Primary Immunodeficiency Disorders

Primary immunodeficiency disorders (PIDs) are a heterogeneous group of >450 inherited defects of the immune system that present chiefly as recurrent, severe, unusual, or atypical infections (the SPUR pattern). For NEET PG the examiner rarely asks the molecular biology in isolation — instead you are given an infection pattern (bacteria vs virus/fungus vs catalase-positive organisms vs Neisseria) plus a lab clue (immunoglobulin level, lymphocyte subset, NBT/DHR) and asked to name the disease, the defect, or the treatment. Master that translation and this "Hard" topic becomes scoring.

Classification — divide by the limb of immunity affected

The single most useful framework is to ask which arm of immunity has failed, because each arm fails against a characteristic class of organism. Roughly 50% of PIDs are antibody (B-cell) defects, 30% combined, 18% phagocytic, and 2% complement.

Arm affected	Typical organisms	Onset clue	Prototype disorders
B-cell / antibody	Encapsulated bacteria (Strep pneumoniae, H. influenzae), Giardia, enterovirus	After 6 months (maternal IgG wanes)	XLA, CVID, selective IgA deficiency, hyper-IgM
T-cell	Viruses (CMV, EBV), fungi (Candida, PJP), intracellular	Early, often <6 months	DiGeorge, chronic mucocutaneous candidiasis
Combined (T+B)	Everything — bacteria, virus, fungus, opportunists	Birth–3 months, FTT	SCID, Wiskott-Aldrich, ataxia-telangiectasia
Phagocyte	Catalase-positive organisms (S. aureus, Serratia, Burkholderia, Nocardia, Aspergillus)	Early, deep abscesses	CGD, LAD, Chediak-Higashi
Complement	Recurrent Neisseria (meningococcus); pyogenic if early components	Any age	C5–C9 (terminal) and C2/C3 deficiency

High-yield: Onset of infections after 6 months of age points to an antibody/B-cell defect, because protective maternal IgG (transplacental) is largely consumed by then. Infections from birth suggest a T-cell or combined defect.

B-cell (antibody) deficiencies

X-linked agammaglobulinaemia (Bruton disease)

• Defect: mutation in BTK gene (Bruton tyrosine kinase) on Xq → B-cell maturation arrests at the pre-B stage. Boys only.
• Hallmark: virtually absent B cells (CD19/CD20 low), all immunoglobulin classes low, and absent tonsils, adenoids and lymph nodes (no germinal centres).
• Clinical: recurrent sinopulmonary and pyogenic infections with encapsulated organisms after 6 months; susceptibility to enteroviral meningoencephalitis and vaccine-associated paralytic polio (avoid live OPV).
• Management: lifelong IVIG (immunoglobulin replacement, ~400–600 mg/kg every 3–4 weeks) + prompt antibiotics. Live vaccines contraindicated.

Common variable immunodeficiency (CVID)

• The commonest symptomatic primary antibody deficiency presenting in adults, with a bimodal peak (childhood and 2nd–3rd decade).
• Defect: heterogeneous (TACI, ICOS, BAFF-R) → B cells present but fail to differentiate into plasma cells; low IgG with low IgA and/or IgM.
• Distinguishing point: B-cell numbers are usually normal (unlike XLA where they are absent).
• Complications: bronchiectasis, granulomatous disease, autoimmunity (ITP, AIHA), and a markedly increased risk of lymphoma and gastric carcinoma.
• Treatment: IVIG replacement.

Selective IgA deficiency

• The most common PID overall (≈1 in 300–700), and most patients are asymptomatic.
• Lab: IgA <7 mg/dL with normal IgG and IgM.
• Associations: recurrent sinopulmonary/GI infections, giardiasis, atopy, autoimmune disease, and the classic anaphylactic reaction to blood products / IVIG (anti-IgA antibodies → give washed/IgA-depleted products).
• No IVIG (it does not replace mucosal IgA and may sensitise).

