIG or SCIG (lower systemic IgA exposure); this is rare but important in selective IgA deficiency
Aseptic meningitis	High-dose Ig; mechanism unclear	Reduce rate; hydration
Thrombotic events	Increased serum viscosity; pro-coagulant factors in Ig preparations	Adequate hydration; avoid in patients with thrombotic risk factors
Renal impairment	Sucrose-containing formulations → osmotic nephrosis	Use non-sucrose formulations
Haemolytic anaemia	Anti-A/Anti-B antibodies in Ig preparation (from non-group-O donors)	Monitor Hb; more common with high-dose IVIG

Absolute: Known anaphylaxis to immunoglobulin preparations (very rare)
Relative: Selective IgA deficiency with confirmed anti-IgA antibodies (use IgA-depleted products)
IVIG is NOT useful in XLA for vaccine-preventable diseases because immunisation is useless ^[2] — the patient cannot mount their own immune response, so you are entirely reliant on the donor pool's antibody content

Exam Point: Why Does IVIG Work in XLA But Vaccines Don't?

In XLA, there are no B cells — so no cells can receive vaccine antigens and produce antibodies. Vaccination is futile. IVIG works by providing pre-formed antibodies from healthy donors — it's passive immunisation, not active immunisation. The patient is essentially borrowing other people's immune response. This is why IVIG must be given repeatedly (IgG half-life ~21 days) — the borrowed antibodies are eventually catabolised and must be replenished.

3.2 HAEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)

HSCT is the definitive curative therapy for severe PIDs where the defect is intrinsic to haematopoietic cells. It replaces the patient's defective immune system with a normal donor immune system.

The procedure involves: Conditioning (high-dose chemotherapy ± radiotherapy to eradicate the diseased marrow and prevent graft rejection) → Donor graft infusion (replace with healthy donor HSCs) → Engraftment (2–3 weeks of cytopenic phase while donor cells repopulate the marrow) → Immunosuppression (prevention of GVHD) ^[12]

In PID (as opposed to malignancy), the goal is immune reconstitution, not tumour eradication. Therefore, conditioning regimens are often reduced-intensity (especially in SCID where the recipient has no T cells to reject the graft — full myeloablative conditioning may not be needed).

Paediatric indications for HSCT include: inborn errors of immunity / primary immunodeficiencies — SCID, Wiskott-Aldrich ^[12]

PID	HSCT Indication	Notes
SCID	Standard of care — HSCT is curative ^[4]^[5]	Urgent: best outcomes if transplanted before 3.5 months of age and before onset of active infection. Newborn screening (TREC) enables pre-symptomatic diagnosis for early HSCT. > 90% survival with matched sibling donor HSCT before infections develop.
WAS	Curative for all manifestations (immunodeficiency + thrombocytopenia + eczema)	Indicated for severe phenotype; mild phenotype may be managed conservatively
CGD	HSCT for severe/refractory disease ^[5]	Particularly when life-threatening infections occur despite prophylaxis
LAD	HSCT for severe LAD (type I, complete CD18 deficiency)	Without HSCT, most die in infancy from overwhelming infection
Severe congenital neutropenia	HSCT if unresponsive to G-CSF or at risk of MDS/AML transformation	Long-term G-CSF use carries leukaemia risk
IL-10R deficiency	Biologics + HSCT ^[5]	HSCT is potentially curative for the early-onset IBD phenotype
Complete DiGeorge	Thymic transplant (NOT standard HSCT) → specialised procedure	Very rare; cultured thymic tissue transplant is the treatment
Other severe CID/IEI	Case-by-case decision	Depends on specific genotype, severity, donor availability

Source	Preference	Rationale
HLA-matched sibling donor (MSD)	First choice ^[12]	Best engraftment, lowest GVHD risk
Matched unrelated donor (MUD)	Second choice	HLA-matched through international registries; higher GVHD risk than MSD
Haploidentical donor (parent)	Third choice	Parent shares 50% HLA; requires T-cell depletion or post-transplant cyclophosphamide to prevent GVHD
Cord blood	Alternative	Rich in HSCs; less stringent HLA matching needed; slower engraftment

Complication	Timing	Mechanism	Relevance to PID
Graft-versus-Host Disease (GVHD)	Acute (< 100 days); Chronic (> 100 days)	Donor T cells attack recipient tissues (skin, GI, liver)	Major cause of morbidity; managed with immunosuppression (ciclosporin, tacrolimus, steroids)
Graft failure/rejection	Early	Host immune cells reject donor graft	Less common in SCID (no host T cells to reject)
Infections during engraftment	Days 0–30 (neutropenic phase)	Profound neutropenia; mucositis breaches barriers	Bacterial and fungal infections; managed with empirical broad-spectrum antibiotics and antifungals
Opportunistic infections	Months 1–6+	Slow immune reconstitution	CMV reactivation, PCP, adenovirus; managed with prophylaxis
Late effects	Years	Conditioning regimen toxicity	Growth failure, endocrine dysfunction (thyroid, gonadal), second malignancies, infertility

Special PID-HSCT Consideration: Pre-Transplant Infection Control

In SCID, the child is profoundly immunodeficient from birth. Before HSCT, the child must be:

Kept in protective isolation (reverse barrier nursing)
Given PJP prophylaxis (co-trimoxazole / Septrin) ^[6]
Given antifungal prophylaxis if neutropenic
NO live vaccines (BCG, rotavirus, oral polio, MMR, varicella) — these will cause disseminated disease
All blood products must be irradiated to prevent transfusion-associated GVHD ^[13]^[14]

Irradiated cellular blood components are used to prevent transfusion-related GVHD in immunocompromised individuals, including patients with congenital immunodeficiency ^[13].

Indications for irradiated blood: (1) Intrauterine transfusion or premature neonates; (2) Congenital cell-mediated immunodeficiencies; (3) Potent immunosuppressants (e.g., purine analogues, ATG); (4) HSCT recipients; (5) HL of any stage ^[14]

3.3 GENE THERAPY

Gene therapy is the frontier of PID treatment — it corrects the genetic defect at the molecular level, avoiding the need for a donor.

Patient's own HSCs are harvested from bone marrow or mobilised peripheral blood
A corrective gene is inserted into the HSCs using a viral vector (typically lentiviral)
Modified HSCs are re-infused into the patient after conditioning
This is an autologous procedure — no GVHD risk

PID	Gene Therapy Status	Product
ADA-SCID	Approved (EMA, FDA)	Strimvelis (retroviral); newer lentiviral vectors
X-linked SCID (IL2RG)	Clinical trials → approvals emerging	Lentiviral IL2RG gene transfer
WAS	Clinical trials with promising results	Lentiviral WAS gene transfer
CGD	Clinical trials	Lentiviral CYBB gene transfer
Others	Under investigation	Various

No donor needed → no GVHD
Patient's own cells → no rejection
Can be offered when no matched donor is available

Insertional mutagenesis — early retroviral vectors inserted near oncogenes → leukaemia risk (seen in early X-SCID trials). Newer lentiviral vectors have a much better safety profile with self-inactivating designs.
Incomplete correction — not all cells may be corrected
Conditioning still needed (usually reduced intensity) to create marrow space

3.4 ANTIMICROBIAL PROPHYLAXIS

Prophylaxis is essential in PIDs where the immune defect cannot be fully corrected, or as a bridge until definitive therapy.

