SUMMARY

 

1. CVID is an antibody deficiency syndrome characterized by decreased serum IgG (IgM and IgA are often decreased) with impaired specific antibody responses. B-cell numbers are typically normal but CD4 T-cell numbers can be decreased. T cell proliferation to mitogens is decreased in approximately one-third of patients.

 

2. Patients most commonly present with recurrent sinus infections and pneumonia. However, more invasive infections have also been reported.

 

3. In addition to infections, CVID is characterized by a high incidence of autoimmune disease as well as an increased incidence of malignancies (lymphoma).

 

4. Patients with low percentage of switched memory B-cells appear to be at increased risk for developing infectious and autoimmune complications.

 

5. While most cases of CVID remain genetically uncharacterized, single gene mutations have been identified in a small percentage of patients. These include defects in TACI, ICOS, CD19, and BAFF-R.

 

6. Immunoglobulin replacement is the cornerstone of CVID therapy.

                                                                                                               

OVERVIEW

 

          CVID is the most common antibody deficiency syndrome with an estimated incidence of 1 in 50,000. The peak age of presentation is in the 20s to 30s. However, CVID can be diagnosed at almost any age from childhood (after age 4) to late adulthood.

 

          The two main features of this disease are 1) Low serum IgG and 2) Impaired antibody responses to specific antigens. Deficiencies in other immunoglobulin isotypes (IgM, and IgA) are also quite common. CD4 lymphopenia can also be seen. Approximately one-third of patients have decreased lymphocyte proliferation to mitogens. Patients with selective IgA deficiency can sometimes progress to develop CVID.

 

          As would be expected from an antibody deficiency syndrome, patients typically present with recurrent sinopulmonary infections with encapsulated organisms. Without appropriate therapy, patients are at risk for developing irreversible lung bronchiectasis. CVID patients can suffer from parasitic (Giardia lamblia ) and bacterial (Campylobacter, Flexispira, Helicobater) gastrointestinal tract infections leading to chronic diarrhea and malabsorption. Campylobacter, Flexispira and Helicobacter can also cause a smoldering bacteremia or cellulitis/fasciitis in patients. Mycoplasma and ureaplasma are underappreciated causes of pulmonary infections as well as septic arthritis.

 

          Patients with CVID are at increased risk for developing autoimmune diseases such as autoimmune hemolytic anemia, autoimmune thrombocytopenia, pernicious anemia, and thyroid disease. These features may precede the development of infections.

 

          Granulomatous disease involving the lungs, lymphoid nodular hyperplasia of the bowel, and celiac-like enteropathy are additional complications. Lymphadenopathy and splenomegaly develop in some patients. Patients with very low or absent switched memory B-cells appear to be at greatest risk for bronchiectasis and autoimmune complications.

 

          CVID patients are also at greater risk for developing malignancies. The risk of lymphoma is increased 300 fold in patients and there is a 50 fold increased risk of gastric carcinoma. There appears to be no increased risk of other malignancies such as breast cancer or skin cancer.

 

         

 

PATHOGENESIS

 

         The exact genetic cause of most CVID cases remains unknown. This is likely a heterogeneous disorder with a common clinical phenotype. In recent years, a number of monogenic causes of CVID have been identified in a minority of patients:

 

1.  TACI Deficiency (AD or AR) TACI is encoded for by the TNFRSF13B gene and is a member of the tumor necrosis factor receptor family. TACI is normally expressed on peripheral B-cells. TACI along with BAFF receptor and BCMA function as receptors for the TNF-like ligands BAFF and APRIL. Interactions between TACI and its ligands mediate T-cell independent class-switch recombination in B-cells. Mutations in TACI occur in up to 10% of CVID cases. However, the diagnostic utility of testing for TACI mutations remains unclear given the fact that many individuals (often relatives of index cases) with this mutation are completely asymptomatic. TACI may act as a susceptibility gene for CVID but environmental factors may also be necessary for the disease to develop. Gene sequencing for TACI is currently available commercially.

 

2.  ICOS Deficiency (AR) The inducible costimulator (ICOS) belongs to the CD28 family of immunoglobulin-like costimulatory surface molecules and is expressed only on activated T-cells (ICOS-ligand is expressed on B-cells). ICOS and ICOS-L interactions lead to signaling that allows B-cells to undergo class-switch recombination and terminal differentiation to memory B-cells and plasma cells. ICOS may account for up to 5% of CVID cases. In the 9 patients described to date, a founder effect tracing back to a specific region of Germany has been implicated. Diagnosis requires sequencing of the gene.

 

3.  CD19 Deficiency (AR) CD19 is part of a co-receptor complex (with CD21, CD81, and CD225) associated with the B-cell receptor. This complex signals the B-cell to decrease the antigenic threshold for activation of the B-cell. Currently 4 patients with homozygous mutations in CD19 have been described. Flow cytometry is useful to identify absence of CD19 on the B-cell surface. Diagnosis is confirmed by sequencing of the gene.

