Immunodeficiency Disorders
Microbiology · Immunology · lean revision notes
Immunodeficiency Disorders
Immunodeficiencies are a favourite NEET PG theme because the pattern of infection — the type of organism plus the age of onset — points directly to the arm of immunity that has failed. Master the "which limb is down → which bug attacks" logic and most questions answer themselves.
Classification
Immunodeficiencies are broadly primary (inherited, intrinsic defect) or secondary (acquired). Primary immunodeficiencies (PIDs) are further split by the immune component affected.
| Component affected | Approx. share of PIDs | Characteristic infections |
|---|---|---|
| B-cell / antibody | ~50% (commonest group) | Pyogenic encapsulated bacteria, Giardia, enteroviruses |
| T-cell / combined | ~20% | Viruses, fungi, intracellular bacteria, Pneumocystis, BCG-osis |
| Phagocyte | ~18% | Catalase-positive organisms (Staph aureus, Serratia, Burkholderia, Aspergillus) |
| Complement | ~2% | Neisseria (terminal C5–C9), encapsulated bacteria (early components) |
High-yield: Antibody deficiencies present after ~6 months of age, because transplacental maternal IgG protects the infant until then. T-cell/combined defects present very early (1–3 months) with failure to thrive, severe viral/fungal infection.
The diagnostic logic: organism → defect
A stepwise approach to the "recurrent infection" vignette:
Encapsulated pyogenic bacteria (Strep pneumo, H. influenzae) → B-cell / antibody → check immunoglobulin levels.
Catalase-positive organisms (S. aureus, Serratia, Nocardia, Aspergillus, Burkholderia) → phagocyte oxidative burst → CGD → NBT / DHR test.
Recurrent Neisseria (meningococcal/gonococcal) → terminal complement (C5–C9, MAC) → CH50 assay.
Viruses, fungi (Candida), Pneumocystis, intracellular organisms from early infancy → T-cell / combined → lymphocyte subsets, T-cell function.
High-yield mnemonic for catalase-positive organisms (CGD bugs): "Cats Need PLACESS to Belch their Hairballs" — but the simplest exam version is S. aureus, Serratia, Burkholderia (Pseudomonas) cepacia, Nocardia, Aspergillus — these make catalase and survive inside the phagocyte that cannot generate hydrogen peroxide of its own.
Primary B-cell (antibody) deficiencies
X-linked agammaglobulinaemia (Bruton)
- Defect: Mutation in BTK (Bruton tyrosine kinase) on the X chromosome → B-cell maturation arrested at the pre-B cell stage in bone marrow.
- Inheritance: X-linked recessive → boys only.
- Findings: Absent/very low B cells (CD19+), all immunoglobulin classes low, absent tonsils and lymph nodes (no germinal centres). T cells normal.
- Onset: ~6 months when maternal IgG wanes.
- Infections: Recurrent pyogenic encapsulated bacteria (otitis, sinusitis, pneumonia), enteroviral meningoencephalitis, and Giardia.
- Management: Lifelong IVIG (immunoglobulin replacement); aggressive antibiotics. Avoid live vaccines (especially OPV — risk of vaccine-associated paralytic polio).
Selective IgA deficiency
- Commonest primary immunodeficiency overall (most are asymptomatic).
- Defect: Failure of IgA-bearing B cells to mature into IgA-secreting plasma cells; IgA low (<7 mg/dL), other isotypes normal.
- Clinical: Often silent; otherwise recurrent sinopulmonary and GI infections (Giardia), association with atopy, autoimmune disease, and coeliac disease.
- Classic pitfall: Anaphylactic transfusion reactions — anti-IgA antibodies react to IgA in donor blood. Give washed RBCs / IgA-deficient products.
Common variable immunodeficiency (CVID)
- Onset usually in 2nd–3rd decade (later than other PIDs).
- Low IgG + IgA and/or IgM with normal/near-normal B-cell numbers but defective differentiation into plasma cells.
- Recurrent sinopulmonary infection, bronchiectasis, plus increased risk of autoimmunity, granulomatous disease, lymphoma and gastric carcinoma.
- Treat with IVIG.
Hyper-IgM syndrome
- Classic (X-linked) defect: CD40 ligand (CD154) on T cells → B cells cannot class-switch.