PID	Prophylaxis	Rationale
CGD	Septrin (co-trimoxazole) + Itraconazole ^[5]	Septrin: covers Staphylococcus, Nocardia, PCP; Itraconazole: covers Aspergillus and other fungi. Together, these two prophylactic agents reduce life-threatening infections significantly
SCID (pre-HSCT)	Septrin ^[5]^[6] + antifungal (fluconazole or itraconazole) + aciclovir (if HSV risk)	PJP is a major killer in SCID; Septrin prophylaxis is mandatory
HIES	Septrin + IVIG + secukinumab ^[5]	Septrin covers staphylococcal skin infections; IVIG supplements poor functional antibody; secukinumab (anti-IL-17A) targets the Th17 pathway deficiency in STAT3 HIES
MSMD	Anti-mycobacterial drugs ^[5]	Long-term anti-TB therapy; avoid BCG exposure
Complement deficiency (C5–C9)	Meningococcal vaccination (MenACWY + MenB) + standby antibiotics	Terminal complement defect → recurrent Neisseria; vaccination is the primary strategy; some centres provide penicillin prophylaxis
Antibody deficiency (on IVIG)	Usually not needed if IgG trough adequate	If breakthrough infections occur despite adequate IVIG, add azithromycin (anti-inflammatory + antimicrobial for bronchiectasis)

Indications for PJP prophylaxis include: primary immunodeficiencies ^[6]

Agent	Dose (Paediatric)	Notes
Co-trimoxazole (Septrin)	TMP 5 mg/kg/day in 1–2 divided doses, given on 3 consecutive days per week (or daily in very high risk)	Must check G6PD status before starting (sulphamethoxazole component can cause haemolysis in G6PD deficiency); other side effects: myelosuppression, hepatotoxicity, skin rash ^[6]
Dapsone	Alternative if Septrin-intolerant	Also check G6PD; less effective
Atovaquone	Alternative	Well-tolerated; more expensive
Pentamidine (nebulised)	Monthly	For older children who cannot tolerate oral agents; does not provide systemic prophylaxis

3.5 VACCINATION GUIDANCE IN PID

This is a critical and frequently examined area. The key principle: live vaccines are dangerous in severe PID; killed/inactivated vaccines are safe but may be ineffective.

Vaccine Type	Examples	In Antibody Deficiency	In T Cell / Combined Deficiency	In Phagocyte Defect	In Complement Deficiency
Live attenuated	BCG, MMR, Varicella, Rotavirus, OPV, Live influenza (LAIV), Yellow fever	Ineffective (no antibody response) but generally safe unless T cell defect coexists	CONTRAINDICATED — risk of disseminated infection (e.g., disseminated BCG, vaccine-strain measles) ^[3]	BCG CONTRAINDICATED in CGD (BCG dissemination) ^[5]; others case-by-case	Generally safe
Killed / inactivated	IPV, DTaP, Hep B, PCV13, MenACWY, HPV, Influenza (injectable)	Safe but likely ineffective → give anyway as some residual response possible in partial deficiency; check post-vaccination titres	Safe but likely ineffective in severe CID; may be useful in partial DiGeorge	Safe and effective (phagocyte function not needed for antibody response)	Safe and IMPORTANT — especially PCV13, MenACWY, MenB, Hib for complement deficiency

BCG in Hong Kong — A PID Diagnostic Clue

In Hong Kong, BCG is given at birth as part of the routine immunisation schedule. This means that a child with undiagnosed SCID, CGD, or MSMD will receive BCG before any screening results are available. Disseminated BCG is a presenting feature of SCID, CGD, and MSMD ^[5]. If a neonate develops persistent BCGitis (non-healing vaccination site, lymphadenitis, or disseminated disease after BCG), this is a red flag that mandates urgent immunological evaluation.

Implementation of SCID newborn screening (TREC assay) in HK can identify SCID before BCG is given, but currently BCG is given on day 0–3 of life, and NBS results may not be available that quickly. This is an active area of policy discussion.

Household members of immunodeficient children should be fully vaccinated (including annual influenza) to create a cocoon of herd immunity
OPV (oral polio vaccine) is contraindicated in household contacts of immunodeficient children (risk of vaccine-derived poliovirus shedding → infection of the immunodeficient child). Use IPV instead.
Rotavirus vaccine in siblings: generally acceptable as transmission risk is low, but some centres advise caution with nappy hygiene

3.6 SUPPORTIVE AND PREVENTIVE CARE

Hand hygiene — the single most effective measure
Avoidance of sick contacts — education for family and school
Water safety — boiled/filtered water in severe CID (Cryptosporidium risk, especially in Hyper-IgM)
Environmental controls — HEPA filters in hospital rooms for profound immunodeficiency
Dental hygiene — regular dental care (gingivitis and periodontal disease are common in phagocyte defects)

The use of irradiated cellular blood components is mandatory to prevent transfusion-related graft versus host disease in immunocompromised individuals, or a 1st-degree family member transfusion ^[13]

When a child with PID (especially T cell or combined deficiency) needs a blood transfusion:

All cellular blood products (packed RBCs, platelets, granulocytes) must be irradiated ^[13]^[14]
Why? Transfused donor lymphocytes can engraft in an immunodeficient recipient who cannot reject them → proliferate and attack the recipient's tissues → TA-GVHD (transfusion-associated graft-versus-host disease) which has 90% mortality ^[13]
Irradiation (25 Gy) renders donor lymphocytes unable to proliferate while preserving RBC/platelet function
In an emergency when irradiated products are not available: ask the blood bank for the oldest bag of blood — after > 14 days storage, lymphocytes should have died ^[13]
Also use CMV-negative or leucodepleted products to reduce CMV transmission risk

Children with PID, especially combined deficiency, are at high risk for failure to thrive
Regular plotting on growth charts (weight, height, head circumference)
Dietitian involvement — optimise caloric intake; manage chronic diarrhoea-related malabsorption
Micronutrient supplementation (zinc, iron, vitamin D) as needed

PID is a chronic, lifelong condition → psychological impact on child and family is significant
Genetic counselling for family (inheritance pattern, carrier testing, prenatal/preimplantation diagnosis for future pregnancies)
Support groups (e.g., Jeffrey Modell Foundation, PID UK, local HK patient groups)
School integration planning — liaise with school about infection control, absences, special arrangements
Transition planning for adolescents → gradual transfer to adult immunology services

Complication	PIDs Affected	Monitoring
Bronchiectasis	CVID, XLA, CGD	Baseline HRCT chest; pulmonary function tests (spirometry) from age 5–6 years; regular respiratory review
Autoimmune cytopenias	CVID, ALPS, WAS	Regular CBC; reticulocyte count; DAT if anaemia develops
Malignancy (especially lymphoma)	CVID, AT, WAS, XLP	Clinical vigilance; regular physical examination for lymphadenopathy; low threshold for biopsy
Granulomatous disease / GLILD	CVID	HRCT monitoring; consider BAL and biopsy if progressive
Sclerosing cholangitis	Hyper-IgM (Cryptosporidium)	LFTs; liver ultrasound; MRCP if cholestatic picture
Endocrinopathies	Post-HSCT	Thyroid function, growth hormone, gonadal function monitoring

