Primary Immunodeficiency


Primary Immunodeficiency, Immunodeficiency

  • Epidemiology
  1. Normal children have recurrent infections
    1. Average child has 5-6 Upper Respiratory Infections/year
    2. Unlucky children (5%) have 11-12 URIs per year
    3. Otitis Media complicates URIs in 30-50% of cases
  2. Primary Immunodeficiency Prevalence
    1. United States: 83 per 100,000
    2. Australia: 12 per 100,000
    3. Sweden: 0.35 per 100,000
  • Causes
  • Antibody or humoral (B-Cell Disorder): 78% of cases in U.S. (55% in Europe)
  1. General
    1. Present after 3 months of age (when maternal antibodies are no longer present)
    2. Recurrent respiratory (ears, sinus, lungs) infections with encapsulated organisms
      1. Streptococcus Pneumoniae
      2. HaemophilusInfluenzae
  2. No B-Cells: Agammaglobulinemia
    1. X-Linked Agammaglobulinemia or XLA (84% of agammaglobulinemia cases in Europe)
      1. Bruton Tyrosine Kinase defect (Btk gene)
      2. Very low serum IgG, IgA and IgM
      3. Infants may have no Tonsils or lymph nodes on exam
      4. Severe infections with encapsulated organisms
      5. Chronic Diarrhea, recurrent varicella
  3. Decreased B Cells or Antibody: Hypogammaglobulinemia
    1. IgA Deficiency (30% of U.S. cases and most common B-Cell Disorder overall in U.S.)
    2. IgG Subclass Deficiency of IgG2, IgG3, IgG4 (26% of U.S. cases)
    3. Common variable Immunodeficiency or CVID (15% in U.S. and 46% in Europe of cases)
      1. Bimodal onset in preschool and in young adults
      2. Two Immunoglobulin subtypes are low (typically including Low total IgG)
      3. Similar to X-Linked Agammaglobulinemia, but more mild
      4. Ear, sinus and lung infections occur as with other Antibody disorders
      5. CVID also present with malabsorption from Infectious Diarrhea (c. difficile, Giardia, Salmonella, Campylobacter, Yersinia)
    4. Transient hypogammaglobulinemia of infancy (3% of U.S. cases)
      1. Increased mild Bacterial respiratory infections
      2. Normal nadir that corrects by age 2-4 years
  • Causes
  • T-Cell Disorders (9-10% of Primary Immunodeficiency in both Europe and U.S.)
  1. General
    1. Most T-Cell Disorders are mixed T-Cell and B-Cell disorders as B-Cells rely on T-Cells
  2. Severe combined Immunodeficiency (SCID)
    1. Severe T cell deficiency causes B Cell dysfunction
    2. X-Linked deficiency or Autosomal Recessive trait (1 in 100,000 live births in U.S.)
    3. Onset before age 3 months
    4. Presents with Diarrhea, opportunistic infections, severe childhood infections and Failure to Thrive
    5. Survival is 90% with diagnosis and Stem Cell Transplant in first 3.5 months of life (contrast with 70% after that age)
      1. Currently being added to routine Newborn Screening panels in U.S. (in about one third of U.S. States as of 2013-14)
      2. False Positive Rate of 1.5% in term infants and 5% in Preterm Infants in NICU (will require re-testing protocol)
  3. Ataxia telangiectasia
  4. Hyper-IgM Syndrome
  5. Wiscott-Aldrich Syndrome
    1. X-Linked disorder, typicalluy diagnosed around 21 months of age
    2. Classic triad of Thrombocytopenia, recurrent Otitis Media and Eczema (present in only 27% of cases)
    3. Thrombocytopenia with Hematemesis, melana, intracranial including life threatening bleeds in up to 30% of children
  6. 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
  • Causes
  • Phagocytic Disorders (8.5% of U.S. and 12.5% of European Primary Immunodeficiency cases)
  1. General
    1. Disorders of Neutrophils or Monocytes
    2. Fungal Lung Infections
    3. Recurrent abscesses or delayed Wound Healing
    4. May present with invasive infections
    5. Catalase positive infections (consider especially if invasive infections)
      1. Staphylococcus aureus
      2. Pseudomonas
      3. Aspergillus
      4. Burkholderia cepacia
      5. Nocardia
      6. Serratia
      7. Candida
  2. Decreased Absolute Neutrophil Count (ANC<500/ul)
    1. Chemotherapy-related Neutropenia
    2. Severe Congenital Neutropenia
      1. Presents in first few weeks of life
      2. Omphalitis
    3. Autoimmune
    4. Cyclic
  3. Decreased Neutrophil function
    1. Chronic Granulomatous Disease (CGD)
      1. Inherited NADPH oxidase abnormality
      2. Results in defect of PMN intracellular killing
      3. Typically diagnosed by age 5 years old