 

4.  BAFF-R Deficiency (AR) As explained above, BAFF-R is expressed on the surface of B-cells along with TACI and can bind BAFF or APRIL which induces T-cell independent induction of class- switch recombination. Diagnosis requires sequencing of the gene.

 

5.  Hepatic Veno-occlusive disease with Immunodeficiency (AR) - This is caused by mutations in the gene for nuclear body protein sp110 (SP110). This condition is characterized by hypogammaglobulinemia and T-cell immunodeficiency as well as veno-occlusive disease. Diagnosis requires sequencing of the gene.

 

 

 

DIFFERENTIAL DIAGNOSIS

 

Differential Diagnosis: It is important to consider other causes of hypogammaglobulinemia before making a diagnosis of CVID. The differential diagnosis includes the following conditions:

 

1.  X-linked or AR agammaglobulinemia

2.  Hyper IgM syndrome

3.  WHIM syndrome

4.  X-linked Lymphoproliferative Syndrome (XLP)

5.  Goods syndrome (thymoma with immunodeficiency)

6.  Transient Hypogammaglobulinemia of Infancy

 

                                  

EVALUATION

 

Step 1: Quantitative Humoral Evaluation

         

                      - Quantitative immunoglobulins (IgG, IgM, IgA)

- Flow cytometry for B-cell, T-cell, and NK cell numbers

 

CVID patients have low IgG (and often low IgM and IgA). B-cell numbers are typically normal but a CD4 lymphopenia may be present. B cell enumeration is useful given some patients with X-linked agammaglobulinemia are sometimes misdiagnosed with CVID.

 

 

 

Step 2:  Functional Humoral Evaluation

 

-Antibody titers to vaccine antigens

 

-Protein and polysaccharide vaccine antibodies should be checked (ex. Tetanus, Diphtheria, and Pneumococcus). If serum antibody titers are low, patients can be vaccinated with repeat titers drawn 4-6 weeks later. Specific antibody responses are absent or low in CVID.

 

Step 3: Additional Evaluation

 

-Lymphocyte flow cytometry for B-cell subpopulations (including switched memory B-cell numbers: CD27+ IgD- IgM-).

-Lymphocyte proliferation to mitogens

-TACI mutation analysis

 

-CVID patients with low percentage of switched memory B-cells have increased infectious and autoimmune complications.

 

-Approximately one-third of CVID patients have decreased lymphocyte proliferation to mitogens.

 

-Up to 10% of CVID patients have mutations in TACI. Genetic testing for this mutation is controversial given the incomplete penetrance of the clinical phenotype.

 

 

                                                                   

MANAGEMENT

 

          Replacement of serum IgG with monthly IVIG or weekly subcutaneous (SC) Ig is the cornerstone of therapy. Typical replacement is started with 400-600mg/kg of IVIG every 4 weeks. Trough IgG levels should be checked after 5 IVIG doses. It is clear that patients who maintain trough IgG levels above 700-900mg/dl have fewer infectious complications. Patients with IgA deficiency may be at greater risk for developing anti-IgA antibodies to trace IgA contained in IVIG products. For such individuals, a low IgA content product (ex. Gammagard SD) should be utilized. SCIg is ideal for patients who benefit from maintaining steady serum levels of immunoglobulins or who are unable to tolerate IVIG due to adverse side effects (headache, chills, nausea, thrombotic events). SCIg should also be considered for patients with difficult venous access.

 

         The addition of prophylactic antibiotics can be considered in patients who continue to have infections despite appropriate immunoglobulin replacement. Two sample prophylaxis regimens are outlined below:

 

-Amoxicillin 20mg/kg divided twice daily (Maximum of 500mg twice daily).

-Azithromycin 10mg/kg once weekly (Maximum of 1 gram once weekly) or Azithromycin 5mg/kg 3 times weekly (max 250mg 3 times weekly)

          

        Close monitoring for autoimmune diseases (particularly cytopenias) and malignancies should be perfomed. Lymphadenopathy may require biopsy to evaluate for lymphoma. The enteropathy seen in some patients with CVID may respond to therapies used for other inflammatory bowel diseases.

 

 

                                                                           

RESOURCES

 

Diagnostic Resources   

 

1. Switched Memory B-cells (CD27+IgM-IgD-) by Flow Cytometry

-Childrens Hospital of Philadelphia B Cell Panel

-Cincinnati Childrens Diagnostic Immunology Laboratory

 

 

Literature Resources

 

1.  Cunningham 1999

     Mt. Sinai 248 patient cohort

 

2.  Alachkar 2006

     Low switched memory B cells correlate with greater complication

 

3.  Knight 2006

      CVID autoimmune and inflammatory complications

 

4.  Bloom 2008

     CVID and joint infections