PID	Treatment	Key Details
XLA	IVIG / SCIG replacement ^[5]	Lifelong; target trough IgG > 5–8 g/L; avoid live vaccines (ineffective, not dangerous unless T cell defect coexists)
CVID	IVIG/SCIG; manage autoimmunity (steroids, rituximab); monitor for malignancy and GLILD	Same Ig replacement principles; more complex due to non-infectious complications
Hyper-IgM	IVIG + Septrin (PJP prophylaxis) + HSCT (curative)	PJP and Cryptosporidium prophylaxis critical; HSCT for X-linked form
Selective IgA deficiency	Usually no treatment (asymptomatic)	Avoid IgA-containing blood products if anti-IgA antibodies present; counsel about anaphylaxis risk
SCID	HSCT (urgent — before 3.5 months if possible) ^[4]^[5]; gene therapy for ADA-SCID and X-SCID	Pre-HSCT: isolation, Septrin prophylaxis, IVIG, irradiated blood, NO live vaccines, NO breastfeeding if CMV-positive mother
DiGeorge (partial)	Manage cardiac anomaly; calcium + vitamin D supplementation; IVIG if significant antibody deficiency; developmental support	Most patients have partial T cell deficiency and improve with age
DiGeorge (complete)	Thymic transplant (specialised)	Very rare; distinct from standard HSCT
WAS	HSCT (curative); supportive: IVIG, platelet transfusion (irradiated), avoid aspirin/NSAIDs; splenectomy controversial	Gene therapy under development
AT	Supportive only (no curative therapy); IVIG if antibody deficiency; avoid radiation exposure; cancer surveillance	No HSCT indication (neurological component not corrected)
HIES	Septrin + IVIG + secukinumab ^[5]; surgical drainage of abscesses; aggressive skin care	Secukinumab (anti-IL-17A monoclonal antibody) targets the Th17 deficiency in STAT3-HIES
CGD	Septrin + Itraconazole prophylaxis ^[5]; HSCT for severe disease ^[5]; IFN-γ (controversial, less used now)	Septrin and itraconazole dramatically reduce infection rate; HSCT is curative
LAD (severe)	HSCT (curative)	Without HSCT, fatal in infancy from overwhelming infections
SCN	G-CSF (filgrastim) to maintain ANC > 1.0 × 10⁹/L; HSCT if G-CSF refractory or leukaemic transformation	Monitor for MDS/AML with long-term G-CSF
Complement deficiency (C5–C9)	Vaccination (MenACWY, MenB, PCV13, Hib); standby antibiotics; family screening	No curative therapy; focus on prevention
HAE	Acute: C1-INH concentrate (Berinert), icatibant (bradykinin B2 receptor antagonist), ecallantide (kallikrein inhibitor); Prophylaxis: C1-INH, lanadelumab (anti-kallikrein mAb)	Adrenaline, antihistamines, and steroids are INEFFECTIVE (not histamine-mediated); must have specific HAE drugs available
MSMD (IFN-γ/IL-12 loop: STAT1 LOF, IFNGR, IL-12RB1)	Anti-mycobacterial drugs ^[5]^[15]; IFN-γ supplementation for IL-12-axis/partial-receptor defects; HSCT for complete IFNGR deficiency	Long-term anti-TB therapy; avoid BCG in patient and at-risk siblings; adult anti-IFN-γ autoantibody phenocopy → anti-mycobacterials ± rituximab
Mendelian viral infections (type I IFN: TLR3, IRF7, IFNAR, TLR7)	Antivirals early (aciclovir for HSV encephalitis, oseltamivir for influenza), vaccination ^[15]	Anti-IFN-I autoantibody phenocopy (severe COVID-19): vaccination, early antivirals, plasma exchange/replacement ^[15]
CMC (IL-17 axis; STAT1 GOF)	Long-term azole antifungal; JAK inhibitor (ruxolitinib) for STAT1 gain-of-function	Watch for azole resistance and for the autoimmunity/aneurysms of STAT1 GOF
CAPS / CINCA-NOMID (NLRP3 GOF)	IL-1 blockade: anakinra (daily IL-1 receptor antagonist) or canakinumab (anti-IL-1β, 4–8-weekly) ^[15]	Start early to prevent deafness, amyloidosis and CNS damage; HK adult with CINCA cleared rash and tongue ulcers after 3 years of canakinumab ^[15]; same drugs are used in systemic JIA/MAS
IL-10R deficiency	Steroids and biologics blocking TNF-α, IL-6 or IL-23 as a bridge → HSCT (curative) ^[5]^[15]	HSCT is the only cure for the neonatal-onset IBD phenotype; conventional IBD therapy alone fails
Primary atopic disorder (STAT6 GOF)	Dupilumab (anti-IL-4Rα) ^[15]; JAK inhibitor as alternative; allergen avoidance, adrenaline auto-injector, growth support	Dupilumab lowered eosinophils, IgE and SCORAD/EASI over 10 doses and allowed catch-up growth in the HK patient ^[15]

5. Important Drug Details for Paediatric Prescribing

Contains trimethoprim + sulphamethoxazole (TMP-SMX)
Investigations prior to treatment: G6PD status, CBC, LFT, RFT ^[6]
Side effects: myelosuppression, liver/renal impairment, skin rash ^[6]
Paediatric dosing for PJP prophylaxis: TMP 5 mg/kg/dose, 3 days/week (typically Mon/Wed/Fri)
Available as oral suspension (important for infants who cannot swallow tablets)

400–600 mg/kg IV every 3–4 weeks
Infusion rate: start slow (0.5 mL/kg/hr) → increase gradually if tolerated
Pre-medication: paracetamol ± cetirizine if prior infusion reactions
Available as 5% or 10% solutions

5–10 μg/kg/day SC, adjusted to maintain ANC > 1.0 × 10⁹/L
Side effects: bone pain, splenic enlargement, long-term risk of MDS/AML

Anti-IL-17A monoclonal antibody
Used off-label in paediatric STAT3-HIES to compensate for defective Th17 responses
Dosing: based on adult protocols; weight-based in children

High Yield Summary — Management of PID

Four pillars: definitive therapy (HSCT/gene therapy), replacement (IVIG/SCIG), prophylaxis (antimicrobials), supportive care (infection avoidance, irradiated blood, vaccines, family support)
IVIG/SCIG is the mainstay for antibody deficiency (XLA, CVID, HIGM) ^[4]^[5] — target trough IgG > 5–8 g/L
HSCT is curative for SCID, WAS, CGD, LAD, SCN, IL-10R deficiency ^[5]^[12] — for SCID, transplant ASAP (before 3.5 months and before active infections)
Gene therapy is approved for ADA-SCID and emerging for X-SCID, WAS, CGD
CGD prophylaxis: Septrin + Itraconazole ^[5]; HIES: Septrin + IVIG + secukinumab ^[5]
Live vaccines are CONTRAINDICATED in T cell / combined deficiency and CGD (BCG) ^[5]
Irradiated blood products are mandatory for all patients with congenital cell-mediated immunodeficiencies ^[13]^[14] — prevents fatal TA-GVHD
HAE: adrenaline/antihistamines/steroids are INEFFECTIVE — use C1-INH concentrate, icatibant, or ecallantide for acute attacks
Delayed treatment → bronchiectasis ^[4] — early diagnosis and IVIG initiation prevents irreversible lung damage
Family-centred care: genetic counselling, household vaccination, psychosocial support, school liaison, transition planning

Active Recall - Management of Primary Immunodeficiency

References

^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp. 406–411, Section 10.3.2 Primary Immunodeficiency) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 638–640, Clinical manifestation, vaccination, warning signs) ^[4] Lecture slides: Investigations of Imm Disorders 2025.pdf (pp. 4, 9, 16 — Molecular diagnostics, treatable PIDs, ESID criteria) ^[5] Senior notes: Jerry's immunodeficiencies.pdf (PID classification table with tests, genes, pathogens, treatments) ^[6] Senior notes: Maksim Medicine Notes.pdf (p. 201, PJP prophylaxis indications and Septrin details) ^[12] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (pp. 28–29, HSCT indications and procedure) ^[13] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (pp. 21–22, TA-GVHD, irradiated blood) ^[14] Senior notes: Ryan Ho Haemtology.pdf (pp. 96, 153 — Irradiated blood indications, HSCT overview including PID indications) ^[15] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (pp. 17–48 entity treatments: HSCT for SCID, IVIG/SCIG for XLA, TMP-SMX + itraconazole + HSCT for CGD, anti-mycobacterials for MSMD, biologics/HSCT for IL-10R deficiency, IL-1 blockade for CAPS/CINCA, dupilumab for STAT6 atopic disorder, vaccination/antivirals for anti-IFN-I phenocopy)

Complications of Primary Immunodeficiency in Children

Understanding complications of PID requires appreciating that the immune system is not only an anti-infection machine — it is a fundamental regulator of tissue homeostasis, self-tolerance, tumour surveillance, and inflammation. When the immune system is defective, complications extend far beyond infections into autoimmunity, malignancy, end-organ damage, and treatment-related morbidity.

