Quick Answer
Primary immunodeficiencies (PIDs) are a compact NEET PG immunology cluster — pattern recognition + one signature lab = the mark.
- B-cell defects — encapsulated bacterial infections after 6 months. Bruton (X-linked, absent B cells, all Ig low), CVID (adult onset, low IgG + IgA), selective IgA deficiency (most common PID, mostly asymptomatic + anaphylaxis to blood products).
- T-cell / combined — early infancy, viral / fungal / PCP. DiGeorge (22q11.2, CATCH-22), SCID (bubble boy, HSCT curative), Wiskott-Aldrich (WATER: Thrombocytopenia + Eczema + Recurrent infections + small platelets).
- Phagocyte defects — CGD (NADPH oxidase — catalase-positive organisms, DHR or NBT test), LAD (delayed cord separation, no pus, leukocytosis), Chediak-Higashi (giant granules), Hyper-IgE (Job — cold Staph abscesses, retained teeth).
- Complement defects — early (C1–C4) SLE-like; late (C5–C9) recurrent Neisseria; C1-INH deficiency = hereditary angioedema.
- Secondary — HIV/AIDS, malnutrition, splenectomy (OPSI risk), chemotherapy, corticosteroids, diabetes, nephrotic syndrome (Ig loss).
- Management — IVIG for antibody defects, HSCT for SCID, avoid live vaccines in T-cell defects.
Immunodeficiency questions are among the most rewarding for NEET PG candidates because a single pattern-recognition move often nails the answer. This NEETPGAI deep dive organises primary immunodeficiencies (PIDs) by defect type — B cell, T cell, combined, phagocyte, complement — and then covers the secondary immunodeficiencies you will meet every day on the wards (HIV, malnutrition, splenectomy, transplant, nephrotic syndrome).
Pair this with the HIV/AIDS management guide for the world's most common secondary immunodeficiency.
Primary immunodeficiencies (PIDs) — the framework
The IUIS classification lists over 400 monogenic PIDs, but the exam-relevant ones sort neatly by the arm of the immune system that fails and the resulting infection pattern.
Infection pattern → likely defect
| Infection pattern | Suspected defect |
|---|
| Encapsulated bacteria (Strep pneumo, Hib, Neisseria) after 6 months | Antibody / B cell |
| Viral, fungal, PCP, live-vaccine complications in infancy | T cell or combined |
| Catalase-positive organisms (Staph, Aspergillus, Nocardia, Serratia, Burkholderia) | Chronic granulomatous disease |
| Delayed cord separation, no pus, leukocytosis | Leukocyte adhesion deficiency |
| Recurrent Neisseria | Late complement (C5–C9) |
| SLE-like autoimmunity + infections | Early complement (C1–C4) |
| Cold Staph abscesses + coarse facies + retained teeth + eczema + high IgE | Hyper-IgE (Job) syndrome |
| Partial albinism + giant granules | Chediak-Higashi |
B-cell (antibody) defects
X-linked agammaglobulinemia (Bruton, XLA)
- BTK gene mutation → block at pre-B to B-cell transition → absent mature B cells, all immunoglobulin classes low.
- Male infant; presents after 6 months when maternal IgG wanes; recurrent sinopulmonary infections with encapsulated bacteria; enteroviral meningoencephalitis; giardiasis.
- Absent tonsils and lymph nodes on physical exam.
- Treatment — lifelong IVIG or SCIG (subcutaneous immunoglobulin) replacement every 3–4 weeks; prompt antibiotics for infections; avoid live vaccines.
Common variable immunodeficiency (CVID)
- Later onset (peak in the second decade or adult); heterogeneous genetic basis (TACI, ICOS, others).
- Low IgG + IgA, ± low IgM, poor vaccine responses. B cells present but non-functional.
- Recurrent sinopulmonary infections plus autoimmunity, granulomatous lung / liver disease, lymphoid hyperplasia, and increased risk of lymphoma and gastric cancer.