Hyper-IgM syndrome

• Defect (commonest, X-linked): CD40 ligand (CD154) on T cells → no class switching.
• Lab: high or normal IgM with low IgG, IgA, IgE.
• Clinical clue: susceptibility to Pneumocystis jirovecii pneumonia (PJP) and Cryptosporidium (sclerosing cholangitis), mimicking a T-cell defect because the CD40L–CD40 axis is needed for cell-mediated immunity too.

High-yield: High IgM + low everything else = Hyper-IgM (CD40L defect). Add PJP susceptibility and you have the perfect single-best-answer.

T-cell deficiencies

DiGeorge syndrome (22q11.2 deletion)

• Defect: microdeletion of chromosome 22q11.2 → failure of development of the 3rd and 4th pharyngeal pouches → thymic and parathyroid hypoplasia.
• Mnemonic — CATCH-22: Cardiac (conotruncal: truncus arteriosus, tetralogy, interrupted aortic arch), Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcaemia (parathyroid aplasia → neonatal tetany/seizures), deletion 22.
• Lab: low T cells (low CD3), normal/raised B cells, low calcium, low PTH.
• Treatment: thymic transplantation or HSCT in complete DiGeorge; otherwise supportive, calcium, cardiac repair. Irradiated blood products to prevent graft-versus-host disease (GVHD).

Chronic mucocutaneous candidiasis

• Persistent Candida infection of skin, nails and mucous membranes due to T-cell defects against Candida (e.g. AIRE mutation in APECED, or STAT1 gain-of-function). Often with endocrinopathy.

Combined (T + B) immunodeficiencies

Severe combined immunodeficiency (SCID) — "the bubble boy disease"

• A paediatric emergency and the most severe PID. Profound failure of both cellular and humoral immunity.
• Genetics:
  • X-linked (commonest, ~45%): defect in the common gamma chain (IL2RG) shared by IL-2,4,7,9,15,21 → T⁻ B⁺ NK⁻ phenotype.
  • Adenosine deaminase (ADA) deficiency (autosomal recessive): toxic metabolite accumulation kills lymphocytes → T⁻ B⁻ NK⁻ (the most lymphopenic); ADA deficiency also gives skeletal abnormalities.
  • JAK3, IL-7Rα, RAG1/2 (Omenn syndrome) etc.
• Clinical: onset in first months — intractable diarrhoea, failure to thrive, oral/diaper candidiasis, PJP, disseminated BCG/rotavirus from live vaccines, absent thymic shadow on CXR.
• Diagnosis: lymphopenia (absolute lymphocyte count <2500–3000/µL in an infant is abnormal), low/absent T cells on flow cytometry; newborn screening by TRECs (T-cell receptor excision circles).
• Definitive treatment: haematopoietic stem cell transplant (HSCT) — curative, best results if done before 3.5 months of age. ADA-SCID also amenable to enzyme replacement (PEG-ADA) and gene therapy.

High-yield (must memorise): SCID — give only irradiated, CMV-negative, leucocyte-depleted blood products; never give live vaccines (BCG, OPV, rotavirus); isolate the child; start PJP prophylaxis with co-trimoxazole; IVIG; and arrange urgent HSCT.

Wiskott-Aldrich syndrome

• X-linked, defect in WAS gene (cytoskeletal WASP protein).
• Triad (mnemonic "WATER" / classic triad): Thrombocytopenia with small platelets (microthrombocytopenia), Eczema, recurrent infections (immunodeficiency).
• IgM low, IgA & IgE high; risk of bleeding, autoimmunity and lymphoma. Treatment: HSCT.

Ataxia-telangiectasia (Louis-Bar syndrome)

• Autosomal recessive, ATM gene (DNA repair defect).
• Triad: progressive cerebellar ataxia (from infancy), oculocutaneous telangiectasia, and immunodeficiency (low IgA/IgG2).
• Markers: raised alpha-fetoprotein (AFP), radiation sensitivity, and high risk of lymphoma/leukaemia. Avoid unnecessary X-rays.