Diseases with a predisposition (mostly genetic) to recurrent infections, malignancy, autoimmune, auto-inflammatory and allergic diseases ^[4]

Delayed treatment associated with complications such as bronchiectasis ^[4]

These two lecture slide points frame the entire complication landscape: (1) PID inherently predisposes to complications beyond infection, and (2) delayed diagnosis compounds the damage.

1. Infectious Complications

Infection is the primary and most immediate complication of PID. The type of infectious complication depends on which arm of the immune system is defective (as discussed in previous sections), but here we focus on the consequences of these infections — i.e., what happens when they accumulate, disseminate, or are not adequately treated.

Delayed treatment associated with complications such as bronchiectasis ^[4]

Recurrent respiratory tract infections with the development of bronchiectasis ^[4]

Which PIDs? Most prominent in CVID, XLA ^[4]^[5], and CGD — any PID with recurrent sinopulmonary infections
Pathophysiology: Recurrent lower respiratory tract infections → chronic inflammation of bronchial walls → destruction of elastic and muscular components → permanent airway dilatation (bronchiectasis). This creates a vicious cycle: dilated airways → impaired mucociliary clearance → mucus stagnation → further bacterial colonisation → more inflammation → more destruction ^[6]
Why it matters: Bronchiectasis is irreversible. Once established, it cannot be undone — only managed (airway clearance physiotherapy, long-term macrolides, treatment of exacerbations). This is why early initiation of IVIG is critical — it prevents the infections that cause the lung damage in the first place
Monitoring: Baseline HRCT thorax at diagnosis; pulmonary function tests (spirometry) from age 5–6 years; regular respiratory review
Pathogens in bronchiectasis exacerbations: Haemophilus influenzae, Streptococcus pneumoniae, Pseudomonas aeruginosa (especially in established bronchiectasis), Staphylococcus aureus ^[6]

The Window of Opportunity

There is a critical window between PID diagnosis and the onset of irreversible bronchiectasis. Starting adequate IVIG replacement (maintaining trough IgG > 5–8 g/L) early — ideally before the first episode of pneumonia — dramatically reduces the risk of developing bronchiectasis. Every month of diagnostic delay represents accumulating lung damage. This is one of the strongest arguments for newborn screening programmes and maintaining a high index of clinical suspicion.

Which PIDs? SCID, CGD, and MSMD (Mendelian Susceptibility to Mycobacterial Diseases) ^[5]
Why? BCG is a live attenuated vaccine given at birth in Hong Kong. In SCID, there are no T cells to contain BCG → it disseminates systemically (osteomyelitis, lymphadenitis, disseminated infection). In CGD, phagocytes cannot kill mycobacteria (catalase-positive). In MSMD, the IFN-γ pathway that activates macrophages to kill intracellular mycobacteria is defective
BCG vaccine will disseminate in SCID ^[5] and CGD ^[5] and MSMD (especially paediatric patients with disseminated mycobacterial infection from WEAK mycobacteria such as BCG vaccine and NTM) ^[5]
Clinical presentation: Non-healing BCG vaccination site (> 12 weeks), ipsilateral axillary lymphadenitis, hepatosplenomegaly, disseminated osteomyelitis, systemic sepsis
Management: Multi-drug anti-mycobacterial therapy (isoniazid, rifampicin, ethambutol ± amikacin); definitive treatment of the underlying PID (HSCT for SCID/CGD)

Which PIDs? XLA — the classic association ^[2]^[5]
Pathophysiology: B cell deficiency → absent immunoglobulins → inability to neutralise enteroviruses (echovirus, coxsackievirus) → chronic CNS infection with persistent viral replication in the meninges and brain parenchyma
Interesting point: XLA patients can handle influenza but NOT enterovirus ^[5] — because influenza clearance relies heavily on T cell responses (intact in XLA), whereas enterovirus clearance is heavily antibody-dependent
Outcome: Progressive encephalitis, intellectual disability, seizures; often fatal or severely debilitating
Prevention: Adequate IVIG replacement (provides passive anti-enteroviral antibodies from the donor pool)

Which PIDs? SCID, Hyper-IgM syndrome, severe CID — any PID with significant T cell deficiency
Why? PJP (formerly PCP) is a fungus that is controlled by CD4+ T cell-mediated immunity. Without functional T cells, Pneumocystis proliferates unchecked in the alveoli → severe interstitial pneumonia with fulminant type 1 respiratory failure
Relevance: PJP is often the presenting infection of undiagnosed SCID in infancy
Prevention: Septrin (co-trimoxazole) prophylaxis is mandatory in T cell and combined immunodeficiencies ^[5]

Which PIDs? Hyper-IgM syndrome (X-linked)
Implications of X-linked Hyper-IgM include increased risk of infections (especially cryptosporidium, a protozoan parasite) ^[4]
Pathophysiology: X-linked Hyper-IgM (CD40L deficiency) impairs T cell–macrophage cooperation → cannot clear Cryptosporidium from the biliary epithelium → chronic biliary infection → inflammatory destruction of intrahepatic bile ducts → sclerosing cholangitis → progressive liver failure
Clinical features: Jaundice, pruritus, hepatomegaly, deranged LFTs (cholestatic pattern with raised ALP and GGT)
Prevention: Safe drinking water (boiled/filtered), avoid untreated water sources; early HSCT may prevent this complication

Which PIDs? CGD (Aspergillus fumigatus is the leading cause of death), SCID, severe congenital neutropenia
In CGD, Aspergillus is the most dangerous pathogen — invasive pulmonary aspergillosis, hepatic aspergillosis, osteomyelitis. Itraconazole prophylaxis is used to prevent this ^[5]
In SCID and severe neutropenia, Candida species can cause invasive disease (candidaemia, hepatosplenic candidiasis)

2. Autoimmune Complications

Autoimmunity is paradoxically common in PID — a defective immune system is not just weak, it is also dysregulated. Loss of immune tolerance mechanisms leads to autoimmune attack on self-tissues.