- Treatment — IVIG / SCIG replacement, treat autoimmunity, screen for malignancy.
Selective IgA deficiency
- Most common primary immunodeficiency worldwide (about 1 in 500 in Europe / India).
- Isolated IgA less than 7 mg/dL with normal IgG and IgM.
- Mostly asymptomatic — usually detected incidentally.
- Clinical associations — recurrent mucosal infections in a minority, celiac disease, IgA nephropathy, autoimmunity.
- Anaphylaxis to blood products — anti-IgA antibodies react to donor IgA; use washed cells or IgA-deficient products.
Hyper-IgM syndrome
- CD40L (CD154) defect on T cells (X-linked, commonest form) or CD40 defect on B cells (AR).
- No class switch — B cells stuck producing IgM only. High IgM, low IgG / IgA / IgE.
- PCP pneumonia, cryptosporidial cholangitis, neutropenia, sclerosing cholangitis.
- Treatment — IVIG, TMP-SMX prophylaxis, boiled water (Cryptosporidium), curative HSCT.
T-cell and combined defects
DiGeorge syndrome (22q11.2 deletion)
CATCH-22 mnemonic — Cardiac defects (tetralogy of Fallot, interrupted aortic arch, truncus arteriosus), Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcaemia (parathyroid hypoplasia). Also velocardiofacial syndrome, Shprintzen syndrome.
- Neonatal hypocalcaemic seizures + cardiac defect + T-cell lymphopenia (variable — 'partial' DiGeorge much more common than complete).
- Complete DiGeorge — treat with thymic tissue transplant or HSCT.
- Partial DiGeorge — supportive; monitor immune function.
- Avoid live vaccines until immune function documented.
Severe combined immunodeficiency (SCID)
The paediatric immunology emergency. Uniformly fatal without treatment; curable with HSCT if diagnosed and transplanted early.
| Subtype | Gene | Phenotype |
|---|
| X-linked SCID (commonest) | IL2RG (common gamma chain) | T minus B plus NK minus |
| ADA deficiency | ADA (adenosine deaminase) | T minus B minus NK minus |
| JAK3 deficiency (AR) | JAK3 | T minus B plus NK minus |
| IL7R | IL7R | T minus B plus NK plus |
| RAG1 / RAG2 | RAG1/2 | T minus B minus NK plus |
| Artemis | DCLRE1C | T minus B minus NK plus, radiosensitive |
| Omenn syndrome | Partial RAG defect | Erythroderma, alopecia, lymphadenopathy, high IgE, eosinophilia |
- Presentation before age 6 months — failure to thrive, chronic diarrhoea, oral thrush, PCP, live vaccine complications (disseminated BCG — critical in India where BCG is given at birth).
- Newborn screening — TREC (T-cell receptor excision circles) assay detects low T-cell output.
- Treatment — HSCT ideally before 3.5 months and before infections; gene therapy for ADA-SCID and X-linked SCID (approved); ADA can bridge with pegylated bovine ADA (Adagen).
- Isolate patient, IVIG, TMP-SMX prophylaxis, no live vaccines, only irradiated CMV-negative leukoreduced blood products.
Wiskott-Aldrich syndrome (WAS)
- X-linked — WASp gene defect affecting cytoskeleton in haematopoietic cells.
- Mnemonic — Wiskott-Aldrich = Thrombocytopenia + Eczema + Recurrent infections (some use TIE — Thrombocytopenia, Immunodeficiency, Eczema).
- Small platelets on peripheral smear — pathognomonic.
- High IgE and IgA, low IgM, normal or low IgG; poor antibody response to polysaccharide antigens.
- Risk of autoimmunity and lymphoma.
- Treatment — HSCT curative; gene therapy in trials; IVIG; splenectomy improves platelet count but increases infection risk.
Ataxia-telangiectasia
- ATM gene defect → DNA repair impairment.
- Progressive cerebellar ataxia (from infancy) + oculocutaneous telangiectasia (over ocular sclera and skin folds) + low IgA and IgG (particularly IgG2, IgG4) + high alpha-fetoprotein.