      4. May first present as omphalitis in infants
      5. Recurrent Pneumonia, abscesses, suppurative adenitis, gastrointestinal infections
    2. Leukocyte adhesion deficiency (type 1)
      1. Presents in first few weeks of life
      2. Delayed Umbilical Cord separation beyond 4 weeks after birth
      3. Erosive perianal ulcers
      4. Omphalitis
    3. Chediak-Higashi Syndrome
  • Causes
  • Complement Disorders: 2% of cases
  1. Autoimmune Condition
  2. Recurrent encapsulated organism infections (manifestations vary depending on missing complement type)
    1. Neisseria infections are most common including Meningitis, Sepsis and Arthritis (associated with C5-C9 deficiencies)
    2. Recurrent infections with Streptococcus Pneumoniae and HaemophilusInfluenzae (associated with C3 deficiency)
  • Signs
  • Red Flags for Primary Immunodeficiency
  1. Most helpful warning signs
    1. Positive Family History of Immunodeficiency
    2. History of Sepsis requiring intravenous antibiotics
    3. Failure to Thrive
    4. Subbarayan (2011) Pediatrics 127(5): 810-6 [PubMed]
  2. Warning sign patterns
    1. Increasing frequency and severity of infections as children become older (opposite of typical pattern)
    2. Recurrent serious infections (at 2 or more sites) with common pathogens
    3. Serious, invasive infections with uncommon pathogens
  3. 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
  4. Physical findings
    1. Failure to Thrive
  5. Miscellaneous
    1. Family History of Primary Immunodeficiency
    2. Autoimmune Disease (e.g. ITP or Hemolytic Anemia)
  • Differential Diagnosis
  1. Asthma or atopic condition
  2. Cystic Fibrosis
  3. Secondary Immunodeficiency
    1. Asplenism
    2. HIV Infection
      1. Presents similarly to T-Cell Immunodeficiency Disorder
  • Labs
  1. Initial Screening
    1. Complete Blood Count with manual differential
      1. Screens for T-Cell Disorders and Phagocytic disorders
      2. See Absolute Lymphocyte Count discriminatory levels under T-Cell Disorders below
    2. Serum Immunoglobulin levels
    3. Complement Levels
    4. Peripheral Smear
      1. Howell-Jolly bodies suggests Asplenism
    5. HIV Test
      1. Age 18 months or older
        1. HIV Antibody testing is sufficient
      2. Age under 18 months
        1. Obtain HIV DNA PCR or HIV RNA at age 14-21 days, age 1 month and age 4-6 months
  2. Specific Immunodeficiency testing
    1. B-Cell function Tests
      1. Quantitative serum IgG, IgM and IgA levels
        1. IgG subclasses are usually not helpful
        2. Low serum Immunoglobulin levels should prompt Serum Albumin testing
          1. Hypoalbuminemia (due to Proteinuria or malabsorption) can cause a secondary Immunodeficiency
      2. IgG Antibody test to Vaccines patient recieved
        1. Timing
          1. First Vaccination: Obtain 4 weeks after initial Vaccination
          2. Two or more prior Vaccinations: 3-fold increase in titers to 2 or more antigens at 3 weeks after Vaccination
        2. Tests
          1. Tetanus, Rubella, Diptheria, or Mumps Antibody titers after Vaccination at any age
          2. Polysaccharide antigens (HaemophilusInfluenzae or Streptococcus Pneumoniae titers) may be drawn if over age 2 years
    2. T-Cell Function tests (Delayed-Type Hypersensitivity)
      1. Absolute Lymphocyte Count (ALC, done in CBC)
        1. Unlikely if normal Lymphocyte Count
        2. Newborn: <3000/mm3 suggests T-Cell Disorder
        3. Infant or child with ALC at 2 S.D. below mean suggests T-Cell disorder (especially SCID)
      2. Candida albicans intradermal skin test at age 1 year or older (or Mumps or Tetanus)
        1. Positive test rules-out T-Cell defects
        2. Most cost-effective test for T-Cell dysfunction
      3. Lymphocyte subset analysis
        1. Estimates percentage of T Cells (CD3, CD4, CD8), B Cells (CD19, CD20), Natural Killer Cells (CD16, CD56)
    3. Phagocytosis function tests
      1. Absolute Neutrophil Count (ANC) <1500/mm3
      2. Granulocyte function tests
      3. Flow cytometry for Neutrophil oxidative burst
    4. Complement function tests
      1. Total complement or CH50 (test when well)
      2. If abnormal, test alternative pathway (CH100 or AH50)
  • 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
  • Resources
  1. National Primary Immunodeficiency Resource Center
  2. Immune Deficiency Foundation