Primary Immunodeficiency

See Also

Epidemiology

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
Primary Immunodeficiency Prevalence
1. United States: 83 per 100,000
2. Australia: 12 per 100,000
3. Sweden: 0.35 per 100,000

Types

Primary Immunodeficiency
1. Rare immune disorders of childhood
2. Genetic abnormalities affecting T-Cells, B-Cells, Phagocytes or Complement
Secondary Immunodeficiency (Acquired Immunodeficiency)
1. Asplenism (e.g. splenectomy, Sickle Cell Anemia)
2. Immunosuppressant
3. Malnutrition
4. Cancer involving Bone Marrow
5. Radiation Therapy
6. HIV Infection or AIDS
  1. Presents similarly to T-Cell Immunodeficiency Disorder

Causes
Antibody or humoral (B-Cell Disorder): 78% of cases in U.S. (55% in Europe)

General
1. Present after 3 months of age (when maternal antibodies are no longer present)
2. B Cell deficiency or maturation defect results in Antibody deficiency
3. Recurrent respiratory (ears, sinus, lungs) infections with encapsulated organisms
  1. Streptococcus Pneumoniae
  2. Haemophilus Influenzae
No B-Cells: Agammaglobulinemia
1. X-Linked Agammaglobulinemia or XLA (84% of Agammaglobulinemia cases in Europe)
  1. Bruton Tyrosine Kinase defect (Btk gene) results in defective B-Cell maturation
  2. Absent peripheral B-Cells results in very low serum IgG, IgA and IgM
  3. Infants may have no Tonsils or Lymph Nodes on exam
  4. Severe respiratory infections with Encapsulated Bacteria (e.g. pneumococcus, H. Influenzae)
  5. Chronic Diarrhea (echoviruses and coxsackie virus), recurrent varicella
Decreased B Cells or Antibody: Hypogammaglobulinemia
1. IgA Deficiency (30% of U.S. cases and most common B-Cell Disorder overall in U.S.)
  1. Low levels or absent IgA
  2. Prone to respiratory or gastrointestinal infections
  3. May be associated with IgG2 or IgG4 deficiency
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, as well as IgM and IgA)
  3. B-Cells may be decreased in number and have defective function (T Cells may also be defective)
  4. Similar to X-Linked Agammaglobulinemia, but more mild
  5. Ear, sinus and lung infections occur as with other Antibody Disorders (e.g. pneumococcus, H. Influenzae)
  6. CVID also present with malabsorption from Infectious Diarrhea
    1. Examples: 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
Increased Immunoglobulin: Hypergammaglobulinemia
1. Hyper-Immunoglobulin E (IgE) Syndrome (Job Syndrome)
  1. Significantly increased IgE levels
  2. Skin disorders (e.g. Eczema) and infections
  3. Recurrent lung infections (staphylococcal empyema)
2. Hyper-Immunoglobulin M or Hyper-IgM Syndrome (HIGM)
  1. CD40 Ligand deficiency (most common cause, X-Linked)
  2. T-Lymphocytes are unable to trigger B-Cells to switch Immunoglobulin production of IgM to IgG, IgA and IgE
  3. IgM levels increase, but other Antibody levels are deficient
  4. Results in recurrent and severe infections (including opportunistic infections)
  5. Results in increased malignancy risk

Causes
T-Cell Disorders (9-10% of Primary Immunodeficiency in both Europe and U.S.)

See HIV Infection (or AIDS)
General
1. Most T-Cell Disorders are mixed T-Cell and B-Cell Disorders as B-Cells rely on T-Cells
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. Subtypes include X-Linked SCID, Autosomal Recessive SCID, Adenosine Deaminase Deficiency
4. Onset before age 3 months
5. Presents with Diarrhea, opportunistic infections, severe childhood infections and Failure to Thrive
6. Specific infections include Otitis Media, Mononucleosis and Candidiasis
7. Survival 90% with diagnosis and Stem Cell Transplant in first 3.5 months of life (contrast with 70% after that age)
  1. Added to routine Newborn Screening panels in about one third of U.S. States as of 2013-14
  2. False Positives 1.5% in term infants and 5% Preterm Infants in NICU (will requires re-testing)
Ataxia Telangiectasia
1. Combined humoral and cell-mediated Immunity deficiency
2. Impaired DNA repair mechanisms result in IgA deficiency (and possibly IgG2 and IgE deficiency)
3. Onset of Telangiectasia by age 3-6 years old
4. Progressive Ataxia affecting disordered ambulation by age 10-12 years old
5. Recurrent sinus and lung infections, autoimmune disorders and malignancy (e.g. Non-Hodgkin Lymphoma)
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 life threatening bleeding (GI Bleeding, Intracranial Bleeding) in up to 30% of children
DiGeorge Syndrome (Velocardiofacial, Congenital Thymic Aplasia)
1. Deletion at 22q11.2 results in incomplete development from third and fourth pharyngeal pouches
  1. Thymus hypoplasia
  2. Hypoparathyroidism with Hypocalcemia
  3. Cardiac abnormalities and altered facial features
2. T Lymphocyte deficiency (low T-Cell numbers and decreased or absent T-Cell response)
  1. Severe Viral Infections from contagious spread or from Live Vaccine
  2. Persistent fungal infections (e.g. Thrush persists >12 months)

Causes
Phagocytic Disorders (8.5% of U.S. and 12.5% of European Primary Immunodeficiency cases)

