Primary Immunodeficiency Disorders

PID Overview - Immune Alarms

• Definition: Genetic defects in immunity; predispose to infections, autoimmunity, malignancy.
• Suspect if (Red Flags):
  • ≥4 new ear infections/year.
  • ≥2 serious sinus infections/year.
  • ≥2 months on antibiotics with little effect.
  • Recurrent deep skin/organ abscesses.
  • Persistent thrush or Failure To Thrive (FTT).
  • Family history of PID.
• Major Categories: Affecting B-cells, T-cells (or both), phagocytes, or complement system.

⭐ Recurrent sinopulmonary infections and failure to thrive are common red flags for PIDs.

B-Cell Deficiencies - Antibody Abyss

• Impaired antibody production → recurrent bacterial infections.
  • Encapsulated: S. pneumo, H. flu.
• X-linked Agammaglobulinemia (XLA/Bruton's)
  • BTK gene defect; no B-cell maturation.
  • Labs: ↓ B-cells (CD19+), all Ig ↓; absent tonsils.
  • 📌 Mnemonic: Bruton's = Boys, BTK, no B-cells.

  ⭐ X-linked Agammaglobulinemia (Bruton's) typically presents after 6 months of age due to waning maternal IgG, with recurrent bacterial infections (especially encapsulated organisms).

• Common Variable Immunodeficiency (CVID)
  • Impaired B-cell differentiation; ↓ IgG, ↓ IgA/IgM.
  • Later onset; sinopulm. infections, autoimmune, ↑ lymphoma risk.
• Selective IgA Deficiency
  • Most common PID; ↓ IgA.
  • Often asymptomatic; sinopulm./GI infections, IgA anaphylaxis.
• Hyper-IgM Syndrome (X-linked)
  • CD40L defect (T-cells); class switching failure.
  • Labs: ↑ IgM, ↓ IgG/IgA/IgE.
  • Rec. pyogenic infections, Pneumocystis jirovecii pneumonia (PJP).

T-Cell & Combined Defects - Cellular Crisis

• Impaired cell-mediated immunity; often life-threatening, presenting as cellular crisis.
• Severe Combined Immunodeficiency (SCID)
  • Pediatric emergency! Profound T-cell deficiency (CD3+ <300/µL).
  • Types: X-linked (IL2RG - commonest), ADA def. (AR), RAG def. (AR).
  • Clinical: FTT, severe recurrent infections (PJP, viral, fungal), chronic diarrhea.
  • Dx: Lymphopenia, absent thymic shadow (CXR), absent TRECs (newborn screen).
  • Rx: HSCT (curative), IVIG, PJP prophylaxis. ⚠️ No live vaccines!

  ⭐ Severe Combined Immunodeficiency (SCID) is a pediatric emergency; suspect in infants with persistent infections, FTT, and lymphopenia. Absent TRECs (T-cell receptor excision circles) on newborn screening is a key diagnostic pointer.

• DiGeorge Syndrome (22q11.2 Deletion)
  • 📌 CATCH-22: Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia.
  • Variable T-cell defect; recurrent viral/fungal infections.
  • Dx: FISH/CMA for 22q11.2 del.
  • Rx: Symptomatic, Ca/Vit D, thymic transplant (complete DGS).
• Wiskott-Aldrich Syndrome (WAS) (X-linked)
  • 📌 Triad (WATE): Wiskott-Aldrich, Thrombocytopenia (small platelets), Eczema, Recurrent infections.
  • ↓ IgM, ↑ IgA/IgE. Risk of malignancy.
  • Rx: HSCT, IVIG.
• Ataxia-Telangiectasia (AT) (AR, ATM gene)
  • 📌 Features (ATAXIA): Ataxia, Telangiectasias (oculocutaneous), ↑ AFP, Immunodeficiency (IgA/IgG def.), X-ray sensitivity, malignancy risk.
  • Rx: Supportive, IVIG.

Phagocytic & Complement Woes - Defense Down

• Phagocytic Defects: Recurrent bacterial/fungal infections.
  • Chronic Granulomatous Disease (CGD):
    • NADPH oxidase defect (↓ROS).
    • 📌 Mnemonic: "CGD = Can't Generate Destruction".

    ⭐ Chronic Granulomatous Disease (CGD) patients are susceptible to catalase-positive organisms (e.g., Staphylococcus aureus, Aspergillus, Serratia, Nocardia). Nitroblue tetrazolium (NBT) test is historically important, Dihydrorhodamine (DHR) flow cytometry is current standard.

  • Leukocyte Adhesion Deficiency (LAD):
    • Integrin (CD18) defect.
    • Delayed umbilical cord separation (>30 days), recurrent infections without pus.
  • Chédiak-Higashi Syndrome:
    • LYST defect; impaired phagolysosome fusion.
    • Partial oculocutaneous albinism, pyogenic infections, giant granules.
• Complement Deficiencies:
  • C1 Esterase Inhibitor Deficiency: Hereditary Angioedema (HAE) - angioedema without urticaria.
  • C5-C9 (MAC) Deficiency: Recurrent Neisseria infections.

High‑Yield Points - ⚡ Biggest Takeaways

• XLA (Bruton's): BTK defect, no B cells, sinopulmonary infections after 6 months.
• SCID: Severe T-cell defect (e.g., IL2RG, ADA), FTT, opportunistic infections, requires HSCT.
• DiGeorge (22q11.2): Thymic hypoplasia (↓ T cells), hypocalcemia, conotruncal cardiac defects.
• Wiskott-Aldrich (WAS): X-linked, triad: eczema, microthrombocytopenia, recurrent infections.
• CGD: Defective NADPH oxidase, recurrent catalase-positive infections, abnormal DHR/NBT test.
• Hyper IgE (Job's): STAT3 mutation, cold abscesses, severe eczema, ↑ IgE, retained primary teeth.