- Radiosensitivity — increased lymphoma / leukaemia risk; avoid diagnostic radiation.
- No cure; supportive; screen for malignancy.
Chronic mucocutaneous candidiasis
STAT1 gain-of-function or AIRE mutations (APECED). Chronic Candida infections of skin, nails, mucosa without systemic invasion. Treat with azoles.
Phagocyte defects
Chronic granulomatous disease (CGD)
- NADPH oxidase defect → phagocytes ingest organisms but cannot generate reactive oxygen species → cannot kill catalase-positive organisms.
- X-linked (gp91phox, CYBB) most common; AR forms in remaining ~30%.
- Catalase-positive organisms — Staphylococcus aureus, Aspergillus, Nocardia, Serratia marcescens, Burkholderia cepacia (mnemonic: "cats need PLACESS" or simpler — Staph, Aspergillus, Nocardia, Serratia, Burkholderia).
- Presentation — recurrent skin abscesses, pneumonia (Aspergillus), suppurative lymphadenitis, liver abscess, granulomatous colitis mimicking Crohn.
- Diagnosis — dihydrorhodamine (DHR) flow cytometry (current standard) or the older nitroblue tetrazolium (NBT) test — colourless → blue on oxidative burst; fails in CGD.
- Treatment — TMP-SMX prophylaxis, itraconazole prophylaxis, interferon-gamma, HSCT curative.
Leukocyte adhesion deficiency (LAD)
- CD18 (integrin beta-2) defect in LAD-1 → neutrophils cannot adhere to endothelium and migrate to tissue.
- Delayed umbilical cord separation (beyond 30 days), no pus formation at infection sites, marked peripheral leukocytosis (30 to 50 thousand per microlitre).
- Recurrent bacterial and fungal skin / mucosal infections; severe periodontitis in older children.
- HSCT curative.
Chediak-Higashi syndrome
- LYST gene mutation → giant lysosomal granules in all cells (neutrophils, melanocytes, platelets, neurons).
- Partial oculocutaneous albinism, silvery hair, recurrent pyogenic infections, peripheral neuropathy, bleeding diathesis.
- Terminal "accelerated phase" — haemophagocytic lymphohistiocytosis (HLH)-like syndrome.
- Diagnosis — giant granules on peripheral blood smear.
- HSCT for HLH phase.
Hyper-IgE (Job) syndrome
- STAT3 (autosomal dominant) most classical; DOCK8 (autosomal recessive) variant.
- FATED mnemonic — Facial coarsening, cold Abscesses (Staph, no inflammation), retained primary Teeth, hyper-IgE (very high, often > 2000 IU/mL), Dermatologic issues (eczema).
- Recurrent Staph aureus abscesses ("cold" because inflammatory response is muted), Candida infections, pulmonary pneumatoceles.
- Treatment — long-term anti-staphylococcal prophylaxis, HSCT considered.
Complement deficiencies
| Deficient component | Clinical picture |
|---|
| C1, C2, C4 (early classical) | SLE-like autoimmunity; C2 deficiency is commonest complement defect |
| C3 | Recurrent severe pyogenic infections + immune complex disease |
| C5–C9 (late) | Recurrent Neisseria (meningococcal + disseminated gonococcal) — vaccinate against meningococcus + prophylactic antibiotics |
| MBL deficiency | Recurrent childhood infections; often subclinical |
| C1 esterase inhibitor | Hereditary angioedema — non-pruritic, non-urticarial angioedema; bradykinin-mediated; C4 low always; C1-INH low or dysfunctional; treat with C1-INH concentrate, ecallantide, icatibant, fresh frozen plasma; long-term androgens (danazol) or lanadelumab |
Screening test — CH50 (total haemolytic complement) — detects any classical-pathway component defect; AH50 for alternative pathway.
Diagnostic approach
- Tier 1 — CBC with differential and morphology (small platelets in WAS; giant granules in Chediak-Higashi; lymphopenia in SCID); quantitative immunoglobulins (IgG, IgA, IgM, IgE); HIV test; CH50.
