Immunodeficiency Disorders

Intro & B-Cell Deficiencies - Antibody Alarms

• Types: Primary (congenital) vs. Secondary (acquired).
• Hallmark: Recurrent, severe, unusual infections.

Key B-Cell Deficiencies:

• X-Linked Agammaglobulinemia (XLA/Bruton's)

  • Defect: BTK gene → no B-cell maturation.
  • Cells: ↓ B-cells (CD19+), ↓ all Ig. Normal T-cells.
  • Infections: Encapsulated bacteria post-6 months (maternal IgG wanes).
  • 📌 Boys, Bruton's, BTK, no B-cells, Bacterial.

  ⭐ XLA presentation typically after 6 months (maternal IgG protection).

• Common Variable Immunodeficiency (CVID)

  • Onset: Later. Normal B-cells, ↓ plasma cells, ↓ IgG, IgA.
  • Infections: Sinopulmonary, Giardia. ↑ Autoimmune risk.

• Selective IgA Deficiency

  • Most common. Often asymptomatic.
  • Labs: Serum IgA < 7 mg/dL. Normal IgG, IgM.
  • Risks: Sinopulmonary/GI infections, anaphylaxis to IgA in blood products.

T-Cell & Combined Deficiencies - Cellular Commandos Down

• DiGeorge Syndrome: Chromosomal 22q11.2 deletion. Thymic aplasia/hypoplasia → ↓ T-cells, parathyroid hypoplasia → hypocalcemia. 📌 CATCH-22: Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia.

• Severe Combined Immunodeficiency (SCID): Multiple genetic defects. Most common: X-linked (IL2RG gene). Also, Adenosine Deaminase (ADA) deficiency. Results in severe T-cell deficiency; B-cell & NK-cell numbers/function vary by type. Recurrent severe infections, failure to thrive.

  ⭐ SCID is a pediatric emergency; live vaccines are contraindicated.

• Wiskott-Aldrich Syndrome (WAS): X-linked recessive, WASP gene defect. 📌 TIE: Thrombocytopenia (small platelets), Infections (recurrent), Eczema. ↓ IgM, ↑ IgA, ↑ IgE.
• Ataxia-Telangiectasia (AT): Autosomal recessive, ATM gene defect (DNA repair). Triad: cerebellar Ataxia, oculocutaneous Telangiectasias, Immunodeficiency (esp. IgA deficiency). ↑ AFP. Increased risk of malignancy (lymphoma, leukemia).

Phagocyte & Complement Defects - Clean-up Crew Crisis

• Phagocyte Defects:

  • Chronic Granulomatous Disease (CGD):
    • Defect: NADPH oxidase (↓ Reactive Oxygen Species, ROS). X-linked/AR.
    • Infections: Catalase (+) organisms (📌 PLACēS: Pseudomonas, Listeria, Aspergillus, Candida, E.coli, S.aureus, Serratia). Granulomas.
    • Dx: Nitroblue tetrazolium (NBT) test (negative), Dihydrorhodamine (DHR) flow cytometry (↓ oxidative burst).
    • 
  • Leukocyte Adhesion Deficiency (LAD-1):
    • Defect: CD18 (integrin $\beta$2 subunit).
    • Features: Recurrent bacterial infections, impaired wound healing, neutrophilia.
    • ⭐ > Delayed umbilical cord separation (>30 days) is a hallmark of LAD-1.
    • Dx: Flow cytometry (↓CD18).
  • Chediak-Higashi Syndrome (CHS):
    • Defect: LYST gene (lysosomal trafficking regulator). AR.
    • Features: Pyogenic infections, partial albinism, neuropathy, giant granules in neutrophils.
    • Dx: Peripheral smear (giant granules).
    • 

• Complement Defects:

  • C3 Deficiency:
    • Impact: Impaired opsonization & MAC formation.
    • Infections: Encapsulated bacteria (e.g., S. pneumoniae, H. influenzae).
  • C5-C9 Deficiency (MAC Complex):
    • Impact: Inability to form Membrane Attack Complex.
    • Infections: Recurrent Neisseria spp. (meningitis, gonococcal).
    • Dx (General): CH50 assay (↓ total complement activity), specific component assays.

Dx & Tx Highlights - Immuno-Fixit Fast Facts

• Initial Screening Tests:
  • Complete Blood Count (CBC) with differential (lymphopenia, neutropenia)
  • Quantitative Immunoglobulin levels (IgG, IgA, IgM)
  • CH50 assay (total classical complement activity)
• Confirmatory Diagnostic Tests:
  • Lymphocyte subset enumeration by flow cytometry (T, B, NK cells; CD markers)
  • Functional B & T cell proliferation assays
  • Dihydrorhodamine (DHR) / Nitroblue Tetrazolium (NBT) test (for Chronic Granulomatous Disease - CGD)
  • Specific genetic testing
• General Management Principles:
  • Prophylactic antibiotics (e.g., TMP-SMX for Pneumocystis jirovecii pneumonia - PCP)
  • Immunoglobulin (IVIG/SCIG) replacement therapy
  • Hematopoietic Stem Cell Transplantation (HSCT) - often curative
  • Gene therapy (emerging option for specific PIDs)
• Key Patient Precautions:
  • ⚠️ Avoid ALL live attenuated vaccines (e.g., MMR, Varicella, Rotavirus, BCG, oral polio)
  • ⚠️ Use irradiated, leukocyte-reduced, CMV-negative blood products if transfusion needed.

⭐ HSCT is curative for many severe PIDs like SCID and WAS.

High‑Yield Points - ⚡ Biggest Takeaways

• X-linked Agammaglobulinemia (Bruton's): Defect in BTK gene, results in no B cells; recurrent bacterial infections after 6 months of age.
• Common Variable Immunodeficiency (CVID): Most common symptomatic primary immunodeficiency (PID), characterized by low IgG, IgA, IgM; typically adult onset.
• IgA Deficiency: Most common PID overall, often asymptomatic; potential for anaphylaxis to IgA-containing blood products.
• DiGeorge Syndrome (22q11.2 deletion): Features thymic hypoplasia (leading to T-cell deficiency), hypocalcemia, and cardiac defects (CATCH-22).
• Severe Combined Immunodeficiency (SCID): Key genetic defects include IL-2R gamma chain or ADA deficiency; results in absent T and B cell function.
• Wiskott-Aldrich Syndrome (WAS): X-linked recessive disorder presenting with Thrombocytopenia, Eczema, and Recurrent infections (WATER); often ↑ IgE, IgA.
• Ataxia-Telangiectasia: Defect in ATM gene; presents with cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency (often IgA/IgG), and ↑ AFP.