- High/normal IgM, low IgG, IgA, IgE.
- Susceptible to pyogenic bacteria AND Pneumocystis jirovecii / Cryptosporidium (because CD40L also activates macrophages — a T-cell helper defect).
High-yield: Pneumocystis pneumonia (PCP) in a boy with high IgM and low IgG = X-linked Hyper-IgM (CD40L defect).
T-cell and combined deficiencies
Severe combined immunodeficiency (SCID)
- "Bubble boy" disease — both T and B cell function fail → presents in first months with failure to thrive, chronic diarrhoea, oral thrush, PCP, disseminated BCG.
- Genetic types:
- X-linked SCID (commonest, ~50%) — mutation in common gamma chain (γc, IL2RG) shared by IL-2,4,7,9,15,21 receptors → T–B+NK– phenotype.
- ADA (adenosine deaminase) deficiency — autosomal recessive; toxic metabolite accumulation → T–B–NK–; the only PID that may be treated with enzyme/gene therapy.
- JAK3, IL-7Rα, RAG1/2 (Omenn syndrome) variants.
- Investigations: Markedly low lymphocyte count, absent thymic shadow on CXR, low T cells. Newborn screening uses TRECs (T-cell receptor excision circles) — low/absent.
- Management: Haematopoietic stem cell transplant (curative); IVIG, PCP prophylaxis; only irradiated, CMV-negative blood; no live vaccines.
High-yield: Absent thymic shadow + lymphopenia + early-onset PCP/thrush = SCID. TRECs is the newborn screening test.
DiGeorge syndrome (22q11.2 deletion)
- Failure of 3rd & 4th pharyngeal pouch development → thymic + parathyroid aplasia.
- CATCH-22 mnemonic: Cardiac defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch), Abnormal facies, Thymic aplasia (T-cell deficiency), Cleft palate, Hypocalcaemia (hypoparathyroidism → neonatal tetany/seizures), 22q11 deletion.
- Lab: Low T cells, normal B cells; hypocalcaemia with low PTH.
- Diagnosed by FISH / chromosomal microarray for 22q11 deletion.
Wiskott–Aldrich syndrome
- X-linked, mutation in WAS gene (WASp protein) → cytoskeletal defect.
- Triad — WATER / "WAITER": Wiskott — Thrombocytopenia (small platelets), Eczema, Recurrent infections (Immunodeficiency).
- Labs: Low IgM, high IgA & IgE, normal/raised IgG; small defective platelets; risk of lymphoma and autoimmunity.
- Treat with HSCT; splenectomy improves platelets but increases sepsis risk.
High-yield: Boy with eczema + bleeding (thrombocytopenia, small platelets) + infections = Wiskott–Aldrich. Low IgM, high IgA/IgE.
Ataxia–telangiectasia
- ATM gene (DNA repair) defect, autosomal recessive.
- Cerebellar ataxia + oculocutaneous telangiectasia + recurrent sinopulmonary infection; raised alpha-fetoprotein (AFP), low IgA; radiosensitivity and lymphoma/leukaemia risk.
Chronic mucocutaneous candidiasis
- Persistent Candida of skin, nails, mucosa due to T-cell defect against Candida; associated with APECED (AIRE gene) and endocrinopathy.
Phagocyte disorders
Chronic granulomatous disease (CGD)
- Defect in NADPH oxidase → phagocytes engulf organisms but cannot generate the respiratory (oxidative) burst (no superoxide/H₂O₂) → cannot kill catalase-positive organisms.
- Inheritance: Most commonly X-linked (gp91phox); also autosomal recessive.
- Clinical: Recurrent abscesses (skin, liver), suppurative lymphadenitis, granuloma formation, osteomyelitis (Serratia), pneumonia/fungal infection (Aspergillus — leading cause of death).
- Investigation of choice: Dihydrorhodamine (DHR) flow cytometry (more sensitive/quantitative) or the older Nitroblue tetrazolium (NBT) test — in CGD the dye is not reduced (stays colourless/yellow; normal neutrophils turn blue).
- Management: Prophylactic co-trimoxazole + itraconazole + interferon-gamma; HSCT is curative.
High-yield: NBT negative / abnormal DHR + catalase-positive infections + granulomas = CGD. Treat with TMP-SMX, itraconazole, IFN-γ.