Autoimmune phenomena such as idiopathic thrombocytopenic purpura and autoimmune haemolytic anaemia in up to 25% of CVID patients ^[4]

Which PIDs? CVID (most common), ALPS, WAS, Hyper-IgM
Implications of X-linked Hyper-IgM include autoimmune complications (especially neutropenia) ^[4]
Types:
- Autoimmune haemolytic anaemia (AIHA): autoantibodies against RBC surface antigens → extravascular haemolysis (warm AIHA with IgG) or intravascular haemolysis (cold AIHA with IgM/complement)
- Immune thrombocytopenia (ITP): autoantibodies against platelet glycoproteins (GPIIb/IIIa, GPIb/IX) → premature platelet destruction in the spleen
- Autoimmune neutropenia: autoantibodies against neutrophil antigens → increased infection risk
- Evans syndrome: combination of AIHA + ITP ± autoimmune neutropenia — strongly suggests underlying PID (especially ALPS or CVID)
Why autoimmunity in PID? Multiple mechanisms:
- Loss of regulatory T cell (Treg) function → unchecked autoreactive lymphocytes
- Defective B cell selection → failure to eliminate autoreactive B cells
- Chronic antigenic stimulation → molecular mimicry, epitope spreading
- Lymphopenia-driven homeostatic proliferation → expansion of autoreactive clones

Which PIDs? Early classical complement deficiency (C1, C2, C4) ^[3]
Pathophysiology: The classical complement pathway is crucial for clearance of immune complexes and apoptotic cells. When C1, C2, or C4 is deficient, immune complexes accumulate in tissues → trigger chronic inflammation → SLE-like disease
Clinical features: photosensitive rash, arthritis, nephritis, serositis — often indistinguishable from idiopathic SLE
C2 deficiency is the most common inherited complement deficiency associated with SLE

Which PIDs? IPEX (FOXP3 mutation → Treg deficiency), IL-10 receptor deficiency ^[5], CVID
IL-10R deficiency: early onset IBD (diarrhea, perianal sepsis, pyoderma gangrenosum) ^[5]
Pathophysiology: IL-10 is the master anti-inflammatory cytokine. When the IL-10 signalling pathway is defective, the gut mucosa cannot dampen immune responses to commensal bacteria → uncontrolled intestinal inflammation → very early-onset IBD (often within the first year of life)
IPEX: FOXP3 mutation → absent/dysfunctional regulatory T cells → autoimmune attack on multiple organs including the gut → severe watery diarrhoea, failure to thrive, type 1 diabetes, eczema

PID significantly increases the risk of malignancy, particularly lymphoid malignancies. The underlying mechanism involves defective immune surveillance, impaired DNA repair, and chronic viral oncogenesis.

CVID: an increased risk of gastrointestinal and lymphoid malignancies ^[4]

Implications of X-linked Hyper-IgM include lymphoproliferative/malignant complications (especially lymphoma/GI involvement) ^[4]

PID	Malignancy Type	Mechanism
CVID	Non-Hodgkin lymphoma ^[2]; GI malignancies	Chronic antigenic stimulation → lymphoproliferation → malignant transformation; defective immune surveillance
Ataxia-Telangiectasia	Lymphoma, leukaemia (ALL, T-cell lymphoma)	ATM gene mutation → defective DNA double-strand break repair → chromosomal instability → oncogenic mutations accumulate
Wiskott-Aldrich syndrome	Non-Hodgkin lymphoma, EBV-driven lymphoproliferation	Immune dysregulation + defective tumour surveillance
X-linked lymphoproliferative disease (XLP / Duncan)	EBV-driven lymphoma ^[2]	Inability to control EBV infection → unchecked EBV-driven B cell proliferation → lymphoma
Hyper-IgM syndrome	Lymphoma, hepatobiliary carcinoma	Chronic biliary infection (Cryptosporidium) → cholangiocarcinoma; chronic immune stimulation → lymphoma
SCID (if surviving without adequate Tx)	Lymphoma	Prolonged immune dysregulation
CGD	Uncommon but possible	Chronic granulomatous inflammation may contribute

Practical implication in paediatrics: Any child with PID who develops unexplained lymphadenopathy, hepatosplenomegaly, constitutional symptoms (fever, weight loss, night sweats), or a new mass requires urgent evaluation for malignancy — low threshold for biopsy.

4. Lymphoproliferative Complications

Lymphoproliferation sits on a spectrum from benign reactive expansion to frank malignancy.

Polyclonal lymphoproliferation with splenomegaly, lymphadenopathy or nodular lymphoid hyperplasia of the small bowel occurs in approximately 1/3 of patients with CVID ^[4]

Which PIDs? CVID — occurs in 8–22% ^[4]
Pathophysiology: The lungs develop non-caseating granulomas and lymphocytic interstitial infiltrates. The exact trigger is unclear but likely involves chronic antigenic stimulation and defective immune regulation
Clinical features: Progressive dyspnoea, cough, restrictive lung disease on spirometry
Imaging: Ground-glass opacities, nodules, and lower-lobe predominant changes on HRCT
Management: Rituximab (anti-CD20) ± azathioprine/MMF; regular HRCT monitoring; corticosteroids for acute flares

Which PIDs? CVID
Multiple lymphoid nodules in the small bowel mucosa → chronic diarrhoea, malabsorption
May be a precursor to lymphoma in some cases

Genetic basis: FAS (CD95) or FAS ligand mutations → defective Fas-mediated apoptosis → lymphocytes that should be eliminated after an immune response persist and accumulate
Clinical features: Massive lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias
Hallmark finding: Elevated double-negative T cells (CD4⁻CD8⁻ TCRαβ⁺) on flow cytometry
Risk: Increased risk of Hodgkin and non-Hodgkin lymphoma

Organ System	Complication	PIDs	Mechanism
Pulmonary	Bronchiectasis ^[4]	CVID, XLA, CGD	Recurrent pneumonia → airway destruction (see 1.1)
	Pneumatoceles ^[5]	HIES	Necrotising staphylococcal pneumonia → cavitation
	GLILD	CVID	Granulomatous/lymphocytic infiltration
Hepatobiliary	Sclerosing cholangitis	Hyper-IgM	Cryptosporidium → biliary destruction (see 1.5)
	Liver abscesses	CGD	Catalase-positive organisms (Staph aureus)
	Granulomatous hepatitis	CGD, CVID	Chronic inflammation
Gastrointestinal	Chronic diarrhoea / malabsorption	CVID, SCID, Hyper-IgM, IPEX	Giardia, Cryptosporidium, enterovirus; autoimmune enteropathy; nodular lymphoid hyperplasia
	Early-onset IBD	IL-10R deficiency, CGD, IPEX	Defective mucosal immune regulation
Neurological	Chronic enteroviral meningoencephalitis	XLA	Inability to clear enteroviruses from CNS (see 1.3)
	Progressive cerebellar ataxia	AT	Neurodegeneration from ATM deficiency (not infection-related)
	Developmental delay	DiGeorge, AT, HIES	Part of the syndromic phenotype
Growth	Failure to thrive ^[3]	SCID, CID, CGD, CVID	Chronic infection → ↑ metabolic demand; chronic diarrhoea → malabsorption; anorexia
Skeletal	Fractures, scoliosis, retained primary teeth	HIES ^[5]	STAT3 dysfunction → connective tissue abnormality
Hearing	Conductive hearing loss	Antibody deficiency	Recurrent otitis media → chronic effusion → conductive loss

6. Complications of Treatment

The treatments for PID carry their own complications. In paediatrics, long-term treatment-related morbidity is a major consideration because these children will be on therapy for decades.