Background
1. Phagocytes (Neutrophils and Macrophages) are critical to clearing infections
General
1. Disorders of Neutrophils or Monocytes/Macrophages
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
Neutropenia - 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 Neutropenia
4. Cyclic Neutropenia
  1. Neutrophil numbers fluctuate in 21 day cycle
Decreased Neutrophil function
1. Chediak-Higashi Syndrome
2. Chronic Granulomatous Disease (CGD)
  1. Inherited PhagocyteNADPH oxidase abnormality
    1. Phagocyte oxidase converts oxygen to Reactive Oxygen Intermediates (ROI)
    2. Without ROIs (e.g. superoxide anions), Phagocytes can not lyse and destroy engulfed Microbes
    3. Results in defect of PMN intracellular killing
  2. Typically diagnosed by age 5 years old
  3. May first present as omphalitis in infants
  4. Recurrent in Intracellular Bacterial and fungal infections, abscesses and Granulomas
    1. Examples: Pneumonia, abscesses, suppurative adenitis, gastrointestinal infections
3. Leukocyte adhesion deficiency (type 1)
  1. Adhesion molecules allow Phagocytes to adhere to vascular endothelium and migrate to infection site
  2. Leukocyte adhesion deficiency presents in first few weeks of life
    1. Delayed Umbilical Cord separation beyond 4 weeks after birth
    2. Omphalitis
  3. Other findings
    1. Poor Wound Healing
    2. Erosive perianal ulcers
    3. Severe Bacterial Infections (e.g. Pneumonia, chronic Skin Infections)

Causes
Complement Disorders: 2% of cases

Autoimmune Condition or Rheumatologic Condition (associated with C1-C4 deficiencies)
1. Systemic Lupus Erythematosus
Recurrent encapsulated organism, esp. pyogenic infections (manifestations vary depending on missing complement type)
1. Complement deficiencies include C1q, C2-C9 (except C4), Factor I, Properdin
2. Neisseria infections are most common including Meningitis, Sepsis and Arthritis (associated with C5-C9 deficiencies)
3. Recurrent infections with Streptococcus Pneumoniae and Haemophilus Influenzae (associated with C3 deficiency)
Hereditary Angioedema
1. C1 Esterase Inhibitor Deficiency

Signs
Red Flags for Primary Immunodeficiency

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]
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
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
Physical findings
1. Failure to Thrive
Miscellaneous
1. Family History of Primary Immunodeficiency
2. Autoimmune Disease (e.g. ITP or Hemolytic Anemia)

Differential Diagnosis

Asthma or atopic condition
Cystic Fibrosis
Secondary Immunodeficiency
1. See Types section above

Labs

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
  3. Low Neutrophil Count (ANC <1500/mm3) may suggest cause for phagocytic disorder
2. Serum Immunoglobulin levels
3. Complement Levels
  1. Complement C3 (Intrinsic and Extrinsic Pathway Function)
  2. Complement C4 (Intrinsic Pathway Function, deficiency in 11% of SLE patients, 1% of U.S. population)
  3. CH50 (Entire Intrinsic Pathway Function)
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
Specific Immunodeficiency testing
1. B-Cell function and Antibody Tests (Humoral Immunity)
  1. Step 1: Quantitative serum IgG, IgM, IgE and IgA levels
    1. IgG subclasses (IgG 1-4) are usually not helpful
    2. Low serum Immunoglobulin levels should prompt Serum Albumin testing
      1. Hypoalbuminemia (e.g. Proteinuria or malabsorption) may cause secondary Immunodeficiency
  2. Step 2: Response to Vaccine (if step 1 Immunoglobulin levels are low)
    1. Obtain pre-Vaccine titers
    2. Administer Vaccine
      1. Encapsulated organism Vaccines (H. Influenzae or Pneumococcus titers) if over age 2 years
      2. Tetanus, Rubella, Diptheria, or Mumps Vaccine at any age
    3. Measure post-Vaccine titers at 4 weeks (3 weeks if two or more prior same antigen Vaccinations)
      1. Expect 2 to 2.5 fold titer increase after Vaccination
      2. Failed titer increase suggests Humoral Immunodeficiency
2. T-Cell Function Tests
  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. Delayed-Type Hypersensitivity (age >1 year old)
    1. Intradermal Skin Test: Candida Albicans, Mumps or Tetanus
    2. Positive test rules-out T-Cell defects
    3. Most cost-effective test for T-Cell dysfunction
  3. Lymphocyte subset analysis (percentage estimates)
    1. T Cells (CD3, CD4, CD8)
    2. B Cells (CD19, CD20)
    3. 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)

Management

See precautions below (Vaccines, Blood Products)
Avoid Microorganism exposure (e.g. Face Masks in public)
Obtain Genetic Counseling if Primary Immunodeficiency identified
Prophylaxis
1. Prophylactic Antibiotics
2. Intravenous Immunoglobulin (IVIG) or Subcutaneous Immunoglobulin for specific Humoral Immunodeficiency
Bone Marrow Transplant Indications
1. Severe Combined Immunodeficiency (SCID)
2. Chronic Granulomatous Disease

Precautions

Vaccines to avoid in patients and their close contacts
Blood Products
1. Specific precautions depending on condition

Resources

National Primary Immunodeficiency Resource Center
1. http://npi.jmfworld.org
Immune Deficiency Foundation
1. http://www.primaryimmune.org

References

Mahmoudi (2014) Immunology Made Ridiculously Simple, MedMaster, Miami, FL
Cooper (2003) Am Fam Physician 68:2001-11 [PubMed]
Reust (2013) Am Fam Physician 87(11): 773-8 [PubMed]
Rosen (1995) N Engl J Med 333(7):431-440 [PubMed]