Chédiak–Higashi syndrome
- Autosomal recessive, LYST gene → defective lysosomal trafficking → giant lysosomal granules in leucocytes; impaired chemotaxis and phagolysosome fusion.
- Features: Partial (oculocutaneous) albinism, recurrent pyogenic infections (esp. S. aureus), peripheral neuropathy, bleeding tendency (platelet defect), progressing to an accelerated lymphoma-like ("accelerated") phase.
- Smear: Giant granules in neutrophils — diagnostic.
Leucocyte adhesion deficiency (LAD-1)
- Defect in CD18 / β2 integrin (LFA-1, Mac-1) → neutrophils cannot adhere/transmigrate.
- Classic clue: delayed separation of the umbilical cord (>21–30 days), no pus formation, marked neutrophilia.
High-yield: Delayed umbilical cord separation + recurrent infections without pus + high neutrophil count = LAD-1 (CD18 defect).
Complement deficiencies
| Component | Consequence |
|---|---|
| C1 inhibitor | Hereditary angioedema (recurrent non-pitting oedema; treat with C1-INH concentrate, NOT antihistamines) |
| C3 | Severe recurrent pyogenic infections + immune-complex disease |
| C5–C9 (MAC) | Recurrent Neisseria infection (meningococcaemia, gonococcaemia) |
| C1q/C2/C4 (early classical) | SLE-like autoimmune disease |
| Decay-accelerating factor (CD55/CD59) | Paroxysmal nocturnal haemoglobinuria |
- Screening tests: CH50 (classical pathway, low if any classical/terminal component deficient) and AH50 (alternative pathway).
High-yield: Recurrent Neisseria meningitidis → test terminal complement (CH50). Vaccinate against meningococcus.
Secondary (acquired) immunodeficiency
Far commoner than primary disease. Causes: malnutrition (commonest cause worldwide), HIV/AIDS, malignancy (esp. lymphoma, myeloma), immunosuppressive drugs/steroids/chemotherapy, diabetes, splenectomy, chronic renal failure, protein-losing states.
HIV / AIDS
- HIV-1 (worldwide) infects CD4+ T cells, macrophages, dendritic cells via gp120 binding CD4 + co-receptor (CCR5 early, CXCR4 late).
- Hallmark: Progressive CD4 count decline → opportunistic infections and malignancies.
WHO clinical staging (immunological correlate via CD4 ranges):
| CD4 count (cells/µL) | Typical complications |
|---|---|
| >500 | Usually asymptomatic / generalised lymphadenopathy |
| 200–500 | Oral thrush, oral hairy leukoplakia, herpes zoster, TB, Kaposi sarcoma |
| <200 | Pneumocystis jirovecii pneumonia (PCP) — AIDS-defining; start PCP prophylaxis (co-trimoxazole) at CD4 <200 |
| <100 | Toxoplasma encephalitis, Cryptococcal meningitis |
| <50 | CMV retinitis, MAC (Mycobacterium avium complex), CNS lymphoma |
- AIDS definition: CD4 <200/µL OR an AIDS-defining illness, regardless of count.
- Diagnosis: 4th-generation ELISA (p24 antigen + antibody) screening → confirmation; viral load (HIV RNA PCR) for monitoring and in the window period/neonates (infant diagnosis uses DNA/RNA PCR, not antibody, because of maternal antibody).
- Treatment: ART for all, start regardless of CD4. First-line per current guidance is typically TDF + 3TC (or FTC) + DTG (dolutegravir-based).
High-yield: PCP prophylaxis (co-trimoxazole) at CD4 <200; MAC prophylaxis (azithromycin) at CD4 <50; Toxoplasma prophylaxis (co-trimoxazole) at CD4 <100 if IgG+.
High-yield: Infant born to HIV-positive mother → diagnose with HIV nucleic acid (DNA/RNA PCR), not antibody test.
