II. 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

III. Types

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

IV. 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. B Cell deficiency or maturation defect results in Antibody deficiency
    3. 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) 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
  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.)
      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
  4. 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

V. 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. Subtypes include X-Linked SCID, Autosomal RecessiveSCID, 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)
  3. 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)
  4. 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
  5. 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)

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

  1. Background
    1. Phagocytes (Neutrophils and Macrophages) are critical to clearing infections
  2. 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
  3. 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
  4. Decreased Neutrophil function
    1. Chediak-Higashi Syndrome
    2. Chronic Granulomatous Disease (CGD)
      1. Inherited Phagocyte NADPH 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)

VII. Causes: Complement Disorders: 2% of cases

  1. Autoimmune Condition or Rheumatologic Condition (associated with C1-C4 deficiencies)
    1. Systemic Lupus Erythematosus
  2. 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 HaemophilusInfluenzae (associated with C3 deficiency)
  3. Hereditary Angioedema
    1. C1 Esterase Inhibitor Deficiency

VIII. 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)

IX. Differential Diagnosis

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

X. 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
      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
  2. 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)

XI. Management

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

XII. 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

XIII. Resources

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

Images: Related links to external sites (from Bing)

Related Studies

Ontology: Immunologic Deficiency Syndromes (C0021051)

Definition (CHV) partial or total loss of body's ability to fight diseases
Definition (NCI) A disorder in which the immune system is unable to mount an adequate immune response.
Definition (NCI_FDA) A deficiency of immune response or a disorder characterized by deficient immune response.
Definition (NCI_NCI-GLOSS) The inability of the body to produce an immune response.
Definition (NCI) Syndromes in which there is a deficiency or defect in the mechanisms of immunity, either cellular or humoral.
Definition (MSH) Syndromes in which there is a deficiency or defect in the mechanisms of immunity, either cellular or humoral.
Definition (CSP) deficiency of immune response or a disorder characterized by deficient immune response; classified as antibody (B cell), cellular (T cell), or combined immunodeficiency, or phagocytic dysfunction disorders.
Concepts Disease or Syndrome (T047)
MSH D007153
ICD9 279.3
ICD10 D84.9
SnomedCT 191005003, 64431000, 234532001
English Deficiency Syndrome, Immunologic, Deficiency Syndrome, Immunological, Deficiency Syndromes, Immunologic, Deficiency Syndromes, Immunological, Immunologic Deficiency Syndrome, Immunologic Deficiency Syndromes, Immunological Deficiency Syndrome, Immunological Deficiency Syndromes, Syndrome, Immunologic Deficiency, Syndrome, Immunological Deficiency, Syndromes, Immunologic Deficiency, Syndromes, Immunological Deficiency, Unspecified immunity deficiency, Unspecified immunity deficienc, Immunodeficiency, unspecified, IMMUNOL DEFIC SYNDROMES, DEFIC SYNDROMES IMMUNOL, IMMUNOL DEFIC SYNDROME, DEFIC SYNDROME IMMUNOL, Immunodeficient, immune deficiency disorder, hypoimmunity, immunodeficiency disorders, immunodeficiency disorders (diagnosis), Immunodeficiency NOS, Immunodeficiency syndromes, Immunity deficiency NOS, Immunologic Deficiency Syndromes [Disease/Finding], Deficiency;immune, immunodeficiencies, immunodeficiency disorder, immune deficiency, immunodeficiency disease, immunodeficiency syndrome, immunodeficiency syndromes, Unspecified immunity deficiency (disorder), Immunodeficiency (disorder), Immune deficiency, Immunological deficiency syndromes, IMMUNO-DEFICIENCY, Immunodeficiency, Immunodeficiency disease, Immunodeficiency disorder, Immunodeficiency disorder (disorder), Immunodeficiency, NOS, immunodeficiency, Immunodeficiency Disorder, Immunodeficiency Syndrome
Italian Immunodeficienza, Immunodeficienza NAS, Deficit immunitario non specificato, Sindrome da immunodeficienza, Sindromi da immunodeficienza
Dutch immunodeficiëntie NAO, niet-gespecificeerde immunodeficiëntie, Immunodeficiëntie, niet gespecificeerd, immunodeficiëntiesyndromen, immunodeficiëntie, Deficiëntiesyndroom, immuno-, Immunodeficiëntiesyndromen, Immunodeficiëntiesyndroom, Syndroom, immunodeficiëntie-
French Déficit immunitaire non précisé, Déficit immunitaire SAI, Déficit immunitaire, Syndromes d'immunodéficience, Déficits immunitaires, Immunodéficiences
German Immunmangel NNB, unspezifischer Immunmangel, Immundefekt, nicht naeher bezeichnet, Immundefekt, Immunmangelsyndrome, Immundefekt-Krankheiten, Immundefektsyndrome, Immundefekte
Portuguese Imunodeficiência NE, Síndromes de Imunodeficiência, Síndromes de Deficiência Imunológica, Imunodeficiência, Síndromes de imunodeficiência
Spanish Inmunodeficiencia NEOM, Deficiencia de la inmunidad no especificada, deficiencia del sistema inmunológico, deficiencia inmunológica no especificada, deficiencia inmunitaria no especificada, deficiencia inmunológica no especificada (trastorno), inmunodeficiencia (concepto no activo), inmunodeficiencia (trastorno), inmunodeficiencia, Inmunodeficiencia, Síndromes de inmunodeficiencia, Síndromes de Inmunodeficiencia
Japanese 免疫不全症NOS, 詳細不明の免疫不全症, 免疫不全症, ショウサイフメイノメンエキフゼンショウ, メンエキフゼンショウNOS, メンエキフゼンショウ, メンエキフゼンショウコウグン, 抗体欠損症候群, 免疫不全症候群
Swedish Immunbristsyndrom
Czech imunodeficience, syndromy imunologické nedostatečnosti, imunodeficity, Imunodeficit, Imunodeficitní syndromy, Imunodeficit NOS, Blíže neurčený deficit imunity
Finnish Immuunivajausoireyhtymät
Russian IMMUNOLOGICHESKOI NEDOSTATOCHNOSTI SINDROMY, ANTITEL NEDOSTATOCHNOSTI SINDROM, АНТИТЕЛ НЕДОСТАТОЧНОСТИ СИНДРОМ, ИММУНОЛОГИЧЕСКОЙ НЕДОСТАТОЧНОСТИ СИНДРОМЫ
Korean 상세불명의 면역결핍
Croatian IMUNOLOŠKA DEFICIJENCIJA, SINDROMI
Polish Zespoły niedoborów immunologicznych, Defekty immunologiczne
Hungarian Immundeficiencia, Immunhiány syndromák, Nem meghatározott immunitas hiány, Immundeficiencia k.m.n.
Norwegian Immunsviktsykdommer, Immunsviktsyndrom, Immuninsuffisienssyndrom, Immundefektsyndrom