Combined PID	Gene	Key extra clue
X-linked SCID	IL2RG (γc)	T⁻B⁺NK⁻
ADA-SCID	ADA	T⁻B⁻NK⁻, ↑deoxyATP
Wiskott-Aldrich	WASP (X)	Small platelets + eczema
Ataxia-telangiectasia	ATM	Ataxia + ↑AFP + telangiectasia
Hyper-IgE (Job)	STAT3	↑IgE, cold abscesses, retained teeth

Phagocyte disorders

Chronic granulomatous disease (CGD)

• Defect: NADPH oxidase (commonest form X-linked, gp91phox/CYBB) → neutrophils phagocytose but cannot generate the respiratory/oxidative burst (no superoxide) → cannot kill catalase-positive organisms.
• Catalase-positive organisms (mnemonic "Cats Need PLACESS to Belch their Hairballs"): Staph aureus, Serratia, Burkholderia cepacia, Nocardia, Aspergillus, Candida, E. coli, Klebsiella.
• Clinical: recurrent abscesses (liver, lung, skin), suppurative lymphadenitis, granuloma formation (may obstruct GI/GU tracts).
• Investigation of choice: Dihydrorhodamine (DHR-123) flow cytometry (most sensitive/quantitative); older test is the Nitroblue tetrazolium (NBT) test — fails to turn blue in CGD.
• Management: prophylactic co-trimoxazole + itraconazole, interferon-gamma, aggressive treatment of infections; HSCT is curative.

High-yield: Catalase-positive infections + abnormal NBT/DHR = CGD. S. aureus and Aspergillus are the classic killers; Burkholderia cepacia and Serratia are exam-favourite "buzz" organisms.

Leucocyte adhesion deficiency (LAD-1)

• Defect: CD18 / integrin (β2) deficiency → neutrophils cannot adhere/transmigrate.
• Triad clue: delayed umbilical cord separation (>3–4 weeks), no pus at sites of infection, and marked peripheral leucocytosis (neutrophils stuck in blood). Recurrent skin/mucosal infections with poor wound healing.

Chediak-Higashi syndrome

• Autosomal recessive, LYST gene → defective phagolysosome fusion.
• Findings: giant cytoplasmic granules in leucocytes (pathognomonic on smear), partial (oculocutaneous) albinism, peripheral neuropathy, recurrent pyogenic infections, and an accelerated phase (HLH-like). Bleeding tendency from platelet dysfunction.

Hyper-IgE syndrome (Job syndrome)

• STAT3 defect (autosomal dominant). Mnemonic FATED: coarse Facies, cold Abscesses (non-inflamed staphylococcal abscesses), retained primary Teeth, raised Eosinophils/IgE, Dermatologic eczema. Recurrent pneumonias with pneumatocele formation.

Complement deficiencies

Component deficient	Consequence
C1 inhibitor	Hereditary angioedema (recurrent non-pruritic angioedema; do not give adrenaline as first line — use C1-INH concentrate / icatibant; low C4)
Early classical (C1, C2, C4)	Pyogenic infections + SLE-like autoimmunity / immune-complex disease (C2 deficiency commonest complement defect)
C3	Severe recurrent pyogenic infections (central component)
Terminal / MAC (C5–C9)	Recurrent Neisseria (meningococcal) infections
MBL	Mild recurrent infections in childhood

High-yield: Recurrent Neisseria meningitidis infection = terminal complement (C5–C9) deficiency → screen with the CH50 test (low/absent) and vaccinate against meningococcus.

Diagnostic flow — turning the clue into the answer

Recurrent infections → characterise the organism + age → order the screening test → confirm with specific assay → treat.

1. Antibody defect suspected (encapsulated bacteria, after 6 months) → quantitative serum immunoglobulins (IgG, IgA, IgM, IgE) + specific vaccine antibody titres + B-cell flow cytometry (CD19/20).
2. T-cell / combined suspected (early viral/fungal, FTT) → absolute lymphocyte count + flow cytometry for CD3/CD4/CD8, CXR for thymic shadow; SCID newborn screen = TRECs.
3. Phagocyte defect suspected (catalase-positive abscesses, poor pus) → DHR/NBT (CGD), CD18 expression (LAD), blood smear for giant granules (Chediak-Higashi).
4. Complement defect suspected (recurrent Neisseria, SLE-like) → CH50 (classical pathway) and AH50 (alternative pathway).