Complication	Mechanism	Frequency
Infusion reactions (headache, fever, chills, myalgia)	Rate-dependent; complement activation by Ig aggregates	Common (~5–15%); reduced with slower rate and pre-medication
Anaphylaxis	Anti-IgA antibodies in IgA-deficient patients	Rare but potentially fatal
Aseptic meningitis	Unknown; possibly immune complex deposition in meninges	Uncommon
Thrombotic events (DVT, PE, stroke)	Increased serum viscosity; pro-coagulant factors	Rare; higher risk in elderly/dehydrated
Haemolytic anaemia	Anti-A/Anti-B isoagglutinins in IVIG	Uncommon; monitor Hb
Renal impairment	Sucrose-containing formulations → osmotic nephrosis	Avoid sucrose formulations

Complications of HSCT include: (1) Complications related to high dose chemotherapy — infection, haemorrhage, veno-occlusive disease of liver (VOD); (2) Complications related to allogeneic HSCT — graft-versus-host disease (GVHD, acute or chronic), graft rejection; (3) Complications related to late/long term effects — cataract (mainly due to total body irradiation), immunodeficiency, endocrine dysfunction and infertility, secondary malignancy; (4) Relapse of disease ^[15]

These are particularly important in the paediatric setting because of the impact on growth, development, fertility, and quality of life over a lifetime:

Timing	Complication	Details
Early (< 1 year)	Neutropenic infections	Bacterial and fungal during engraftment phase
	Oral/GI mucositis	Conditioning regimen toxicity; managed with supportive care
	Veno-occlusive disease (VOD) of liver	Conditioning damages hepatic venous endothelium → painful hepatomegaly, ascites, jaundice ^[15]^[16]
	Acute GVHD	Donor T cells attack recipient skin (rash), GI (diarrhoea), liver (hepatitis)
	Graft failure/rejection	More common with mismatched donors
Late (> 1 year)	Chronic GVHD	Autoimmune-like syndrome: skin sclerosis, oral/ocular sicca, bronchiolitis obliterans, liver involvement
	Endocrine dysfunction and infertility ^[15]	Growth hormone deficiency, hypothyroidism, hypogonadism, T2DM; gonadal toxicity from conditioning
	Cataract (mainly due to total body irradiation) ^[15]	TBI damages the lens → posterior subcapsular cataract
	Secondary malignancy ^[15]^[16]	Post-transplant lymphoproliferative disease (PTLD) — EBV-driven B cell proliferation in immunosuppressed state; post-treatment MDS/AML; solid organ tumours
	Immunodeficiency ^[15]	Immune reconstitution takes 1–2 years; re-vaccination needed 6–12 months post-HSCT
	Cardiovascular disease	Metabolic effects of immunosuppressants; chronic GVHD ^[16]
	Osteoporosis, AVN	Steroid use for GVHD management ^[16]

Paediatric-Specific HSCT Complications

Children undergoing HSCT face unique long-term issues:

Growth failure: conditioning regimen (especially TBI) damages the growth plate; growth hormone deficiency from hypothalamic–pituitary axis injury. Monitor height velocity; consider GH replacement if GH-deficient.
Pubertal delay/infertility: alkylating agents and TBI are gonadotoxic. Fertility preservation should be discussed before HSCT when age-appropriate (sperm banking for adolescent males; ovarian tissue cryopreservation is experimental in paediatrics).
Neurocognitive effects: cranial irradiation (if used) → learning difficulties, reduced processing speed. Regular psychoeducational assessment.
Psychosocial impact: prolonged hospitalisation, isolation, school absence → anxiety, depression, social difficulties. Child psychology/psychiatry input essential.

Complication	Details
Insertional mutagenesis	Early retroviral vectors (gamma-retroviral) caused T-cell leukaemia in X-SCID gene therapy trials due to insertion near oncogenes (LMO2). Newer self-inactivating lentiviral vectors have dramatically reduced this risk
Incomplete correction	Not all stem cells may be transduced → variable immune reconstitution; may need "top-up" therapy
Conditioning toxicity	Reduced-intensity conditioning is used but still carries myelosuppression/infection risk

Often underappreciated but profoundly important in paediatric practice:

Domain	Impact	Management
Child	Frequent hospitalisations → school absence → academic underperformance; social isolation from infection avoidance measures; body image issues (e.g., eczema in WAS, scars from abscesses in CGD); anxiety about medical procedures	Child psychologist; play therapy; hospital school liaison; developmentally appropriate education about their condition
Parents/Caregivers	Chronic stress; guilt (genetic condition); financial burden of treatment (IVIG, hospital visits); disruption to employment; relationship strain	Social worker support; genetic counselling; parent support groups; respite care
Siblings	May feel neglected ("glass child" phenomenon); may be carriers; anxious about their own health	Family-centred care; sibling support; carrier testing when age-appropriate with genetic counselling
Adolescent-specific	Non-adherence to prophylaxis (developmental rebellion); concerns about fertility, sexuality, body image; transition anxiety (paediatric → adult services)	Transition programmes; dedicated adolescent clinic; peer mentoring; reproductive counselling

PID	Infectious Complications	Non-Infectious Complications
XLA	Bronchiectasis ^[4]; chronic enteroviral meningoencephalitis; sinusitis; otitis media	Hearing loss; limited autoimmunity (rare)
CVID	Bronchiectasis ^[4]; recurrent pneumonia; chronic diarrhoea	Autoimmune cytopenias (AIHA, ITP) in up to 25% ^[4]; granulomatous disease in 8–22% ^[4]; GLILD; increased risk of GI and lymphoid malignancies ^[4]; nodular lymphoid hyperplasia
Hyper-IgM	PJP; Cryptosporidium → sclerosing cholangitis ^[4]; recurrent sinopulmonary infections	Autoimmune neutropenia ^[4]; lymphoma ^[4]; hepatobiliary carcinoma; chronic liver disease
SCID	Disseminated BCG; PJP; CMV; Candida; fatal opportunistic infections	FTT; TA-GVHD if non-irradiated blood; complications of HSCT
DiGeorge	Variable (depends on degree of T cell deficiency)	Cardiac anomalies; hypocalcaemia → seizures; developmental delay; psychiatric comorbidity (schizophrenia in adolescence)
WAS	Recurrent infections (sinopulmonary → opportunistic as disease progresses)	Bleeding (micro-thrombocytopenia); autoimmunity; eczema; lymphoma
AT	Sinopulmonary infections; bronchiectasis	Progressive cerebellar ataxia (wheelchair-bound by adolescence); lymphoma/leukaemia; endocrine dysfunction
HIES	Pneumatoceles ^[5]; cold staphylococcal abscesses; invasive fungal infections	Fractures, scoliosis, retained primary teeth ^[5]; vascular anomalies (coronary artery aneurysms in STAT3-HIES)
CGD	BCG dissemination ^[5]; invasive aspergillosis; liver abscesses; lymphadenitis	Granulomatous inflammation → GI obstruction, urinary obstruction; IBD-like colitis
LAD	Overwhelming bacterial infections; necrotising soft tissue infections	Poor wound healing; severe periodontitis → tooth loss
Complement (early)	Encapsulated bacteria	SLE-like autoimmune disease
Complement (terminal)	Recurrent Neisseria meningitis	Rare autoimmunity
HAE	Not primarily infectious	Laryngeal oedema → airway obstruction → death if untreated; abdominal attacks mimicking surgical abdomen

