Immunodeficiency Disorders

Overview & Classification - Immune System Gaps

• Immunodeficiency: Immune system failure/dysfunction leading to ↑ susceptibility to infections & diseases.
• Types:
  • Primary (PID): Intrinsic, often genetic, defects in immune cells/proteins.
    • B-cell (antibody) defects (e.g., XLA)
    • T-cell (cellular) defects (e.g., DiGeorge)
    • Combined B & T cell (e.g., SCID)
    • Phagocytic cell defects (e.g., CGD)
    • Complement system defects
  • Secondary (SID): Acquired; more common (e.g., HIV, malnutrition, immunosuppressive drugs).
• Warning Signs (📌 SPURR):
  • Severe infections
  • Persistent infections
  • Unusual organisms/sites
  • Recurrent infections
  • Runting (Failure to Thrive) / Family Hx

⭐ The majority of Primary Immunodeficiencies are X-linked, leading to a higher prevalence in males. SCID is a pediatric emergency!

B-Cell Deficiencies - Antibody Alarms

• XLA (Bruton's): 📌 Boys, Bruton, BTK gene, B-cells absent/↓, recurrent Bacterial infections.
  • XLR; Onset: 6-12 mo.
  • Labs: ↓ All Ig, absent/↓ B-cells (CD19+).
  • Infections: Encapsulated bacteria, enteroviruses.
• CVID: Onset: Bimodal (20-40 yrs).
  • Labs: ↓ IgG, ↓ IgA/IgM; B-cells N/↓, poor Ab response.
  • Infections: Sinopulmonary, autoimmune, ↑ lymphoma risk.
• Selective IgA Deficiency: Most common PID. Often asymptomatic.
  • Labs: ↓ IgA, N IgG/IgM.
  • Infections: Sinopulmonary, GI; anaphylaxis to IgA-products.
• Hyper-IgM (X-linked): CD40L defect.
  • Labs: ↑/N IgM, ↓↓ IgG, IgA, IgE. N B-cells.
  • Infections: P. jirovecii, encapsulated bacteria, opportunistic.

  ⭐ CVID patients have an increased risk of developing autoimmune diseases and lymphoma.

T-Cell & Combined Deficiencies - Cellular Chaos Crew

• DiGeorge Syndrome (22q11.2 del)
  • 📌 CATCH-22: Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia.
  • Labs: ↓ T-cells, variable Ig.
  • 
• Severe Combined Immunodeficiency (SCID)
  • Genes: IL2RG (X-linked), ADA, RAG.
  • Features: Severe recurrent infections (viral, fungal, bacterial), Failure To Thrive (FTT).
  • Labs: Markedly ↓ T-cells (<20% lymphocytes), B-cells variable/non-functional, ↓ Ig.

  ⭐ SCID: Infancy onset, persistent infections, FTT. Absent thymic shadow on CXR is key.

• Wiskott-Aldrich Syndrome (WAS, X-linked)
  • Triad: Eczema, Thrombocytopenia (small platelets), Recurrent infections.
  • Labs: ↓ T-cells, ↓ IgM, ↑ IgA, ↑ IgE.
• Ataxia-Telangiectasia (ATM, AR)
  • Triad: Cerebellar Ataxia, Oculocutaneous Telangiectasias, Immunodeficiency (recurrent sinopulmonary infections).
  • Labs: ↓ T-cells, ↓ IgA/IgE/IgG2. ↑ AFP (Alpha-fetoprotein).

Phagocyte & Complement Defects - Defense Downfalls

• Phagocytic Defects:
  • Chronic Granulomatous Disease (CGD): NADPH oxidase defect; NBT test ➖. Recurrent infections with catalase ➕ organisms. 📌 CGD: Susceptibility to Catalase-positive organisms (e.g., S. aureus, Aspergillus).
  • Leukocyte Adhesion Deficiency (LAD): CD18 defect. Delayed umbilical cord separation (>30 days), recurrent bacterial infections.
  • Chediak-Higashi Syndrome: LYST gene defect. Giant granules in phagocytes, partial albinism, recurrent pyogenic infections.
• Complement Deficiencies:
  • C1/C2/C4: Associated with SLE-like syndrome.
  • C3: Results in severe pyogenic infections.
  • C5-C9 (MAC): Leads to recurrent Neisseria infections.
  • C1 Inhibitor Deficiency: Causes Hereditary Angioedema (HAE).

⭐ Nitroblue Tetrazolium (NBT) test is negative in CGD, indicating defective phagocytic oxidative burst.

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Secondary IDs & Approach - Acquired Achilles' Heels

• Causes: HIV/AIDS, malnutrition, drugs (immunosuppressants, chemo), malignancy, splenectomy.
• Diagnosis:
  • Initial: History, Physical Exam.
  • Screening: CBC with diff, Ig levels, CH50.
  • Confirmatory: Flow cytometry, NBT test, genetic tests.
• Management: Prophylaxis, IVIG, HSCT, Gene Rx.

⭐ A CBC with differential is a crucial initial screening test for suspected immunodeficiency.

High‑Yield Points - ⚡ Biggest Takeaways

• Bruton's (XLA): BTK defect, no B-cells/Igs, recurrent bacterial infections after 6 months.
• DiGeorge Syndrome: 22q11.2 deletion, T-cell deficiency, hypocalcemia, cardiac defects.
• SCID: Severe T-cell defect (e.g., IL-2Rγ, ADA), early severe infections, requires HSCT.
• Wiskott-Aldrich: X-linked WASp, Thrombocytopenia, Eczema, Recurrent infections.
• CGD: NADPH oxidase defect, recurrent catalase (+) infections, abnormal DHR/NBT test.
• Selective IgA Deficiency: Most common, often asymptomatic, risk of anaphylaxis to IgA.
• CVID: Adult onset, low Igs, recurrent infections, risk of autoimmunity, lymphoma.