Primary Immunodeficiency

1. Epidemiology: Normal children have recurrent infections
   1. Average child has 5-6 Upper Respiratory Infections/year
      1. Unlucky children (5%) have 11-12 URIs per year
      2. Otitis Media complicates URIs in 30-50% of cases
2. Causes: Primary Immunodeficiency
   1. Antibody or humoral (B-Cell Disorder): 50% of cases
      1. General
         1. Onset after 6 months of age
         2. Recurrent respiratory encapsulated infections
      2. X-Linked Agammaglobulinemia (XLA; Btk gene related)
         1. Very low serum IgG, IgA and IgM
         2. Severe infections with encapsulated organisms
         3. Chronic Diarrhea, recurrent varicella
      3. IgA Deficiency
      4. Transient hypogammaglobulinemia of infancy
         1. Increased bacterial respiratory infections
         2. Normal nadir that corrects by age 2-4 years
      5. Common variable Immunodeficiency (CVID)
         1. Bimodal onset in preschool and in young adults
         2. Low total IgG
         3. Similar to XLA, but more mild
   2. T-Cell disorder: DiGeorge Syndrome (Velocardiofacial)
      1. Deletion at 22q11.2 results in Thymus hypoplasia
      2. T Lymphocyte deficiency
         1. Severe viral infection or from live Vaccine
         2. Thrush persists >12 months
      3. Hypoparathyroidism with Hypocalcemia
      4. Cardiac abnormalities and altered facial features
   3. Mixed T-Cell and Antibody Disorders
      1. Severe combined Immunodeficiency (SCID)
         1. Severe T cell deficiency causes B Cell dysfunction
         2. X-Linked deficiency or Autosomal recessive trait
         3. Presents with Diarrhea or Failure to Thrive
      2. Ataxia telangiectasia
      3. Wiscott-Aldrich Syndrome
      4. Common variable Immunodeficiency
      5. Hyper-IgM Syndrome
   4. Phagocytic Disorders: 15-20% of cases
      1. General
         1. Fungal Lung Infections
         2. Recurrent abscesses or delayed Wound Healing
      2. Decreased Absolute Neutrophil Count (ANC<500/ul)
         1. Chemotherapy-related Neutropenia
         2. Other causes: Congenital, autoimmune, cyclic
      3. Decreased Neutrophil function
         1. Chronic Granulomatous Disease (CGD)
            1. Inherited NADPH oxidase abnormality
            2. Results in defect of PMN intracellular killing
            3. Catalase positive infections
               1. Staphylococcus aureus
               2. Pseudomonas
               3. Aspergillus
         2. Leukocyte adhesion deficiency
         3. Chediak-Higashi Syndrome
   5. Complement Disorders: 2% of cases
      1. Autoimmune condition
      2. Recurrent encapsulated organism infections
         1. Neisseria infections are most common
         2. Infection types related to missing complement type
3. Red Flags for Primary Immunodeficiency
   1. Recurrent and persistent infections
      1. Otitis Media (>8 episodes/year)
         1. Or complicated by Mastoiditis
      2. Severe bacterial Sinusitis (>1 episode/year)
      3. Pneumonia (>1 episode/year)
      4. Enteric infections (e.g. Giardia, Cryptosporidium)
      5. Skin Abscesses
      6. Unusual sites of infection (e.g. liver, Spleen)
      7. Opportunistic infections (e.g. Aspergillus, Nocardia)
      8. Persistant Thrush after age 1 year
      9. Infection despite >2 months of antibiotic use
      10. Infection clears only with parenteral antibiotics
   2. Physical findings
      1. Failure to Thrive
   3. Miscellaneous
      1. Family History of Primary Immunodeficiency
      2. Autoimmune disease (e.g. ITP or Hemolytic Anemia)
4. Differential Diagnosis
   1. Asthma or atopic condition
   2. Cystic Fibrosis
   3. Secondary Immunodeficiency
      1. HIV Infection
      2. Asplenism
5. Labs
   1. Initial Screening
      1. Complete Blood Count with manual differential
      2. Erythrocyte Sedimentation Rate (ESR)
         1. Chronic infection unlikely with normal ESR
      3. Peripheral Smear
         1. Howell-Jolly bodies suggests Asplenism
   2. Other tests to consider
      1. B-Cell function Tests
         1. Quantitative serum IgG, IgM and IgA levels
            1. IgG subclasses are usually not helpful
         2. Antibody test to Vaccines patient recieved
            1. Tetanus Antibody titers
            2. Streptococcus Pneumoniae titers (in over age 2)
      2. T-Cell Function tests (Delayed-Type Hypersensitivity)
         1. Absolute Lymphocyte Count (ALC, done in CBC)
            1. Unlikely if normal Lymphocyte Count
         2. Candida albicans intradermal skin test
            1. Positive test rules-out T-Cell defects
            2. Most cost-effective test for T-Cell dysfunction
         3. HIV Test
      3. Phagocytosis function tests
         1. Absolute Neutrophil Count (ANC)
         2. Flow cytometry for Neutrophil oxidative burst
      4. Complement function tests
         1. Total complement or CH50 (test when well)
6. Precautions
   1. Vaccines to avoid in patients and their close contacts
      1. Oral Polio Vaccine (live Vaccine)
      2. Varicella Vaccine (live Vaccine)
      3. BCG vaccine
      4. MeaslesVaccine
   2. Blood Products
      1. Specific precautions depending on condition
7. Resources
   1. National Primary Immunodeficiency Resource Center
      1. http://npi.jmfworld.org
   2. Immune Deficiency Foundation
      1. http://www.primaryimmune.org
8. References
   1. Cooper (2003) Am Fam Physician 68:2001-11
   2. Rosen (1995) N Engl J Med 333(7):431-440