High Yield Summary — Complications of PID

Bronchiectasis is the cardinal preventable complication — results from recurrent sinopulmonary infections in antibody deficiency (CVID, XLA); delayed treatment → bronchiectasis ^[4]; once established, it is irreversible. Early IVIG prevents it.
CVID has the broadest complication profile: infections + autoimmune cytopenias (up to 25%) + granulomatous disease (8–22%) + lymphoid and GI malignancies + GLILD + nodular lymphoid hyperplasia ^[4]
Hyper-IgM has increased risk of infections (especially Cryptosporidium), autoimmune (especially neutropenia), and lymphoproliferative/malignant complications (especially lymphoma/GI involvement) ^[4]
Disseminated BCG is a presenting complication in SCID, CGD, and MSMD — critical in the Hong Kong context where BCG is given at birth ^[5]
HSCT complications include: infection, haemorrhage, VOD, GVHD (acute and chronic), graft rejection, late effects (cataract, endocrine dysfunction, infertility, secondary malignancy, immunodeficiency) ^[15]
Malignancy risk is elevated in CVID, AT, WAS, XLP, and Hyper-IgM — lymphoma is the predominant type; regular surveillance is essential
Autoimmunity in PID is paradoxical but common — SLE in complement deficiency, cytopenias in CVID/ALPS/WAS, enteropathy in IPEX/IL-10R deficiency
Growth failure, hearing loss, neurocognitive impairment, and psychosocial difficulties are major paediatric-specific complications requiring multidisciplinary management

Active Recall - Complications of Primary Immunodeficiency

References

High Yield Summary

PID = genetically determined defects in immunity; now called Inborn Errors of Immunity (IEI) ^[2]^[4]
559 entities, 10 IUIS categories (2024 update) ^[4]
Most common PID overall = Selective IgA deficiency; most common severe PID = CVID ^[2]^[4]
Antibody deficiency is the most common category (36.3%) — presents after 4–6 months with sinopulmonary/GI infections by encapsulated bacteria ^[2]
XLA: Btk mutation → no B cells → pan-hypogammaglobulinaemia → absent tonsils → IVIG treatment ^[2]^[3]
CVID: most common severe PID; heterogeneous; late-onset hypogammaglobulinaemia; infections + autoimmunity + lymphoproliferation + malignancy ^[4]^[5]
SCID: T⁻ ± B⁻ ± NK⁻; fatal without HSCT; present with FTT + severe infections + absent thymus; lymphopenia in infants = < 2,500/μL ^[2]^[3]
DiGeorge: 22q11.2 deletion → CATCH-22 (Cardiac, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcaemia) ^[2]^[3]
CGD: NADPH oxidase defect → can't kill catalase-positive organisms → granulomas; BCG dissemination important in HK ^[2]^[3]^[5]
LAD: CD18 deficiency → neutrophils can't leave vessels → absent pus, delayed cord separation, neutrophilia ^[2]^[3]
Complement: early (C1,2,4) → SLE; C3 → encapsulated bacteria; C5-9 → Neisseria; C1-INH → hereditary angioedema ^[3]^[5]
Warning signs: SPUR infections, FTT, FHx of unexplained early death, persistent lymphopenia, complications from live vaccines ^[3]
Many are treatable: IVIG for antibody deficiency, HSCT for SCID, gene therapy for ADA-SCID; delayed treatment → bronchiectasis ^[4]
Mechanism-first rule (GC 144): pathway → gene → pathogens → tests → treatment. Loss of a defence → infection by what that defence kills (opsonisation → encapsulated bacteria; MAC → Neisseria; respiratory burst → catalase-positive bacteria/Aspergillus; T cells → viruses/PJP/Candida/BCG; IFN-γ loop → mycobacteria/Salmonella; type I IFN → one severe virus; IL-17 → mucocutaneous Candida). Gain of function or loss of a brake → inflammation/autoimmunity/atopy. Replace what is missing (IVIG, HSCT), block what is overactive (anakinra, dupilumab), cover the gap (Septrin, itraconazole), avoid live organisms. ^[8]
Narrow-spectrum "Mendelian infections": MSMD (STAT1 LOF, IFNGR, IL-12RB1 → BCG-osis, NTM, Salmonella; anti-mycobacterials); Mendelian viral infections (TLR3 → HSV encephalitis; IRF7/IFNAR/TLR7 → severe influenza/COVID-19; EVER/DOCK8 → HPV tree-man); CMC (IL-17 axis, STAT1 GOF) ^[8]
Same gene, opposite disease: STAT1 LOF = MSMD vs STAT1 GOF = CMC; STAT3 LOF = HIES; STAT6 GOF = primary atopic disorder (dupilumab); NLRP3 GOF = CAPS/CINCA (fever + urticaria ± deafness/aseptic meningitis; somatic mosaic milder; IL-1 blockade); IL-10R LOF = neonatal Crohn's (HSCT) ^[8]
Phenocopies: autoantibodies against IFN-I (severe COVID-19), IFN-γ (adult NTM in East Asians), IL-17/22 (CMC in APECED); somatic mutations (NLRP3, FAS) ^[8]

High Yield Summary — Differential Diagnosis

50% of children with recurrent infections are normal and healthy ^[2] — always start by asking: are the infections truly SPUR (Severe, Persistent, Unusual, Recurrent)?
Exclude structural/anatomical causes (site-specific infections: same lobe pneumonia → bronchial obstruction; recurrent meningitis → midline defect) and secondary immunodeficiency (HIV, drugs, nephrotic syndrome, malnutrition, malignancy) before diagnosing PID ^[2]
Pattern of infections narrows the PID category: sinopulmonary with encapsulated bacteria → antibody; viral/fungal/opportunistic → T cell/combined; skin abscesses with catalase-positive organisms → phagocyte; Neisseria → complement ^[2]^[3]
CVID is the most common severe PID but must exclude secondary causes of hypogammaglobulinaemia ^[4]
XLA: absent B cells + absent tonsils + pan-hypogammaglobulinaemia; CVID: B cells present but dysfunctional + late onset + autoimmunity/lymphoproliferation ^[2]^[4]
PID can present with non-infectious manifestations: autoimmunity, malignancy, lymphoproliferation, eczema, granulomatous disease, early-onset IBD ^[1]^[2]^[3]
In Hong Kong, BCG dissemination may be the first presentation of SCID, CGD, or MSMD ^[5]
Immunisation history is critical: complications from live vaccines (BCG, rotavirus, oral polio) are red flags for PID ^[3]

High Yield Summary — Diagnosis of PID

Diagnostic approach: Clinical history → Physical examination → Phenotypic investigations → Genetic testing ^[4]. No single screening test catches all PIDs.
First-line: CBC with differential + Serum Ig (IgG/A/M/E) + CXR + HIV test.
CBC interpretation in IEI (GC 144): ALC low → SCID; ANC low → SCN; ANC high → LAD; PLT low → WAS; AEC high → primary atopic/HIES. ^[10]
IgGAME interpretation: low IgGAM → XLA; high IgE → HIES; high IgM → HIGM; high IgGAM → CGD; low IgM → WAS/DOCK8/AT. ^[10]
ESID criteria for CVID: clinical features + ↓IgG + ↓IgA (×2) + impaired vaccine response or ↓switched memory B cells + exclude secondary causes + Dx after age 4 + no profound T cell deficiency. ^[4]
DHR flow cytometry is the gold standard for CGD diagnosis (low/absent fluorescence). ^[5]
Newborn screening: TREC for SCID, KREC for XLA ^[5] — enables pre-symptomatic detection and early HSCT.
Genetic testing is important for all cases: diagnosis, family studies, prognostication, prenatal diagnosis, defining new diseases. ^[4]
Absent thymus on CXR → SCID or complete DiGeorge; pneumatoceles → HIES; bronchiectasis → CVID/XLA (delayed treatment). ^[2]^[5]
Always use age-appropriate reference ranges — lymphopenia < 2,500/μL in infants is a red flag for SCID. ^[3]