Ontology: Primary immune deficiency disorder (C0398686)

Concepts Disease or Syndrome (T047)
SnomedCT 58606001
Dutch primair immunodeficiëntiesyndroom, primaire immuundeficiëntiesyndromen
French Syndrome d'immunodéficience primaire, Syndromes d'immunodéficience primaire
German primaeres Immundefektsyndrom, Primaere Immunmangelsyndrome
Italian Sindrome da immunodeficienza primaria, Sindromi da immunodeficienza primaria
Portuguese Síndrome de imunodeficiência primária, Síndromes de imunodeficiência primária
Spanish Síndrome de inmunodeficiencia primario, deficiencia inmunológica primaria (trastorno), deficiencia inmunológica primaria, Síndromes de inmunodeficiencia primaria
Japanese 原発性免疫不全症候群, ゲンパツセイメンエキフゼンショウコウグン
Czech Primární deficit imunity, Syndromy primární imunodeficience
English Primary immunodeficiency syndromes, primary immunodeficiency, immunodeficiencies primary, immunodeficiency primary, Primary immune deficiency disorder, primary immune deficiency disorder (diagnosis), Primary immunodeficiency, Primary immune deficiency disorder (disorder), Primary immune deficiency disorder, NOS, Primary immunodeficiency syndrome
Hungarian Elsődleges immunhiány syndromák, Primaer immunhiány syndroma