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A. Epidemiology [1]navigator

  1. Prevalence is ~1:50,000
  2. Male = Female
  3. Bimodal Age of Presentation
    1. Earliest peak is age 6-10 years
    2. Over 65% of patients present at age >20 years
  4. Patterns of Inheritance
    1. Autosomal recessive
    2. Autosomal dominant
    3. X-Linked
    4. Sporadic (majority of cases)

B. Characteristics [1,2] navigator

  1. Primary Immune Deficiency
    1. Recduced CD27+ memory B cells
    2. Impaired B-cell teriminal differentiation
    3. Impaired immunoglobulin (Ig) production
    4. Recurrent infections
  2. Hypogammaglobulinemia
    1. Low or absent serum IgG or IgA subclasses with recurrent infections
    2. 10-20% of persons have no identifiable peripheral B cells
    3. Mature B cells in 80-90% of persons fail to differentiate to plasma cells
    4. Granulomatous disease may occur during hypogammaglobulinemia [4]
  3. Defects in cell mediated immunity
    1. Decreased CD4+ T cell proliferation
    2. Low IL2, interferon gamma, IL4, IL5 production
    3. Low levels of CD40 ligand (CD40L, gp39) on CD4+ cells
    4. Noncaseating granulomatous disease may be found in about 10% of patients [4]
    5. Unclear if this is due to infection or to autoimmune type (such as sarcoid) disease [2]
  4. Recurrent bacterial infections
  5. Various other immunologic abnormalities
    1. Splenomegaly in 40-70%
    2. Malignancy - leukemia, lymphoma most common
    3. Coombs' positive Hemolytic Anemia
    4. Autoimmune thrombocytopenia
    5. May present with rheumatoid arthritis, systemic lupus, inflammatory bowel disease [2]

C. Etiology [1] navigator

  1. Spontaneous mutations appear most commonly, poorly characterized
  2. ~10% of cases are familial
  3. TACI Mutations
    1. TACI is transmembrane activator and calcium-modulator and cyclophilin ligand interactor
    2. Several B-cell stimulatory factors interact with TACI protein
    3. Mutations in TACI occur in ~10% of CVID patients
  4. Inducible Costimutor Protein (ICOS) Deficiency
    1. ICOS is an Ig-like molecule belonging to CD28 superfamily
    2. ICOS deficiency is an autosomal recessive monogenic cause of CVID

D. Clinical Manifestations [5]navigator

  1. Respiratory infections
    1. Sinusitis
    2. Otitis media
    3. Bronchitis and Pneumonia
    4. Encapsulated organisms (S. pneumoniae and H. influenzae) most common
    5. Chronic Lung damage with Staphylococcus aureus and Pseudomonas aeruginosa
    6. Rare: mycobacteria, pneumocystis, fungi
  2. Gastrointestinal Disease
    1. Giardia lamblia infection - severe chronic diarrhea and malabsorption
    2. Increased risk for bacterial enteric pathogens - salmonella, shigella, campylobacter
    3. Malabsorption syndromes
    4. Increased incidence gastric adenocarcinoma and intestinal lymphoma
    5. Severe malabsorption may lead to life-threatening weight loss [2]
  3. Autoimmune Disease
    1. ~20% of CVID patients develop autoimmune processes
    2. Most common are Coombs' positive hemolytic anemia and autoimmune ITP
    3. Neutropenia ± anti-granulocyte Abs may occur
    4. Pernicious anemia (~10% of CVID)
    5. Incidence of usual rheumatologic diseases increased in CVID
    6. Vitiligo sometimes seen
    7. Granulomatous disease (~10% of patinets) may have an autoimmune etiology [4]
  4. Other
    1. Herpes zoster (shingles): up to 20% of patients
    2. Herpes simplex and Epstein-Barr Virus incidence increased
    3. Echovirus infections, often severe
    4. Benign Lymphoproliferative diseases - splenomegaly, lymphadenopathy (30%)
    5. Malignant Lymphomas - increased incidence (more common in females with CVID)

D. Diagnosis navigator

  1. Serum Ig levels much decreased
    1. IgG and IgA consistently decreased
    2. IgM variably decreased
  2. T cell abnormalities
    1. May be related to B cell defects
    2. Abnormal T cell activation
    3. Deficient production of IL2, 4,5 and interferon gamma
  3. Recurrent Infections (as above)
  4. ACE Levels may be elevated in any patient with inflammatory disease

E. Treatmentnavigator

  1. Immune Globulin (Ig) Replacement [3,5,6]
    1. Ig replacement therapy prevents infections
    2. Intravneous (IVIg) and Subcutenaous (SCIg) Ig are now available
    3. Typical IVIg doses are 300mg/kg for adults, 400mg/kg for children, given q4 weeks
    4. SCIg doses are usualy 1.3X higher than IVIg doses
    5. Using 2X doses reduces number and duration of infections ~40% [6]
  2. IV infused PEG-conjugated IL2 [7]
    1. T cell abnormalities reversed
    2. Ab production by B cells
    3. Significant reduction in diarrhea, respiratory infections, joint pains, asthma
  3. Granulomatous Disease [2]
    1. Appears to be due to T cell (autoimmune) dysfunction similar to sarcoid
    2. May cause severe disease, particularly in lungs requiring glucocorticoid therapy

References navigator

  1. Huston DP. 2006. Ann Intern Med. 145(6):456
  2. Sicherer SH and Winkelstein JA. 1998. JAMA. 279(1):58 abstract
  3. Subcutaneous Immune Globulin. 2007. Med Let. 49(1258):31
  4. Mechanic LJ, Dikman S, Cunningham-Rundles C, et al. 1997. Ann Intern Med. 127(8):613 abstract
  5. Wong JT and Girardet C. 1995. NEJM. 332(10):663 (Case Record)
  6. Eijkhout HW, van der Meer JWM, Kallenberg CGM, et al. 2001. Ann Intern Med. 135(3):165 abstract
  7. Cunningham-Rundles C, Kazbay K, Hassett J, et al. 1994. NEJM. 331(14):918 abstract