Primary Immunodeficiency
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.
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)
- 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
- 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].
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]
- Clinical features: recurrent sinopulmonary and GI infections [2][3]
- 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]
-
"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]
- 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
- Most common form: X-linked (CD40 ligand / CD154 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⁺
- Most common form: X-linked SCID (IL-2Rγ chain / common gamma chain deficiency)
| 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]:
- Conotruncal cardiac anomalies (e.g., tetralogy of Fallot, interrupted aortic arch, truncus arteriosus, VSD)
- Hypoplastic thymus → impaired T cell immunity
- 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)
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]
-
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)
| Category | Key Points |
|---|---|
| Immune dysregulation | Includes ALPS (autoimmune lymphoproliferative syndrome), IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked), familial HLH |
| Defects of intrinsic and innate immunity | Includes MSMD (Mendelian susceptibility to mycobacterial disease — e.g., IFN-γ receptor deficiency, IL-12/IL-12R deficiency), epidermodysplasia verruciformis, TLR signalling defects |
| Autoinflammatory disorders | Includes FMF (familial Mediterranean fever), TRAPS, CAPS, PFAPA; characterised by recurrent fevers and systemic inflammation WITHOUT autoantibodies or autoreactive T cells |
| Bone marrow failure | Includes Fanconi anaemia, dyskeratosis congenita, Shwachman-Diamond syndrome — overlap with haematology |
| Phenocopies of PID | Conditions that present as inherited immunodeficiencies but arise from somatic mutations or autoantibodies [4] |
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]:
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)
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 |
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)
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
-
Bronchiectasis — tram-track opacities, ring shadows, signet-ring sign
-
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 | Anti-mycobacterial drugs [5]; IFN-γ supplementation; HSCT in severe cases | Long-term anti-TB therapy; avoid BCG |
| IL-10R deficiency | Biologics (anti-TNF) + HSCT [5] | HSCT is curative for the early-onset IBD phenotype |
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)
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
[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) [4] Lecture slides: Investigations of Imm Disorders 2025.pdf (pp. 4, 9, 15, 21, 28 — CVID complications, Hyper-IgM complications, bronchiectasis, molecular diagnostics) [5] Senior notes: Jerry's immunodeficiencies.pdf (PID classification table with pathogens, complications, treatments) [6] Senior notes: Maksim Medicine Notes.pdf (p. 303, Bronchiectasis aetiology and pathophysiology) [15] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p. 34, HSCT complications) [16] Senior notes: Ryan Ho Haemtology.pdf (pp. 153, 156 — HSCT overview, complications, PTLD, late effects)
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]
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
Bronchiolitis
Bronchiolitis is an acute viral lower respiratory tract infection, most commonly caused by respiratory syncytial virus (RSV), predominantly affecting infants and children under 2 years of age, characterized by inflammation and obstruction of the small airways (bronchioles) leading to wheezing, tachypnoea, and respiratory distress.
Angelman Syndrome
Angelman syndrome is a neurodevelopmental disorder typically recognized in early childhood (usually by age 1–3 years), caused by loss of function of the maternally inherited UBE3A gene on chromosome 15q, and characterized by severe intellectual disability, absent or minimal speech, ataxic movements, frequent seizures, and a characteristically happy demeanor with frequent smiling and laughter.