- Tier 2 — Lymphocyte subsets by flow cytometry (CD3, CD4, CD8, CD19, CD16/56); specific antibody responses to protein antigens (tetanus) and polysaccharide antigens (pneumococcal PPSV23); DHR / NBT for CGD; complement components; CD40L expression.
- Tier 3 — Genetic testing (whole-exome sequencing) — currently the gold standard for most PIDs.
Secondary immunodeficiencies
Far more common than PIDs in clinical practice.
HIV / AIDS
CD4 T-cell depletion → opportunistic infections at defined thresholds:
- CD4 <500 — TB, HZV shingles.
- CD4 <200 — PCP, oesophageal candidiasis, primary CNS lymphoma (rare at this level, more common below 50).
- CD4 <100 — Toxoplasma, cryptococcal meningitis, disseminated MAC, CMV retinitis, PML.
- Treatment — early ART (TLD in India), prophylactic TMP-SMX at CD4 <200, azithromycin at CD4 <50, fluconazole for CrAg-positive at CD4 <100.
Malnutrition
- Protein-energy malnutrition (kwashiorkor, marasmus, severe acute malnutrition) — thymic atrophy, reduced CD4, impaired cell-mediated immunity, poor vaccine response.
- Anergy to skin testing.
- Micronutrient deficiencies — vitamin A (measles severity), zinc (impaired thymic function), iron (variable effect), vitamin D (TB susceptibility).
Iatrogenic
- Chemotherapy — neutropenia (risk peaks 7–14 days post-cycle); febrile neutropenia is an emergency needing empirical broad-spectrum antibiotics within an hour.
- Corticosteroids — dose- and duration-dependent T-cell dysfunction; PCP prophylaxis for prednisolone equivalent above 20 mg/day for over 4 weeks in patients with additional risk.
- Transplant immunosuppression — CNIs (ciclosporin, tacrolimus), mTOR inhibitors, anti-thymocyte globulin — opportunistic infections (CMV, PCP, BK virus, fungal).
- Biologics — anti-TNF (reactivate TB — screen with IGRA before; hepatitis B reactivation); rituximab (hepatitis B, PCP); JAK inhibitors (herpes zoster).
Splenectomy / functional asplenia
- Surgical, traumatic, or functional (sickle cell autosplenectomy by adulthood; coeliac disease).
- OPSI (overwhelming post-splenectomy infection) — Strep pneumoniae, Hib, Neisseria meningitidis, Capnocytophaga; mortality up to 50%.
- Vaccination — pneumococcal (PCV15/20 followed by PPSV23), Hib, meningococcal ACWY + B, annual influenza; ideally 2 weeks pre-elective splenectomy.
- Lifelong penicillin prophylaxis (first 2 years, and always in children under 5); standby amoxicillin-clavulanate for any fever; medical alert card.
Diabetes mellitus
- Neutrophil dysfunction (poor chemotaxis, phagocytosis, oxidative burst) plus microvascular disease → mucormycosis (especially in DKA), Staph infections, foot ulcers, urinary tract infections.
Nephrotic syndrome
- Urinary loss of immunoglobulins (particularly IgG) → hypogammaglobulinaemia and risk of encapsulated infections; also lose complement factors, antithrombin.
- Peritonitis with S. pneumoniae is a classic paediatric complication.
NEET PG MCQ traps
- Bruton XLA — X-linked, absent B cells, absent tonsils, all Ig low, boys after 6 months.
- CVID — later onset, low IgG + IgA, autoimmunity + granulomas + lymphoma risk.
- Selective IgA deficiency — most common PID, anaphylaxis to blood products.
- Hyper-IgM — CD40L defect, no class switch, high IgM only, PCP and Cryptosporidium.
- DiGeorge CATCH-22 — 22q11.2, cardiac + hypocalcaemia + thymic hypoplasia.
- SCID — HSCT before 3.5 months; disseminated BCG is a huge Indian pitfall.