High Yield Summary — Management of PID

Four pillars: definitive therapy (HSCT/gene therapy), replacement (IVIG/SCIG), prophylaxis (antimicrobials), supportive care (infection avoidance, irradiated blood, vaccines, family support)
IVIG/SCIG is the mainstay for antibody deficiency (XLA, CVID, HIGM) ^[4]^[5] — target trough IgG > 5–8 g/L
HSCT is curative for SCID, WAS, CGD, LAD, SCN, IL-10R deficiency ^[5]^[12] — for SCID, transplant ASAP (before 3.5 months and before active infections)
Gene therapy is approved for ADA-SCID and emerging for X-SCID, WAS, CGD
CGD prophylaxis: Septrin + Itraconazole ^[5]; HIES: Septrin + IVIG + secukinumab ^[5]
Live vaccines are CONTRAINDICATED in T cell / combined deficiency and CGD (BCG) ^[5]
Irradiated blood products are mandatory for all patients with congenital cell-mediated immunodeficiencies ^[13]^[14] — prevents fatal TA-GVHD
HAE: adrenaline/antihistamines/steroids are INEFFECTIVE — use C1-INH concentrate, icatibant, or ecallantide for acute attacks
Delayed treatment → bronchiectasis ^[4] — early diagnosis and IVIG initiation prevents irreversible lung damage
Family-centred care: genetic counselling, household vaccination, psychosocial support, school liaison, transition planning

High Yield Summary — Complications of PID

Bronchiectasis is the cardinal preventable complication — results from recurrent sinopulmonary infections in antibody deficiency (CVID, XLA); delayed treatment → bronchiectasis ^[4]; once established, it is irreversible. Early IVIG prevents it.
CVID has the broadest complication profile: infections + autoimmune cytopenias (up to 25%) + granulomatous disease (8–22%) + lymphoid and GI malignancies + GLILD + nodular lymphoid hyperplasia ^[4]
Hyper-IgM has increased risk of infections (especially Cryptosporidium), autoimmune (especially neutropenia), and lymphoproliferative/malignant complications (especially lymphoma/GI involvement) ^[4]
Disseminated BCG is a presenting complication in SCID, CGD, and MSMD — critical in the Hong Kong context where BCG is given at birth ^[5]
HSCT complications include: infection, haemorrhage, VOD, GVHD (acute and chronic), graft rejection, late effects (cataract, endocrine dysfunction, infertility, secondary malignancy, immunodeficiency) ^[15]
Malignancy risk is elevated in CVID, AT, WAS, XLP, and Hyper-IgM — lymphoma is the predominant type; regular surveillance is essential
Autoimmunity in PID is paradoxical but common — SLE in complement deficiency, cytopenias in CVID/ALPS/WAS, enteropathy in IPEX/IL-10R deficiency
Growth failure, hearing loss, neurocognitive impairment, and psychosocial difficulties are major paediatric-specific complications requiring multidisciplinary management

Primary Immunodeficiency

1. Definition

2. Epidemiology

2.1 Incidence and Prevalence

2.2 Distribution by Category

2.3 Sex Distribution

2.4 Hong Kong Context

2.5 Age of Presentation

3. Anatomy and Functional Immunology Review (Paediatric Focus)

3.1 The Two Arms of Immunity

3.2 Key Organs

3.3 Key Cell Types and Their Functions

B Lymphocytes (Humoral Immunity)

T Lymphocytes (Cellular Immunity)

Phagocytes

Complement System

Natural Killer (NK) Cells

3.4 Immunoglobulin Classes

3.5 Normal Paediatric Immunological Values (Age-Specific)

3.6 Mechanism-First Framework: Predict Every Entity From the Broken Node [8]

The Four Questions

Question 1: The Four Quadrants of Immunity

Question 2: Pathogen → Pathway (the rule that replaces most memorisation)

Question 3: Developmental Block → Lab Signature and Age of Onset

Question 4: Same Gene, Opposite Disease — Loss vs Gain of Function

Timing Rule: Why Each Category Presents When It Does

Treatment Follows Mechanism

Worked Example: Deriving CGD From First Principles

4. Aetiology (Focus on Hong Kong Relevance) and Pathophysiology

4.1 Overview: The "Molecular Basis" Principle

4.2 Differential Diagnosis of Recurrent Infections in Children (Before Considering PID)

4.3 IUIS Classification of PID (10 Categories) [2][4]

4.4 Detailed Aetiology and Pathophysiology by Category

CATEGORY 1: PREDOMINANTLY ANTIBODY (HUMORAL) DEFICIENCY (36.3% — most common category)

A. X-linked Agammaglobulinaemia (XLA / Bruton's Agammaglobulinaemia)

B. Common Variable Immunodeficiency (CVID)

C. Hyper-IgM Syndrome (HIGM)

D. Selective IgA Deficiency

CATEGORY 2: COMBINED IMMUNODEFICIENCY (CID) (19.8%)

CATEGORY 3: CID WITH ASSOCIATED/SYNDROMIC FEATURES (15.2%)

A. DiGeorge Syndrome (22q11.2 Deletion Syndrome)

B. Wiskott-Aldrich Syndrome (WAS)

C. Ataxia-Telangiectasia (AT)

D. Hyper-IgE Syndrome (HIES / Job Syndrome)

E. X-linked Lymphoproliferative Disease (XLP / Duncan Disease)

CATEGORY 4: PHAGOCYTE DEFECTS (14.9%)

A. Chronic Granulomatous Disease (CGD)

B. Leukocyte Adhesion Deficiency (LAD)

C. Cyclic Neutropenia and Severe Congenital Neutropenia (Kostmann Syndrome)

CATEGORY 5: COMPLEMENT DEFICIENCY

CATEGORY 4: DISEASES OF IMMUNE DYSREGULATION

CATEGORY 6: DEFECTS OF INTRINSIC AND INNATE IMMUNITY — "MENDELIAN / MONOGENIC INFECTIONS" [8]

A. Mendelian Susceptibility to Mycobacterial Disease (MSMD) [8]

B. Mendelian Viral Infections — Type I Interferon Pathway Defects [8]

C. Chronic Mucocutaneous Candidiasis (CMC) — IL-17 Pathway Defects [8]

CATEGORY 7: AUTOINFLAMMATORY DISORDERS [8]

PRIMARY ATOPIC DISORDERS (a newly recognised IEI group) [8]

CATEGORY 9: BONE MARROW FAILURE

CATEGORY 10: PHENOCOPIES OF IEI [8]

5. Classification Summary

6. Clinical Features

6.1 Warning Signs Suggestive of PID ("10 Warning Signs")

6.2 Clinical Features by PID Category

6.3 Symptoms (with Pathophysiological Basis)

6.4 Signs (with Pathophysiological Basis)

6.5 Non-Infectious Manifestations (Beyond Infections)

7. Approach to a Child with Suspected PID — Summary Framework

Active Recall - Primary Immunodeficiency

References

1. Level 1: Differential Diagnosis of Recurrent Infections in Childhood

A. Non-Immunologic Structural/Functional Defects [2]

B. Secondary Immunodeficiency [2]

C. Normal Healthy Child

2. Level 2: Differential Diagnosis Within PID — Which Arm Is Affected?

Master Differential Table: Pattern Recognition by PID Category

Clinical Features Summary by PID Category (from Felix Lai) [3]

3. Specific PID Entities — Key Differentiating Features

3A. Within Antibody Deficiency

3B. Within Combined / T Cell Deficiency

3C. Within Phagocyte Defects