Key differentials and "spot the diagnosis" patterns
| Clue in stem | Diagnosis |
|---|---|
| Absent tonsils/lymph nodes, low all Ig, boy | X-linked agammaglobulinaemia (Bruton) |
| Anaphylaxis to blood transfusion | Selective IgA deficiency |
| Eczema + thrombocytopenia (small platelets) + infections | Wiskott–Aldrich |
| Hypocalcaemic tetany + cardiac defect + absent thymus | DiGeorge (22q11) |
| Delayed umbilical cord separation, no pus | LAD-1 |
| Albinism + giant granules + infections | Chédiak–Higashi |
| Catalase-positive infections, granulomas, NBT negative | CGD |
| Recurrent Neisseria | Terminal complement (C5–9) |
| Ataxia + telangiectasia + ↑AFP | Ataxia–telangiectasia |
| High IgM, low IgG, PCP in a boy | Hyper-IgM (CD40L) |
| Late onset (adult), low Ig, bronchiectasis, lymphoma | CVID |
Complications across the group
- Bronchiectasis from recurrent sinopulmonary infection (antibody deficiencies, CVID).
- Autoimmunity (IgA deficiency, CVID, complement deficiency, Wiskott–Aldrich).
- Malignancy — lymphoma (Wiskott–Aldrich, ataxia–telangiectasia, CVID), gastric carcinoma (CVID).
- Vaccine-associated disease — live vaccines (OPV, BCG, MMR, rotavirus) can disseminate in T-cell/combined defects → avoid live vaccines in SCID, DiGeorge, agammaglobulinaemia.
- Graft-versus-host disease / transfusion reactions — give irradiated, CMV-negative, leucodepleted blood in T-cell defects.
Recently asked / exam angle
- NBT vs DHR test for CGD — DHR (flow cytometry) is now the preferred, quantitative test; questions often ask "investigation of choice in CGD."
- Pattern-recognition vignettes: organism + age of onset → defect arm (the single most tested concept per the syllabus blurb).
- Catalase-positive organism list repeated frequently (Staph aureus, Serratia, Nocardia, Aspergillus, Burkholderia cepacia).
- CATCH-22 / 22q11 FISH in DiGeorge, and hypocalcaemia as the presenting sign.
- CD4 thresholds for opportunistic-infection prophylaxis (200 / 100 / 50) — high-yield medicine–microbiology overlap.
- Infant HIV diagnosis by PCR, and 4th-generation ELISA (p24 + antibody) for screening.
- TRECs for SCID newborn screening.
- Wiskott–Aldrich triad and immunoglobulin pattern (low IgM, high IgA/IgE).
- Hyper-IgM (CD40L) presenting with PCP despite normal IgM.
- Hereditary angioedema (C1-INH) distinguished from allergic angioedema (no urticaria, unresponsive to antihistamine/adrenaline).
Rapid revision
- Antibody deficiencies present after 6 months (maternal IgG wanes); T-cell defects present at 1–3 months.
- Bruton agammaglobulinaemia = BTK mutation, X-linked, absent B cells and tonsils, low all Ig; avoid OPV.
- Selective IgA deficiency = commonest PID, risk of anaphylactic transfusion reaction → give washed/IgA-deficient blood.
- CVID = adult-onset low Ig, bronchiectasis, autoimmunity, lymphoma & gastric cancer risk.
- Hyper-IgM = CD40L defect → high IgM, low IgG, gets PCP.
- SCID: absent thymic shadow + lymphopenia; X-linked γc (IL2RG) commonest; ADA deficiency treatable by gene therapy; screen with TRECs; cure with HSCT.
- DiGeorge (22q11) = CATCH-22: cardiac, abnormal facies, thymic aplasia, cleft palate, hypocalcaemia.
- Wiskott–Aldrich = eczema + thrombocytopenia (small platelets) + infections; low IgM, high IgA/IgE.
- CGD = NADPH oxidase defect, catalase-positive organisms + granulomas; NBT negative / DHR abnormal; treat with TMP-SMX, itraconazole, IFN-γ.
- Chédiak–Higashi = LYST gene, albinism, giant granules, neuropathy; LAD-1 = CD18 defect, delayed umbilical cord separation, no pus, neutrophilia.
- Terminal complement (C5–C9) deficiency → recurrent Neisseria; C1-INH deficiency → hereditary angioedema.
- HIV: AIDS = CD4 <200 or AIDS-defining illness; PCP prophylaxis <200, Toxoplasma <100, MAC <50; diagnose infants by PCR, screen adults by 4th-gen ELISA; start ART for all.