- X-linked SCID — IL2RG common gamma chain; T minus B plus NK minus.
- Wiskott-Aldrich — thrombocytopenia + eczema + infections; small platelets, high IgE / IgA.
- Ataxia-telangiectasia — ATM gene; high AFP; radiosensitive; avoid diagnostic radiation.
- CGD — NADPH oxidase; catalase-positive organisms; DHR or NBT test.
- LAD — delayed cord separation + no pus + leukocytosis; CD18 defect.
- Chediak-Higashi — giant granules + partial albinism + LYST mutation.
- Hyper-IgE (Job) — cold Staph abscesses + retained teeth + coarse facies + eczema; STAT3.
- C5–C9 deficiency — recurrent Neisseria; vaccinate meningococcus.
- C1-INH deficiency — hereditary angioedema; C4 always low; icatibant, C1-INH concentrate.
- Nephrotic syndrome — IgG loss → encapsulated infections; pneumococcal peritonitis.
- Splenectomy — OPSI risk; vaccinate + penicillin prophylaxis.
- Live vaccines contraindicated in T-cell defects — BCG, oral polio, MMR, varicella, yellow fever, rotavirus.
- Blood products in T-cell defects — irradiated, CMV-negative, leukoreduced (to prevent transfusion-associated GVHD and CMV).
- Newborn screening for SCID — TREC assay (T-cell receptor excision circles).
India context
- India National PID Registry — a collaborative effort of the Indian Society of Primary Immunodeficiency Diseases (SPID) to systematically capture PIDs. Under-diagnosis remains a major challenge.
- BCG-related complications — because BCG is a universal birth vaccine in India, disseminated BCG in undiagnosed SCID and other combined defects is a real cause of infant mortality. Any infant with disseminated BCG needs an immediate immunodeficiency workup.
- HSCT access — MHDs at AIIMS, CMC Vellore, PGIMER Chandigarh, Tata Medical Center Kolkata and Christian Medical College have paediatric HSCT programmes. Cost, matched donor availability and delayed diagnosis remain hurdles.
- Gene therapy — ex vivo lentiviral gene therapy for ADA-SCID is available at select centres internationally; India is developing indigenous programmes.
- Newborn screening for SCID — not yet in national newborn screening programmes but pilot programmes at some tertiary centres.
- Immunoglobulin availability — IVIG remains expensive; PMJAY and state schemes provide partial coverage for approved PIDs.
Frequently asked questions
How do you clinically approach a suspected primary immunodeficiency?
The best clinical starting point is the SPUR mnemonic — Severe, Persistent, Unusual, Recurrent infections — together with pattern recognition. Recurrent encapsulated bacterial infections (Streptococcus pneumoniae, H. influenzae, Neisseria) after 6 months of age point to antibody deficiencies. Recurrent viral, fungal or opportunistic infections in early infancy suggest T-cell or combined defects. Recurrent skin and deep abscesses with catalase-positive organisms (Staphylococcus aureus, Aspergillus, Nocardia, Serratia, Burkholderia) suggest chronic granulomatous disease. Recurrent Neisseria infections point to late complement (C5-C9) deficiency. Delayed umbilical cord separation with leukocytosis but no pus suggests leukocyte adhesion deficiency. First-tier workup includes CBC with differential, quantitative immunoglobulins (IgG, IgA, IgM, IgE), lymphocyte subsets by flow cytometry, complement CH50, specific antibody responses to vaccines (tetanus, pneumococcal polysaccharide), and HIV testing to rule out secondary causes.
What is severe combined immunodeficiency (SCID) and why is it a paediatric emergency?