Investigation of choice memory line: Igs for B, flow cytometry for T/SCID, DHR for CGD, CH50 for complement.

Management principles (common to all PIDs)

• IVIG replacement for antibody deficiencies (XLA, CVID, hyper-IgM) — keep trough IgG protective.
• Co-trimoxazole prophylaxis for PJP in T-cell/combined defects and CGD.
• Irradiated, leucocyte-depleted, CMV-negative blood products in T-cell/combined defects to prevent transfusion-associated GVHD.
• Live vaccines (BCG, OPV, MMR, rotavirus, varicella) are contraindicated in T-cell and severe combined defects.
• HSCT is curative for SCID, WAS, CGD, LAD; gene therapy for ADA-SCID and X-SCID.
• IgA-deficient patients with anti-IgA antibodies need IgA-depleted/washed products.

Key differentials

• Secondary immunodeficiency (far commoner than primary): HIV, malnutrition, malignancy, immunosuppressants, splenectomy, protein-losing states — always exclude before labelling a child "primary".
• Physiological hypogammaglobulinaemia of infancy vs transient hypogammaglobulinaemia of infancy vs true XLA — timing of recovery and B-cell numbers differentiate.
• Cystic fibrosis / primary ciliary dyskinesia for recurrent sinopulmonary infection without an immune defect.

Recently asked / exam angle

• "Recurrent infection with catalase-positive organisms, abnormal NBT test" → CGD (NADPH oxidase defect); best confirmatory test = DHR flow cytometry.
• "Boy with absent tonsils, low all immunoglobulins, B cells absent" → X-linked agammaglobulinaemia (BTK defect); treat with IVIG, avoid OPV.
• "Neonate with hypocalcaemic seizures, conotruncal cardiac defect, low T cells" → DiGeorge (22q11.2 deletion).
• "High IgM, low IgG/IgA, PJP and Cryptosporidium" → Hyper-IgM (CD40L defect).
• "Thrombocytopenia with small platelets + eczema + infections in a boy" → Wiskott-Aldrich (WASP, X-linked).
• "Recurrent Neisseria meningitis" → terminal complement (C5–C9) deficiency, screen with CH50.
• "Delayed cord separation + leucocytosis + no pus" → LAD-1 (CD18 defect).
• "Most common PID overall / mostly asymptomatic / anaphylaxis to blood" → selective IgA deficiency.
• "Ataxia + telangiectasia + raised AFP + lymphoma risk" → ataxia-telangiectasia (ATM).
• "T⁻B⁻NK⁻ SCID" → ADA deficiency; "T⁻B⁺NK⁻ SCID" → X-linked (γc/IL2RG).

Rapid revision

1. Infections after 6 months = antibody defect; from birth = T-cell/combined.
2. XLA: BTK, boys, no B cells, no tonsils, all Igs low → IVIG.
3. CVID: normal B cells, low IgG+IgA/IgM, adult onset, lymphoma/gastric Ca risk.
4. Selective IgA deficiency: commonest PID, mostly asymptomatic, anaphylaxis to IVIG/blood.
5. Hyper-IgM: CD40L defect, high IgM low rest, gets PJP/Cryptosporidium.
6. DiGeorge = CATCH-22: 22q11 deletion, low T cells, hypocalcaemia, conotruncal heart defects.
7. SCID: emergency; X-linked γc (T⁻B⁺NK⁻) commonest, ADA (T⁻B⁻NK⁻) most severe; cure = HSCT before 3.5 months; screen by TRECs.
8. Wiskott-Aldrich: small platelets + eczema + infection (WASP, X-linked).
9. Ataxia-telangiectasia: ATM gene, ↑AFP, radiosensitive, lymphoma risk.
10. CGD: NADPH oxidase, catalase-positive organisms, NBT negative / DHR is test of choice.
11. LAD-1: CD18, delayed cord separation, no pus, leucocytosis.
12. Terminal complement (C5–9) deficiency → recurrent Neisseria; screen with CH50.