SCID is a group of inherited disorders characterised by profound defects in both T-cell and B-cell function — the classic 'bubble boy' disease. The commonest form is X-linked SCID from mutations in the IL2RG gene encoding the common gamma chain (T minus, B plus, NK minus phenotype). Autosomal-recessive forms include adenosine deaminase (ADA) deficiency and JAK3 mutations. Presentation is in the first 6 months with failure to thrive, chronic diarrhoea, oral thrush, PCP pneumonia, live vaccine complications (BCG dissemination) and skin rash. SCID is the only primary immunodeficiency that is uniformly fatal without treatment but is curable with early haematopoietic stem cell transplantation (best outcome if performed before age 3.5 months and before onset of infections) or gene therapy for ADA deficiency and X-linked SCID. Newborn screening using T-cell receptor excision circles (TRECs) enables detection before symptomatic infections.
Why does splenectomy require lifelong vaccination and prophylaxis?
The spleen is the main site of opsonisation and clearance of encapsulated organisms, and asplenic patients are at up to 50-fold increased lifetime risk of overwhelming post-splenectomy infection (OPSI) — a rapidly fatal sepsis with mortality up to 50 percent. The at-risk organisms are Streptococcus pneumoniae (~50 percent of OPSI), Haemophilus influenzae type b, Neisseria meningitidis and Capnocytophaga canimorsus (dog bite). Every asplenic patient — surgical or functional (sickle cell autosplenectomy) — needs (1) vaccination ideally 2 weeks before elective splenectomy or 2 weeks post-emergency splenectomy — pneumococcal (PCV15/20 followed by PPSV23), Hib, meningococcal ACWY and B, annual influenza; (2) lifelong penicillin V or amoxicillin prophylaxis, particularly for the first 2 years post-splenectomy and always in children under 5; (3) a medical alert card and standby amoxicillin-clavulanate for febrile illness; (4) urgent evaluation for any fever.
What is IRIS and how does it relate to secondary immunodeficiency?
Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical worsening of an underlying opportunistic infection or unmasking of a previously subclinical infection after starting ART in advanced HIV — as the immune system recovers, it mounts a robust inflammatory response against residual antigens. The commonest triggers are TB (paradoxical worsening of lymphadenopathy or new infiltrates), cryptococcal meningitis (raised ICP, worsening headache), CMV retinitis, PML from JC virus and Kaposi sarcoma. Risk factors are CD4 under 50, high viral load and rapid CD4 recovery. Management principle — do not stop ART unless life-threatening; treat the underlying opportunistic infection, add corticosteroids for severe cases (paradoxical TB IRIS, tuberculous meningitis IRIS). This is why cryptococcal-meningitis induction is completed and ART delayed by 4 to 6 weeks, and TB-HIV co-infection has structured ART initiation timing based on CD4.
Which primary immunodeficiencies must you never miss on NEET PG?
Six high-yield PIDs that recur on NEET PG stems: (1) Bruton X-linked agammaglobulinemia — male infant, absent B cells, all immunoglobulins low, encapsulated bacterial infections after 6 months when maternal IgG wanes, treat with IVIG replacement; (2) SCID — infant with failure to thrive, PCP, thrush, live-vaccine complications, T minus B plus/minus NK plus/minus, curable only with HSCT or gene therapy; (3) DiGeorge syndrome — CATCH-22 (cardiac, abnormal facies, thymic hypoplasia, cleft palate, hypocalcaemia; 22q11.2 deletion); (4) Wiskott-Aldrich — WATER mnemonic (Wiskott, Ataxia — no, actually the WAS mnemonic is Thrombocytopenia + Eczema + Recurrent infections; small platelets, X-linked, high IgE and IgA, low IgM); (5) Chronic granulomatous disease — NADPH oxidase defect, recurrent catalase-positive infections (Staph, Aspergillus, Nocardia, Serratia, Burkholderia), dihydrorhodamine flow assay or nitroblue tetrazolium; (6) Chediak-Higashi — giant lysosomal granules, partial albinism, recurrent pyogenic infections, LYST mutation.
This content is for educational purposes for NEET PG exam preparation. It is not a substitute for professional medical advice, diagnosis, or treatment. Clinical information has been reviewed by qualified medical professionals.
Written by: NEETPGAI Editorial Team
Reviewed by: Pending SME Review
Last reviewed: July 2026
